Metal-Free Carbonyl-Assisted Regioselective Hydration of Alkynes: An

Letter Cite This: Org. Lett. 2019, 21, 5059−5063

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Metal-Free Carbonyl-Assisted Regioselective Hydration of Alkynes: An Access to Dicarbonyls Shalini Verma,† Manoj Kumar,† Pawan K. Mishra, and Akhilesh K. Verma* Department of Chemistry, University of Delhi, Delhi 110007, India

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S Supporting Information *

ABSTRACT: Metal-free regioselective hydration of o-alkynylaldehydes with the assistance of neighboring carbonyl oxygen is disclosed. The developed protocol provides a facile route to synthesize a series of multisubstituted carbonyl containing scaffolds that enable the potential application toward the synthesis of highly diversified 5-azaindoles. γ-Carbolines and 2,8diazacarbazoles can also be accessed directly without isolating the dicarbonyl compounds. The developed methodology is operationally simple and environment-friendly, tolerates a wide variety of functional groups, and is applicable toward large scale synthesis.

A

Scheme 1. Regioselective Hydration of 2-Alkynylindole/ Pyrroles-3-carbaldehydes

lkynes are a resourceful class of organic compounds having tremendous importance in organic transformations for complex organic molecule synthesis.1 They have served as superior surrogates for a variety of functional groups such as ketones, aldehydes, acids, and amines.2 Among them, hydration of alkynes into ubiquitous carbonyls is a promising field because of its versatility in further transformations.3 Sustainability, cleanliness, and simple addition of water across the C−C triple bond make the hydration process 100% atom economic, convenient, and environment friendly. Earlier, toxic mercury salts along with acids have been used for the alkynes hydration.4 Later, other metal complexes, such as Fe,5 Pd,6 Pt,7 Ru,8 Au,9 Ti,10 Ir,11 Co,12 Ag,13 etc.,14 were proven to be applicable for this transformation. In particular, gold complexes have gained significant attention in this field, as they trigger the electrophilic activation of alkynes toward a variety of nucleophiles.9,15 In addition, organic acids such as trifluoromethanesulfonic acid, p-toluenesulfonic acid, etc. are also known to be active for the hydration of alkynes.16 Vasudevan et al. reported the hydration of alkynes in superheated water using microwave irradiation.17 The majority of these protocols were established for terminal alkynes, and only modest success has been achieved in the case of unsymmetrical internal alkynes, as they suffer from regioselectivity issues. To circumvent this problem, the concept of neighboring group assisted hydration of alkynes was proposed by different groups which prove to be an elegant route.18 In 2013, Lee et al. reported oxygenative addition of alkynes tethered with pyridine N-oxide (Scheme 1a).18a Later, Li et al. reported Pd-catalyzed amide oxygen assisted hydration of alkynes (Scheme 1b).18b Recently, Wu et al. noted gold-catalyzed © 2019 American Chemical Society

regiospecific hydration of N-tosyl propargylic amines where the tosyl group directs the hydration.18c Dicarbonyls are useful synthone for the construction of a wide range of small molecules. We were particularly interested in the application of this process to access 5-azaindoles owing to their physicochemical,19 pharmacological,20 and medicinal properties.21 Despite having a broad range of activities, 5azaindoles are not much explored.22 Reported strategies for the synthesis of 5-azaindoles mainly rely on palladium-catalyzed heteroannulation of aminopyridines with alkynes or alkenes.23 The reported procedures were often encountered with the regioselective issues, low yields, and substrate scope in the case of an internal alkyne. The use of expensive metal catalysts, poor selectivity, limited substrate scope, and intolerance of the −OH group restricted their applications for industrial purposes. Therefore, the Received: May 9, 2019 Published: June 14, 2019 5059

DOI: 10.1021/acs.orglett.9b01649 Org. Lett. 2019, 21, 5059−5063

Letter

Organic Letters

Scheme 2. Scope of 2-Alkynylindole 3-Carbaldehydea,b

development of a sustainable process avoiding hazardous and expensive metal catalysts for the hydration of complex alkynes is of immense importance. Keeping these challenges in mind and our ongoing work on alkyne chemistry,24 herein we have disclosed carbonyl oxygen assisted regioselective hydration of readily accessible o-alkynylaldehydes and their application in the synthesis of 5-azaindoles, γ-carbolines, and 2,8-diazacarbazoles in an aqueous medium without isolating dicarbonyl compounds. In order to determine the optimal reaction conditions, we initiated our studies with 2-(phenylethynyl)-1H-indole-3carbaldehyde 1a as a model substrate. The reaction of 1a in H2O at 100 °C for 12 h provided the desired product 2a in 64% yield (Table 1, entry 1). An increase in the temperature Table 1. Optimization of Reaction Conditionsa

a

Reactions were performed using 0.5 mmol of 1a−p in 2 mL of solvent (H2O/dioxane (4:1)) at 100 °C for 6 h. bIsolated yield. CCDC no. of 2c: 1900785. entry

solvent/cosolventc

T (°C)

t (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12e

H2O H2O H2O H2O/DMF H2O/MeOH H2O/DMSO H2O/ACN H2O/Dioxane Dioxane DMF MeOH H2O/Dioxane

100 110 90 100 100 100 100 100 100 100 100 100

12 12 12 8 24 24 24 6 5 24 24 6

64 62 46d 68 trace trace trace 78 NR NR NR 76

yields, respectively. Substrates 1d−f bearing electron-rich aromatic (4-n-butyl-phenyl and 8-OMe-naphthyl) and heteroaromatic substituents on alkyne afforded the corresponding products 2d−f in 82−93% yields. Moreover, substrate 1g having an electron-withdrawing −CF3 substituted alkyne furnished the product 2g in 60% yield. Furthermore, substrate 1h−j bearing aliphatic alkynes afforded the corresponding products 2h−j in 79−84% yields. Aliphatic alkyne 1k having a −OH group was reacted smoothly and gave the products 2k in 72% yield. Substrates 1l and 1m having 5-bromo and 2,5dimethoxyphenyl substitution on the indole ring also proved favorable to provide the products 2l and 2m in 66% and 68% yield, respectively. In addition, 2-alkynylbenzofuran-3-carbaldehydes 1n−p were also found to be viable substrates and were efficiently converted into the desired products 2n−p in good yields. Encouraged by the above results, the scope of developed chemistry was extended for the hydration of diversified pyrrolo-2-alkynyl-3-carbaldehydes 4a−m to synthesize more pharmacologically relevant pyrrole core containing carbonyls (Scheme 3). Multisubstituted pyrrole cores with a variety of

a Reactions were performed using 0.5 mmol of 1a in 2.0 mL of solvent. bIsolated yield. cH2O: cosolvent (4:1). dRecovery of starting material. eIn distilled deionized water.

did not produce a noticeable change in yield of 2a (entry 2), while a decrease in temperature gave the product 2a in 46% yield along with the recovery of starting material (entry 3). We anticipated that the addition of DMF as a cosolvent to the reaction mixture would accelerate the reaction by enhancing the solubility of 1a. Expectedly, the reaction was completed in 8 h with a 68% yield of 2a (entry 4). Then, various solvents were tested in combination with H2O; among them, H2O− dioxane was found to be superior in terms of yield and time (entries 5−8). However, dioxane itself did not afford the desired product (entry 9). Switching to other solvents such as DMF and MeOH did not afford the desired product 2a (entries 10−11). Further, the desired product was obtained in 76% yield when the reaction was performed in distilled deionized water under standard reaction conditions. This result rules out the possibilty of a catalytic role of traces of metal present in water. This was further supported by ICP MS analysis of the reaction mixture (see SI, Table S1). Under the optimized reaction conditions, the generality of the reaction was explored using functionalized orthoalkynylaldehydes 1a−p (Scheme 2). Gratifyingly, a wide range of substitution on alkynes was well tolerated under the standardized reaction conditions. N-Me and N-Ph protected substrates 1b−c bearing an electron-neutral phenyl ring provided the desired products 2b and 2c in 90% and 82%

Scheme 3. Scope of 2-Alkynylpyrrole 3-Carbaldehydea,b

a Reactions were performed using 0.5 mmol of 4 in 2 mL of solvent (H2O/dioxane (4:1)) at 100 °C for 3 h. bIsolated yield. CCDC no. of 5k: 1900783.

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Letter

Organic Letters aromatic, aliphatic, and heteroaromatic groups attached to alkynes were compatible under standard reaction conditions. It is worth mentioning here that −OH substituted groups on alkynes were amenable with the reaction conditions which instead usually underwent the Meyer−Schuster type rearrangement.25 Hydration of 1-methyl-2-(aryl/alkylethynyl)-1H-pyrrole-3,4-dicarbaldehyde 4a−d using optimized reaction conditions provided the desired products 5a−d in 82−92% yields. Subsequently, 1-methyl-2,5-bis(2-oxo-2-aryl/alkylethyl)-1Hpyrrole-3,4-dicarbaldehydes 5e−g were synthesized in excellent yield by the hydration of substrate 4e−g under standard reaction conditions. The practical utility of this methodology was further explored toward the hydration of 2chloro-1-methyl-5-(aryl/alkylethynyl)-1H-pyrrole-3,4-dicarbaldehyde 4h−i. Electron-neutral phenyl 4h and aliphatic n-butyl 4i substituted alkynes furnished the products 5h and 5i in 88% and 84% yields, respectively. Further, the hydration of 3chloro-1-methyl-5-(aryl/alkylethynyl)-1H-pyrrole-2,4-dicarbaldehyde 4j−m afforded the corresponding products 5j−m in 78−88% yields. To further evaluate the potential of the developed protocol, the synthesized products were transformed directly into valuable γ-carbolines,26 5-azaindoles, and diazacarbazoles27 in one pot by further heating for 2 h with NH4OAc (Scheme 4).

Scheme 5. Synthetic Application

4j (Scheme 6). The one-pot strategy of the dicarbonyls is likely to be of high synthetic utility. Scheme 6. One-Pot Synthesis of 5j

To gain insight into the mechanism, we have performed two control experiments. When we performed the hydration of substrate 4n (bearing two alkyne and two carbonyl groups), at 100 °C for 3 h, the product 11a was obtained in 76% yield; however product 11b was not observed (Scheme 7a). This

Scheme 4. Application of Hydrated Productsa,b

Scheme 7. Control Experiments

a

Reactions were performed using 0.5 mmol of 1 and 4 in 2.0 mL of solvent [H2O/dioxane (4:1)] at 100 °C for 3 h; then NH4OAc was added (2.0 equiv). bIsolated yield.

Substrates 1a and 1b provided the γ-carbolines 6a and 6b in 76% and 89% yields, respectively. The reaction of 4a−d provided the corresponding carbaldehyde substituted azaindoles 7a−d in 82−88% yields. Substrates 4h and 4m bearing a chloro group gave the corresponding products 7e and 7f in 85% and 87% yield, respectively. Further, we extended the application of this chemistry for the synthesis of biologically important 2,8-diazacarbazoles 8a−b in good yields from substrates 4f−g. To illustrate the synthetic utility of the developed chemistry, heterocycles 9 and 10 were synthesized28 from respective starting substrates 2b and 2a in water (Scheme 5). Alternatively, taking advantage of the free Cl group in product 5j, the Sonogashira reaction was performed to afford the desired product 11a which could be further functionalized. In order to demonstrate the practical utility of the methodology, the reaction of 1b has been carried out on a gram scale (with 1 g) which provides an 88% yield of 2b (Scheme 5). Finally, one-pot synthesis of dicarbonyl 5j was achieved in 54% yield without isolating the Sonogashira coupling product

result suggests the significant involvement of the nitrogen lone pair in the reaction. Further, when we carried out the reaction of 1b using D2O at 100 °C, 90% incorporation of deuterium was observed in product 12a. This result suggests that two hydrogen atoms at the triple bond were originated from the water (Scheme 7b). To further support the mechanism; we heated the product 2c at 100 °C for 6 h, and only 10% incorporation of D was observed in the product 13a. This result suggests that the incorporation of D/H takes places during the reaction via keto−enol tautomerization. Based on the findings of control experiments (Scheme 7) and previous reports,18,29 we have proposed a plausible mechanism for the regioselective hydration of alkynes (Scheme 8). The lone pair of heteroatoms which are in resonance with the carbonyl group of o-alkynylaldehydes facilitates the regioselective 6-endo-dig attack of the oxygen onto alkyne to form the reactive species A. Nucleophilic attack of D2O on species A leads to the generation of six-membered hemiacetal B. The unstable hemiacetal B could then engage in 5061

DOI: 10.1021/acs.orglett.9b01649 Org. Lett. 2019, 21, 5059−5063

Organic Letters

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Scheme 8. Proposed Reaction Mechanism

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01649. Data and spectral copies of 1H, 13C NMR, and HRMS for target compounds (PDF) Accession Codes

CCDC 1900783 and 1900785 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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rearrangement with the concomitant tautomerization of enolic species C to afford the hydrated product 2. In summary, we have described a metal-free, carbonylassisted synthesis of structurally diversified di-/tricarbonyl compounds by the regioselective hydration of o-alkynylaldehydes under mild conditions in good to excellent yields. The protocol is atom economical and environment-friendly and has been successfully extended for the one-pot synthesis of biologically potential γ-carbolines, 5-azaindoles, and diazacarbazoles. The key steps involved in the reaction have been supported by control experiments. Synthetically, this reaction holds much promise due to its ease of operation and simplicity. The synthesized molecules containing carbonyls along with −Cl provide a synthetically useful handle for further modification.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Akhilesh K. Verma: 0000-0001-7626-5003 Author Contributions †

S.V. and M.K. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The Research work was supported by SERB (EMR/2017/ 003218/OC) and University of Delhi. S.V., M.K., and P.K.M. are thankful to CSIR and UGC respectively for fellowships. 5062

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