Rhodium Catalyzed Synthesis of Benzopyrans via Transannulation of

Letter Cite This: Org. Lett. 2018, 20, 3762−3765

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Rhodium Catalyzed Synthesis of Benzopyrans via Transannulation of N‑Sulfonyl-1,2,3-triazoles with 2‑Hydroxybenzyl Alcohols Dongari Yadagiri, Manthena Chaitanya, Angula Chandra Shekar Reddy, and Pazhamalai Anbarasan* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India

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ABSTRACT: An efficient and novel rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles with in situ generated oquinone methides (o-QMs) from 2-hydroxybenzyl alcohols has been achieved for the synthesis of substituted benzopyrans in good yields. The developed reaction involves nucleophilic attack of o-QM to α-imino rhodium carbenoid to generate a carbonyl ylide followed by 6π-electrocyclization and isomerization. Furthermore, the utility of the methodology was demonstrated in the one-pot synthesis and construction of polyheteroaromatics. Scheme 1. Synthesis of Benzopyran from o-QMs

α-Imino metal carbenoids, generated from N-sulfonyl-1,2,3triazoles and mainly rhodium(II) catalyst, have emerged as a potential intermediate in contemporary organic synthesis for the construction of various nitrogen-based heterocycles of therapeutic importance.1 Unlike the traditional metal carbenoids that are generated from α-diazocarbonyl compounds, α-imino metal carbenoids have distinctive reactivity due to the presence of electrophilic carbene carbon and nucleophilic nitrogen. By employing this unique reactivity, diverse nitrogen based complex structural motifs/heterocycles were synthesized in combination with suitable coupling partners. In particular, generation of N-,2 O-,3 and S-ylides4 followed by cyclization reactions have been an attractive method for the construction of various nitrogen-, oxygen-, and sulfur-containing heterocycles. Among them, O-ylides5 and carbonyl ylides6 were well studied only in an intramolecular version, possibly due the high electronegativity of oxygen and less stability of oxygen-based ylides. Thus, generation of O-ylides in an intermolecular fashion and functionalization would further widen the synthetic utility of the α-imino metal carbenoids. o-Quinone methides (o-QMs) are another class of short-lived and highly reactive intermediates frequently encountered in synthesis, as well as in biological applications.7 In synthesis, oQMs are readily generated from 2-hydroxybenzyl alcohol derivatives and enable straightforward synthesis of various substituted (hetero)aromatics.8 For instance, [4 + 2]-annulation of o-QMs with electron-rich alkenes affords the benzopyrans,9 a subunit widely present in therapeutically important molecule and natural products10 (Scheme 1a). However, the complete potentials of o-QMs in organic synthesis are yet to be explored. Keeping the importance and reactivity of o-QMs in mind,11 we anticipated that the lower stability and high reactivity of in situ generated o-QMs would favor the intermolecular oxygenbased ylide formations from α-imino metal carbenoids. © 2018 American Chemical Society

Subsequent functionalization of generated oxygen-based ylides would possibly afford the potential substituted heteroaromatics (Scheme 1b). Based on the importance mentioned and our continuous interest in the functionalization of N-sulfonyl-1,2,3triazoles,12 we herein disclose the rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles with 2-hydroxybenzyl alcohols to benzopyran derivatives via generation of potential reactive intermediates, viz. α-imino metal carbenoids and oquinone methides. To test our hypothesis, 2-hydroxybenzyl alcohol 1a and Nsulfonyl-1,2,3-triazoles 2a were chosen as model substrates. Initially, treatment of 1 equiv of 1a with 2 equiv of 2a in the presence of 2 mol % of rhodium acetate in toluene at 100 °C afforded the benzopyran 3aa in 10% yield (Table 1, entry 1). The formation of product was identified by spectroscopic techniques and unambiguously confirmed by X-ray analysis (Table 1). Received: April 27, 2018 Published: June 20, 2018 3762

DOI: 10.1021/acs.orglett.8b01338 Org. Lett. 2018, 20, 3762−3765

Letter

Organic Letters Table 1. Transannulation of 2a with 1a: Optimization.a

entry

Rh(II)

solvent

temp (°C)

yieldb (%)

1 2 3 4 5 6 7 8 9 10

Rh2(OAc)4 Rh2(Oct)4 Rh2(Piv)4 Rh2(S-NTTL)4 Rh2(Oct)4 Rh2(Oct)4 Rh2(Oct)4 Rh2(Oct)4 Rh2(Oct)4 Rh2(Oct)4

toluene toluene toluene toluene toluene benzene C6H5Cl CHCl3 1,2-DCE CCl4

100 100 100 100 120 120 120 120 120 120

10 38 35 20 72 (25)c 50 63 57 50 44

Scheme 2. Transannulation of 1 with 2a: Scope of Triazole

a

Reaction conditions: 1a (1 equiv), 2a (2 equiv), Rh(II) (2 mol %), solvent (1 mL for 0.13 mmol), temp, 8 h. bIsolated yields. c90 °C.

To improve the yield of 3aa, various rhodium(II) catalysts, such as Rh2(Oct)4, Rh2(Piv)4, and Rh2(S-NTTL)4, were examined. Although all of them showed improved performance, Rh2(Oct)4 gave an increased yield of 38% (Table 1, entries 2− 4). Next, various solvents and temperatures were also screened employing Rh2(Oct)4 as catalyst. Increasing the temperature to 120 °C in toluene afforded the product 3aa in 72% yield. On the other hand, decreasing the reaction temperature 90 °C gave only 25% of 3aa. Furthermore, all of the solvents (benzene, chlorobenzene, chloroform, 1,2-dichloroethane (1,2-DCE), and carbontetrachloride) tested gave inferior results, compared to toluene. On the basis of these studies, 2 mol % of Rh2(Oct)4 in toluene at 120 °C for 8 h was chosen as the optimized conditions for further investigation. Having identified suitable reaction conditions for the transannulation of 2 with 1, the scope and generality of the developed transformation were investigated. At first, various substituted 4-aryl-N-sulfonyl-1,2,3-triazoles 2 were examined. Interestingly, all of them underwent efficient rhodium-catalyzed transannulation with 1a to afford the corresponding substituted benzopyrans 3 (Scheme 2). For instance, changing the sulfonyl moiety at the N1 position of triazole afforded the corresponding benzopyrans 3aa−da in good yields. Simple alkyl (methyl, ethyl and tert-butyl)-substituted aryl-containing triazoles led to the formation of the corresponding benzopyrans (3ea−ga and 3ka) in ∼60% yield. Treatment of electron-donating p-anisyl- and electron-withdrawing p-nitrophenyl-substituted triazoles smoothly underwent a reaction to furnish the corresponding benzopyrans (3ia and 3ja) in good to moderate yield. Formation of biologically important p- and m-fluorophenyl-substituted benzopyrans 3ha and 3la were achieved in 67% and 62% yields, respectively. Interestingly, readily functionalizable and sterically hindered o-bromophenyl substituted triazole also gave the product 3ma in good yield. Furthermore, thiophene, a heteroaryl-substituted triazole also provided benzopyrans 3na in 62% yield. Next, the scope and generality of 2-hydroxybenzyl alcohols 1 with triazole 2a were investigated under the optimized conditions. Initially, substituted aryl at the benzylic position was studied (Scheme 3). p-Methyl, p-methoxy, and mmethylphenyl substitutions afforded the corresponding products (3ab, 3ac, and 3af) with good to moderate yield.

†

1 mmol scale reaction.

Scheme 3. Transannulation of 2 with 1a: Scope of 2Hydroxybenzyl Alcohols

Similarly, p-fluoro- and m-trifluoromethylphenyl-substituted benzopyrans (3ad and 3ag) were achieved in 73 and 55% yields, respectively. Electron-withdrawing and readily enolizable methylketone was well tolerated under the optimized conditions to give the product 3ae in 64% yield. Sterically hindered 1naphthyl- and o-chlorophenyl-substituted 2-hydroxybenzyl alcohols also efficiently underwent a reaction to afford products 3ah and 3ai in good yield. Formation of thiophene-substituted 3763

DOI: 10.1021/acs.orglett.8b01338 Org. Lett. 2018, 20, 3762−3765

Letter

Organic Letters benzopyran 3aj was also obtained in 56% yield. Next, substitutions on the phenol moiety were also examined. Alkyl substitution, such as 4-tert-butyl and 6-methyl, provided the benzopyrans 3ak and 3am in 62% and 56% yields. Similarly, 4fluoro-substituted benzopyran 3al was isolated in 69% yield. In general, N-sulfonyl-1,2,3-triazoles were achieved from corresponding alkyne and sulfonyl azide via a copper-catalyzed cycloaddition reaction.13 Thus, integration of copper-catalyzed synthesis of 2 and its rhodium catalyzed transannulation with 1 would reveal a new one-pot construction of benzopyran via regioselective functionalization of the terminal alkyne (Scheme 4). The reaction of phenylacetylene and tosyl azide in the

Scheme 6. Mechanistic Investigation

the reaction was performed with 7 and 1a under the present reaction conditions. Unfortunately, no formation of 3aa was identified; instead, 89% of 7 was recovered. These experiments suggested the potential formation of o-quinone methide 6 as possible intermediate, which subsequently would undergo cyclization with azavinyl carbene to 3aa. On the basis of the control experiments, a plausible mechanism for the formation of benzopyran 3 from triazole 2 and 2-hydroxybenzyl alcohol 1 was postulated (Scheme 7). The

Scheme 4. One-Pot Synthesis of Benzopyran 3aa

presence of 10 mol % of CuTC in toluene at room temperature for 3 h furnished the N-sulfonyl-1,2,3-triazole 2a. Subsequent addition of 2-hydroxybenzyl alcohol 1a and 2 mol % of Rh2(Oct)4 in the same pot followed by heating at 120 °C for 8 h afforded the expected benzopyran 3aa in 58% yield. After having shown the synthesis of various substituted benzopyrans via transannulation of 2 with 1, demonstration of the synthetic utility of the developed methodology was envisaged through the synthesis of biologically important polycyclic heteroaromatics such as chromenoindole 4 and 5. Copper-catalyzed C−N bond cross coupling14 of orthobrominated benzopyran 3ma in the presence of 5 mol % of CuI, 10 mol % of DMEDA, and K3PO4 at 70 °C in toluene furnished the dihydrochromeno[3,2-b]indole 4 in 83% yield (Scheme 5a). Subsequently, dihydrochromeno[3,4-b]indole 5

Scheme 7. Plausible Mechanism

Scheme 5. Synthetic Utility

reaction starts with the formation of reactive α-imino rhodium carbenoid I from N-sulfonyl-1,2,3-triazole 2 through trapping of ring-opened isomer α-diazoimine I with a rhodium catalyst with extrusion of nitrogen. Similarly, another reactive intermediate, oquinone methide (o-QM) II, could be generated from thermalinduced dehydration of 2-hydroxybenzyl alcohol 1. Formation of benzopyran 3 could be readily explained through the initial attack of o-QM II on to the electrophilic rhodium carbenoid carbon of I to generate the carbonyl ylide intermediate III. Subsequent 1,3-rhodium migration12a,16 to produce triene IV followed by 6π-electrocyclisation would lead to the formation of cyclized oxonium intermediate V. Deprotonation and isomerization in V could furnish the benzopyran 3 along with the regeneration of active rhodium catalyst. Alternatively, the formation of 3 could also be explained through a tandem O− H insertion/elimination/6π-electrocyclization reaction sequence. In conclusion, we have developed an efficient and novel method for the synthesis of benzopyrans from readily accessible N-sulfonyl-1,2,3-triazoles and 2-hydroxybenzyl alcohols. The reaction involves the generation of carbonyl ylide from two reactive intermediates, viz. α-imino rhodium carbenoid and o-

was also accomplished from the corresponding ortho-chlorinated benzopyran 3ai in 40% yield under slightly modified conditions with 20 mol % of CuI. To understand the possible mechanistic pathway, various control experiments were performed. Heating the toluene solution of 1a at 120 °C followed by HRMS analysis of crude reaction mixture showed the possible presence of o-quinone methide 6 with [M + Na]+ peak at 205.0636 (Scheme 6). Subsequently, treatment of the reaction mixture with 2a under the optimized conditions afforded the product 3aa in 51% yield. A similar result was observed in the presence of 2 mol % of Rh2(Oct)4. Next, to test the involvement of α-amino-β-ketone 7 as intermediate, which could be generated from 2a and water,15 3764

DOI: 10.1021/acs.orglett.8b01338 Org. Lett. 2018, 20, 3762−3765

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Organic Letters

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quinone methide followed by electrocylization and isomerization. The developed reaction tolerates various functional groups and allows the synthesis of diverse substituted benzopyrans in good to moderate yields. Furthermore, the developed method was successfully extended to the one-pot transformation and utility of the synthesized benzopyrans were shown through the ready conversion into biologically important chromenoindoles, a class of nitrogen and oxygen-based polyheterocyclic compounds.

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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.8b01338. Experimental details, characterization data, and 1H and 13 C NMR spectra of isolated compounds (PDF) Accession Codes

CCDC 1838726 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

Pazhamalai Anbarasan: 0000-0001-6049-5023 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank DST-SERB, New Delhi, India (Project No. SR/S1/ OC-48/2012 and EMR/2016/003677/OC), for funding this work. D.Y. thanks IITM, and M.C. and A.C.S.R. thank CSIR for fellowships. We also thank Mr. Ramkumar (IITM) for singlecrystal analysis support.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01338 Org. Lett. 2018, 20, 3762−3765