Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Regiodivergent Dearomatization Reaction of Nitrosocarbonyl Intermediates with β‑Naphthols Sumitava Mallik, Vinod Bhajammanavar, Arka Probha Mukherjee, and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
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S Supporting Information *
ABSTRACT: The divergent reactivity of nitrosocarbonyls in oxidative dearomatization of β-naphthols is reported. In the presence of quinidine catalyst, their reactions with αunsubstituted β-naphthols proceeded through the N-center to furnish α-imino-β-naphthalenones in high yields. Upon exposure to α-substituted β-naphthols in the presence of copper catalyst, an alteration of regioselectivity was observed to produce αaminoxylation products. The reaction is scalable, tolerates a wide spectrum of functional groups, and represents a rare example of dearomatization of α-unsubstituted β-naphthols.
S
Scheme 1. Dearomatization Reaction of Nitrosocarbonyls with β-Naphthols towards Bioactive β-Naphthalenones
ynthetic planning harnessing the ambident nature of reaction partners is highly alluring as dissimilar bonds can be fabricated from a single source through judicious tuning of the reaction conditions.1,2 In this context, nitrosocarbonyl intermediates have attracted considerable attention.2 They are prototypes of ambident electrophiles that have extensively been utilized in diverse C−N and C−O bond-forming processes through aldol,3 ene,4 Henry,5 and various types of cycloaddition reactions.6 Despite these accomplishments, applications of nitrosocarbonyl intermediates in dearomatization7 reactions are largely underdeveloped, and such reactions with simple aromatic alcohols, such as naphthols, heretofore are not reported. β-Naphthalenones are privileged scaffolds that can be found in a large variety of natural products and pharmaceuticals with diverse biological activities (Scheme 1).8 Consequently, synthetic endeavors toward this molecular framework are in high demand. Traditionally, they have been synthesized through the dearomatization of β-naphthols using suitable electrophiles.9 However, the majorities of these processes employed α-substituted β-naphthols (R ≠ H), lacking the pivotal α-hydrogen to halt the undesired rearomatization process after the initial substitution step (Scheme 1). The dearomatization reaction of β-naphthols without α-substitution (R = H) is increasingly challenging. Their oxidative dearomatization processes, for example, synthesis of naphthoquinones using stoichiometric oxidants, are usually cumbersome and often result in a mixture of products, which limits their synthetic utility and efficacy in complex targets.10 We envisioned that reaction of nitrosocarbonyls with βnaphthols could be a transformative route to access dearomatized products (Scheme 1). In the presence of a suitable catalyst, N-selective nucleophilic addition reaction would produce the intermediate A. Owing to weak N−O bond energy (55 kcal mol−1) and high acidity of the α-hydrogen, the intermediate A may experience water elimination via N−O bond cleavage, leading to the formation of stable C−N double © XXXX American Chemical Society
bond, and thus, favorable rearomatization can be overruled. However, it is worth noting that generation of nitrosocarbonyls requires an in situ oxidation method, and electron-rich βnaphthols should not be affected by this oxidation process, posing significant challenge to materialize this strategy. Herein, we report the development of this approach to demonstrate an unprecedented dearomatization reaction of nitrosocarbonyl intermediates with α-unsubstituted β-naphthols in the presence of quinidine catalyst to offer α-imino-β-naphthalenones in very high yields with exquisite regioselectivity. Received: February 19, 2019
A
DOI: 10.1021/acs.orglett.9b00628 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Further, when dearomatization reaction was considered with α-substituted β-naphthols in the presence of copper catalyst, αaminoxylation with a switch in regioselectivity (from nitrogen selectivity to oxygen selectivity) was observed to furnish βnaphthalenones bearing a quaternary stereogenic center. We commenced our investigations using β-naphthol 1a as a model substrate and commercially available hydroxamic acid 2a as nitrosocarbonyl precursor (Table 1). Gratifyingly, when
Scheme 2. Scope of the Dearomatization Reaction of Nitrosocarbonyls to Access α-Imino-β-naphthalenonesa
Table 1. Optimization of Reaction Conditionsa
entry
solvent
1 2 3 4 5 6 7 8 9 10 11 12d
DCE DCE DCE DCE DCE DCE DCE THF CH3CN EtOH DCE DCE
oxidant MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 MnO2 CuCl, Py, O2
catalyst
yieldb (%)
cinchonidine quinine quinidine NEt3 DABCO DBU quinidine quinidine quinidine quinidine quinidine
30 84 85 92 57 65 66 52 40 c c 65
a
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), MnO2 (5 equiv), catalyst (20 mol %), N2, solvent (2 mL), 1 h. bYields of isolated products. cNo reaction with the recovery of 1a. dCuCl (0.1 equiv), pyridine (0.2 equiv), O2 balloon, 2 h. DCE: 1,2-dichloroethane; DABCO: 1,4-diazabicyclo[2.2.2]octane; DBU: 1,8diazabicyclo[5.4.0]undec-7-ene.
mixture of 1a and 2a in DCE was exposed to mild MnO2 oxidant at room temperature, the reaction proceeded selectively via nitrogen-center (N-selectivity), delivering the desired α-imino-β-naphthalenone 3a in 30% yield (entry 1). Despite the low yield, this outcome intriguingly validated our hypothesis. Our earlier studies5 revealed cinchona alkaloids as effective bases for nitroso aldol process with a high level of Nselectivity, and thus, they were tested in the dearomatization reaction. The presence of a catalytic amount of quinine, cinchonidine, or quinidine improved the reaction outcome significantly, and the best result was obtained in the case of quinidine (20 mol %), offering 3a in 92% isolated yield (entries 2−4). Screening of other organic bases such as NEt3, DABCO, and DBU gave inferior results (entries 5−7). Changing reaction solvents (entries 8−10) and consideration of a copper-based aerobic oxidation in lieu of MnO2 (entry 12) had a deleterious effect. Notably, nitrosocarbonyls are highly reactive species, and often, slow addition2 (using syringe pump) of the precursor, hydroxamic acid, into the reaction mixture for a considerably long period of time is unavoidable to maintain high reaction yield and selectivity. However, this dearomatization protocol obviated such restrictions in the reaction setup, and all of the reaction components were mixed together at once. Having acquired the optimal conditions, we next investigated the substrate scope of the dearomatization reactions (Scheme 2). The protocol is very general and a series of βnaphthol having alkyl (3b,c), alkoxy (3d,e), aryl (3f−j), and heteroaryl (3m) substitutions at the 6- and 7-positions
a
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), MnO2 (5 equiv), quinidine (20 mol %), DCE (2 mL), N2, 1 h. Yields of isolated products are given.
furnished the dearomatized products in uniformly high yields (84−96%). The reaction of 2,7-naphthalenediol selectively took place only in one ring, delivering 3k with free hydroxyl group in 82% yield. Important functional groups such as aldehyde (3f), allyl (3r), and various halogens (3j,l) were undisturbed. The reaction efficiency of different hydroxamic acids (2) was also explored. Similar to carbobenzyloxy (Cbz)protected hydroxylamine 2a, various derivatives thereof having electron-donating as well as electron-withdrawing substitutions in the aryl ring effectively participated in this reaction to produce desired products 3n−u in high to excellent yields. Hydroxamic acids derived from 2-thienylmethanol and chiral menthol gave 3v and 3w in 84% and 88% yields, respectively. Other hydroxamic acids with easily removable protecting groups such as Fmoc-NHOH, and Boc-NHOH are also efficient for dearomatization reaction, affording 3x and 3y in very high yields (80−87%). The product 3y was crystallized, and X-ray analysis unambiguously established the N-selectivity of the reaction that coupled with N−O bond cleavage and Zgeometry of the imine group of the product. Interestingly, when α-substituted β-naphthol 4 was reacted with hydroxamic acid 2 under the standard reaction conditions, we observed an alteration of regioselectivity (Scheme 3). Here, the dearomatization reaction proceeded B
DOI: 10.1021/acs.orglett.9b00628 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Notably, both types of dearomatization processes were scalable. The β-naphthalenones 3a and 5a were synthesized on a gram scale with comparable efficiency and selectivity as observed in small-scale reactions (Scheme 4a). Further,
Scheme 3. Dearomatization Reaction of Nitrosocarbonyls via α-Aminoxylation of α-Substituted β-Naphtholsa
Scheme 4. Gram Scale Reaction, Post-functionalization, and Effect of Chiral Bisoxazolidine Ligand
product 3a was reduced using NaBH4 in methanol, giving αamido-β-naphthol 6 in 92% yield. The reduction of dearomatized product 5a with NaBH4 in ethyl acetate/ methanol mixture took place chemoselectively, furnishing alcohol 7 as a single diastereomer in 86% yield. An asymmetric dearomatization of 4a was also attempted using chiral bisoxazolidine ligand in combination with Cu(OTf)2 catalyst. The product 5a was formed in high yield with the desired Oselectivity; however, asymmetric induction was negligible (Scheme 4b). In conclusion, the divergent reactivity of nitrosocarbonyl intermediates, generated in situ from readily available hydroxamic acids, has been demonstrated based on a regioselective oxidative dearomatization reaction. The reaction of α-unsubstituted β-naphthols in the presence of quinidine catalyst resulted in N-selectivity, forging α-imino-β-naphthalenones in high yields. When α-substituted β-naphthols were employed in combination with the Cu(OTf)2/bipyridine complex as catalyst, the N-selectivity was switched to Oselectivity to give α-aminoxylation products with a quaternary stereocenter. Both dearomatization reactions11 feature operational simplicity, can be executed on a gram scale, and display very broad substrate scope with high functional group compatibility. The synthetic utility of this protocol has been showcased in the production of carbocyclic frameworks bearing C−N or C−O bond. Further, applications of nitrosocarbonyl chemistry in organic synthesis are underway in our laboratory.
Reaction conditions: α-substituted β-naphthols 4 (0.2 mmol), hydroxamic acids 2 (0.22 mmol), MnO2 (5 equiv), Cu(OTf)2 (5 mol %), 2,2′-bipyridine (5 mol %), DCE (2 mL), N2, 7 h. Yields of isolated products are given. a
via the oxygen center (O-selectivity) to give α-aminoxylation product 5a in 25% yield, and no N-selective product was detected even after prolonging the reaction time. We believe that steric hindrance is largely responsible for such deviation. To improve the α-aminoxylation yield further, we have screened various Lewis acids as catalyst (Scheme 3). In the presence of Cu(OTf)2 (5 mol %), O-selectivity was preserved, and the product 5a was isolated in 40% yield. Satisfyingly, when 2,2′-bipyridine was used as a ligand with Cu(OTf)2 catalyst, the dearomatization reaction was very clean to dispense 5a in 88% isolated yield. Utilizations of other Lewis acids such as Fe(OTf)3, In(OTf)3, Sc(OTf)3, and La(OTf)3 had a deleterious effect. This O-selective dearomatization reaction catalyzed by Cu(OTf)2/2,2′-bipyridine displayed remarkable substrate scope: employment of various α-methyl-, -ethyl-, and -allyl-substituted β-naphthols in combination with a wide spectrum of hydroxamic acids were fruitful, and the desired aminoxylative dearomatized products 5a−t were prepared in good to excellent yields (79−92%). The more reactive benzoyl-substituted hydroxylamine was also suitable substrate, affording 5u in 82% yield. The observed O-selectivity for these compounds was also apparent from the crystal structure of product 5e.
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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.9b00628. Complete experimental details and characterization data for the prepared compounds (PDF) C
DOI: 10.1021/acs.orglett.9b00628 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Accession Codes
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CCDC 1872038−1872039 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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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Mahiuddin Baidya: 0000-0001-9415-7137 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge DST (EMR/2014/000225) for financial support. S.M. and V.B. thank IIT Madras for HTRA. We also thank the Department of Chemistry, IIT-Madras, for instrumental facilities.
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DOI: 10.1021/acs.orglett.9b00628 Org. Lett. XXXX, XXX, XXX−XXX
