Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
α‑Angelica Lactone in a New Role: Facile Access to N‑Aryl Tetrahydroisoquinolinones and Isoindolinones via Organocatalytic α‑CH2 Oxygenation Thanusha Thatikonda,† Siddharth K. Deepake,†,‡ and Utpal Das*,†,‡ †
Division of Organic Chemistry, CSIR − National Chemical Laboratory, Pune 411008, India Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 04/02/19. For personal use only.
‡
S Supporting Information *
ABSTRACT: A method for the direct oxidation of various Naryl tetrahydroisoquinolines and isoindolines to the corresponding lactams using α-angelica lactone as a catalyst was developed. The utility of the method was further demonstrated by synthesis of indoprofen and indobufen.
T
catalysts, high reaction temperature, and longer reaction periods. Formations of dihydroisoquinolinone via cross-dehydrogenative coupling reactions are well-known but only as a byproduct.5 Very recently, oxidation of N-alkyl tetrahydroisoquinolines to the corresponding lactams using gold nanoparticles (Scheme 1a) and
he lactam moiety has attracted particular interest in the chemical community because it is present in a myriad of natural products and clinically approved medicinal agents.1 A number of natural products with biological activities and synthetic pharmaceutical compounds containing an isoquinolinone/ isoindolinone scaffold are known (Figure 1).
Scheme 1. Lactam Formation via C−H Oxidation of Cyclic Amines
Figure 1. Bioactive natural products and pharmaceuticals containing an isoquinolinone and isoindolinone scaffold.
a copper−salicylate complex (Scheme 1b) as catalyst in the presence of either t-BuOOH or oxygen as oxidant was reported.6 This process looks attractive, but in many cases, the reaction requires higher temperature and longer reaction periods. 9HFluoren-9-imine offers an alternative to metal catalysts; however, the substrate scope is limited by the requirement of a stoichiometric amount of fluorenimine along with reflux temperature.7a During the preparation of this paper, Das group reported α-oxygenation of tertiary and secondary amines by visible light using Rose Bengal as catalyst.7b Consequently, the ACS GCI pharmaceutical roundtable identified“amide formation avoiding poor atom economy reagents” as the most desired green chemistry research area and organocatalysis as one of the “more
Consequently, development of an efficient catalytic method to synthesize compounds containing a isoquinolinone or isoindolinone core in a direct and cost-effective manner is of huge importance. A straightforward method for the synthesis of the isoquinolinone/isoindolinone core would be direct oxygenation of the α-methylene group of isoquinoline/isoindoline derivatives. However, selectiveoxidations of the α-methylene groupof amines to amides are notoriously challenging because of the higher reactivity of the amines in comparison to that of the α-methylene carbon.2 In general, α-oxygenation of amines requires a stoichiometric amount of organic or metal peroxides as oxidant and use of transition-metal-based catalysts.3 Recently, gold nanoparticles supported on alumina (Au/Al2O3) were developed for the catalytic oxidation of cyclic and acyclic amines to the corresponding lactams and amides.4 However, the reaction requires use of an air-sensitive catalyst, multistep synthesis of © XXXX American Chemical Society
Received: January 21, 2019
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DOI: 10.1021/acs.orglett.9b00224 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Substrate Scopea,b
aspirational reactions”.8 In the past decade, unsaturated γlactones have emerged as a very useful and versatile class of vinylogous nucleophiles.9 We herein report commercially available α-angelica lactone as an efficient organocatalyst for C−H amidations of N-aryl tetrahydroisoquinolines and isoindolines in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base under oxygen atmosphere (Scheme 1c), thus imitating nature’s oxidant combination of O2/NAD(P)H. In many known examples,4,6 molecular oxygen has been used as the greenest possible oxidant, though it is a kinetically poor one10 and acts so mainly in the presence of metal reagents/catalysts.4,6,11 This protocol also shows high selectivity toward benzylic C−H oxidation, and no undesired oxidative Mannich-type reaction of N-aryl tetrahydroisoquinoline with lactone is detected, as reported by Doyle and others. 12 We commenced our optimization reactions by using N-phenyl-1,2,3,4-tetrahydroisoquinoline 1a as a model substrate. The initial reaction was performed with 1a in the presence of α-angelica lactone (25 mol %) (A) and DABCO as base in THF under oxygen atmosphere. The oxidation product, benzolactam 2a, was obtained in 41% yield (Table 1, entry 1). The yield was improved to 58 and 81% Table 1. Optimization Studiesa
entry
base
catalyst
yield (%)b
c
DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO
A A A A A B C D E F
41 58 81 49 85 72 67 63 54 ND
1 2d 3 4e 5f 6 7 8 9 10 a
a Reaction conditions: 1 (0.1 mmol), DABCO (0.3 mmol), A (25 mol %), THF (0.5 mL), rt for 36 h under O2 atmosphere (balloon). b Isolated yields.
when DABCO was used in 2 and 3 equiv, respectively (entries 2 and 3). The yield of 2a decreased to 49% when 10 mol % of catalyst A was used (entry 4). Marginal improvement of isolated yield was observed upon using 50 mol % of A (entry 5). Other lactone catalysts B−E were also investigated, but they were found to be less effective than α-angelica lactone A (entries 6−9) in terms of chemical yields. Notably, with itaconic anhydride F, no oxidation product was observed (entry 10). Further, the effect of various solvent and bases on the oxidation reaction were also studied (see the Supporting Information (SI) for details). Using the optimized reaction conditions (entry 3), the scope for α-angelica lactone (A)-catalyzed benzylic CH2 oxidation of different tetrahydroisoquinoline derivatives was investigated (Table 2).
N-Aryl/heteroaryl-substituted tetrahydroisoquinolines 1a−1x gave the corresponding oxidized products 2a−2x in a good to excellent yields. The optimized reaction conditions successfully included substrates containing strong electron-withdrawing group substitutions at the para- and meta-positions on the Nphenyl ring. Corresponding products 2b−2e were obtained in good to excellent yields (71−85%). The presence of a keto functional group is beneficial for further transformations as in 2c. However, reaction with electron-withdrawing groups substituted at the ortho-position on the N-phenyl ring gave the corresponding products 2f−2g in moderate yields (52% each), probably because of the steric hindrance on the α-position of the tetrahydroisoquinoline. Similarly, halogen groups substituted on the N-phenyl ring also gave the corresponding products 2h−2l in good yields (52− 84%). The carbon−bromine bond in 2i creates a good reaction site for further transformations, and as a result, substrate 2i may be considered as a precursor of a known BCATm inhibitor.13 The presence of electron-donating groups like tert-butyl, methyl, and
Reaction condition: 1a (0.1 mmol), DABCO (0.3 mmol), catalyst A (25 mol %), in THF (0.5 mL) at rt for 36 h under O2 (balloon) atmosphere. bIsolated yield. c0.1 mmol of DABCO was used. d0.2 mmol of DABCO was used. e10 mol % of A was used. f50 mol % of A was used. ND = not determined.
B
DOI: 10.1021/acs.orglett.9b00224 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters methoxy substituted at the para-, meta-, and ortho-positions of the N-phenyl ring furnished the desired products 2m−2p with 59− 84% yields. Heteroaryl group (pyridyl and thiophenyl)substituted 1,2,3,4-tetrahydroisoquinolines gave the desired products 2q and 2r in 76 and 74% yields, respectively. Next, we examined the substitution effect on the attached aryl ring of the tetrahydroisoquinoline moiety, 6,7-dimethoxyl N-4-chlorophenyl 1,2,3,4-tetrahydroisoquinoline, and 6,7-dimethoxyl N-4methylphenyl 1,2,3,4-tetrahydroisoquinoline was chosen as a substrate. The corresponding lactams 2s and 2t were obtained in 52 and 59% yields, respectively. Similarly, 7-chloro N-4chlorophenyl 1,2,3,4-tetrahydroisoquinoline, 7-bromo N-4chlorophenyl 1,2,3,4-tetrahydroisoquinoline, and 5-nitro N-4chlorophenyl 1,2,3,4-tetrahydroisoquinolines gave the desired lactams 2u, 2v, and 2w in yields of 63, 56, and 47%, respectively. N4-Chlorophenyl-substituted (S)-1,2,3,4-tetrahydro-3-isoquinolinemethanol was also proven to be a good substrate in our protocol to give the corresponding lactam 2x in 49% yield. The methylenehydroxy group in 1x remained untouched and retained itsoptical activity. However, no reaction was observed withN-allyl and N-phenylsulfonyl-protected substrates 1y and 1y′. We also observed that N-phenyl tetrahydroquinoline was not compatible with the present protocol and failed to afford any product like 2z. We have examined the feasibility of our methodology on a larger scale. Benzolactam 2h was obtained in 81% yield on a 1.5 g scale reaction (Scheme 2).
Scheme 3. Application in the Synthesis of Indoprofen and Indobufen
Table 4. Mechanistic Investigations
entry 1 2 3 4 5 6 7
condition no base no catalyst A N2 or argon atmosphere H2O as solvent THF/H2O18 (4 equiv, 492 μL/8 μL) TEMPO or BHT (1 equiv) CuCl2 (1 equiv)
result no reaction no reaction no reaction no reaction >98% unlabeled, no O18-labeled 2a
