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Pd/Cu Co-Catalyzed Oxidative Tandem C–H Aminocarbonylation and Dehydrogenation of Tryptamines: Synthesis of Carbolinones Hui Han, Shang-Dong Yang, and Ji-Bao Xia J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03266 • Publication Date (Web): 22 Feb 2019 Downloaded from http://pubs.acs.org on February 22, 2019
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The Journal of Organic Chemistry
Pd/Cu Co-Catalyzed Oxidative Tandem C–H Aminocarbonylation and Dehydrogenation of Tryptamines: Synthesis of Carbolinones a,b
Hui Han, a
b
a,c
Shang-Dong Yang and Ji-Bao Xia*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lanzhou 730000, China b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
c
Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou 215123, China
Abstract: The Pd/Cu co-catalyzed oxidative tandem C–H aminocarbonylation and dehydrogenation is developed affording carbolinones with molecular oxygen as the terminal oxidant. Natural product strychnocarpine and its derivatives are prepared conveniently using this strategy.
INTRODUCTION Over 80% of all known active pharmaceutical ingredients (APIs) contain heterocyclic aromatic rings with a majority of N-containing aromatic heterocycles. The carbolinone ring system appears as a substructure in a large number of biologically active indole alkaloids and APIs (Figure 1).1 For example, strychnocarpine, a natural tetrahydro-β-carbolinone isolated from Strychnos elaeocarpa, exhibits stimulation of 5-hydroxytryptamine (5-HT) receptors.2 Alosetron, a tetrahydro-γ-carbolinone, is a FDA-approved drug molecule treating women with severe diarrhea-predominant irritable bowel syndrome. In addition, carbolinones are versatile intermediates for the synthesis of indole-containing natural products.3 Therefore, chemists have devoted great efforts to the development of efficient methods toward these structures. There are two general strategies for the synthesis of carbolinones. One is acid promoted Fischer indole synthesis from the corresponding hydrazone intermediates.4 The other is condensation of tryptamine derivatives with hazardous triphosgene or chloroformates followed by acid promoted Friedel-Crafts acylation.5 Recently, transition-metal-catalyzed cyclizations have also been reported for the synthesis of these scaffolds to avoid harsh reaction conditions and multi-step syntheses.6
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Figure 1. Selected Carbolinone-containing Natural Products and Pharmaceutical Drugs
Due to high atom economy, step economy, and dramatic reduction of waste, tandem reaction has attracted much interest in synthetic chemistry and lots of effcient tandem reactions have been developed.7 In the past decade, chemists have achieved great success in transition-metal-catalyzed direct functionalizations of C–H bond, and C–H carbonylation of organic molecules with CO has been realized for the synthesis of various carbonyl compounds, such as acids,8 ketones,9 esters,10 amides,11 imides,12 and so on.13 The strategy of using a directing group to control the site selectivity in C–H carbonylation is widely applied in these reactions. Using amine as a native directing group, metal-catalyzed arene C–H aminocarbonylation of amines has been emerged to be a more straightforward and atom-economic method for the synthesis of benzolactams.14,15 However, stoichiometric and expensive copper or silver salts are usually used as oxidants. 14 Therefore, it is highly desirable using molecular oxygen (O2) as an oxidant in these reactions. One pioneering example is the Orito’s Pd-catalzyed C–H aminocarbonylation for the synthesis of benzolactams, using sub-stoichiometric Cu(OAc)2 and air as the oxidants.16 In 2009, Saura-Llamas and co-workers reported inspiring cyclopalladation of L-tryptophan methyl ester hydrochloride to generate six-membered cyclopalladated complex, which could react with CO affording the corresponding tetrahydro-β-carbolinone in good yield (Scheme 1a).17 To the best of our knowledge, there are only one example of catalytic C–H carbonylation for the synthesis of carbolinone derivative. Gaunt and co-workers reported an elegant Pd-catalyzed C–H carbonylation of N-aryl tryptophan with stoichiometric perester and O2 as the co-oxidants under acidic conditions, but the substituent on the amine limited to aryl group.18 Herein, we disclose a Pd/Cu co-catalyzed oxidative C–H aminocarbonylation with 1 atm CO for the divergent synthesis of carbolinones under mild neutral reaction conditions (Scheme 1b). Tetrahydro-β and γ-carbolinones were obtained via Pd/Cu co-catalyzed oxidative C–H aminocarbonylation with O2 as the terminal oxidant. By simply controlling the reaction conditions, Pd/Cu co-catalyzed tandem C–H aminocarbonylation and dehydrogenation was disclosed leading to β-carbolinones for the first time.
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The Journal of Organic Chemistry
Scheme 1. Synthesis of Carbolinones via C–H Carbonylation
RESULTS AND DISCUSSION Targeted to strychnocarpine 2a, N-methyltryptamine 1a was chosen as the model substrate to optimize the reaction conditions. With Rh(PPh3)3Cl as a catalyst, up to 25% yield of 2a was obtained when using 2 equivalents of Cu(OAc)2 as oxidant in diglyme at 110 ºC under a balloon pressure of CO (Table 1, Entry 1 and Table S1 in Supporting Information). When switching Rh catalyst to Pd catalyst, 2a was obtained in 81% yield with Pd(OAc)2 as catalyst in toluene (Table 1, entry 2). To our delight, tandem C–H aminocarbonylation and dehydrogenation was achieved affording β-carbolinone 3a in 66% yield under identical conditions when prolong the reaction time (Table 1, entry 3). Replacing Cu(OAc)2 with other oxidants, such as Ag2CO3, K2S2O8 and oxone, gave 2a in less than 10% yield (Table S2 in Supporting Information). Lowering temperature to 80 ºC led to a slightly higher yield (Table 1, entry 4). The yield remained unchanged when the catalyst loading was decreased to 2.5 mol% but with longer reaction time (Table 1, entry 5). Next, we investigated the reaction with catalytic amount of Cu(OAc)2 using molecular oxygen (O2) as the oxidant (Table S2). The best result was obtained when using 2.5 mol% Pd(OAc)2, 10 mol% Cu(OAc)2, and 75 mol% O2 at 80 ºC (Table 1, entry 6).19 Moderate yield was obtained with 1.0 mol% Pd(OAc)2 as catalyst (Table 1, entry 7). However, formamide 4 was also formed as a byproduct without C–H carbonylation, which maybe obtained by protonation of acyl palladium intermediate. Solvent screening revealed that toluene was the best choice. Other solvents gave 2a in diminished yield, such as THF, DMF, CH3CN, and diglyme (Table S2). We then optimized the reaction conditons for the tandem C–H aminocarbonylation and dehydrogenation leading to β-carbolinone 3a. Good yield of 3a was obtained with 10 mol% Pd(OAc)2, 50 mol% Cu(OAc)2, 2 equivalents of O2 at 110 ºC (Table 1, entry 9). Control experiments showed that no desired product was obtained in the absence of Pd(OAc)2, which reveals the importance of the palladium catalyst (Table 1, entries 10 and 11). Acylation of
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amine with Cu(OAc)2 affording 5 is the side reaction without Pd(OAc)2 catalyst (Table 1, entries 11). Table 1. Development of Pd/Cu Co-catalyzed Tandem C–H Aminocarbonylation and Dehydrogenation for the Synthesis of β-Carbolinones
a
a
b
Entry
Catalyst
Cu(OAc)2
O2
T (°C)
Time (h)
Yield of 2a (%)
Yield of 3a (%)
1c
Rh(PPh3)Cl (10 mol%)
2 equiv
-
110
24
25
trace
2
Pd(OAc)2 (10 mol%)
1 equiv
-
110
3
81
trace
3
Pd(OAc)2 (10 mol%)
1 equiv
-
110
18
