Gold(I)-Catalyzed Oxidation of Acyl Acetylenes to Vicinal Tricarbonyls

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Gold(I)-Catalyzed Oxidation of Acyl Acetylenes to Vicinal Tricarbonyls Alexey Yu. Dubovtsev,* Dmitry V. Dar’in, and Vadim Yu. Kukushkin* Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russian Federation

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S Supporting Information *

ABSTRACT: Efficient gold(I)-catalyzed oxidation of COR2-functionalized internal alkynes to vicinal tricarbonyl compounds by 2,6-dichloropyridine N-oxide proceeds under mild conditions (DCM, rt). This catalytic reaction provides a good to excellent yielding route to diverse tricarbonyls such as α,β-diketoesters, 1,2,3-triketones, and α,β-diketoamides. The utility of these compounds was also demonstrated by facile one-pot synthesis of important azaheterocyclic systems.

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Scheme 1. General Routes to VTCs

icinal tricarbonyl compounds (VTCs) along with their hydrate forms have proven to be useful synthetic building blocks.1,2 Owing to their highly electrophilic nature, VTCs demonstrate great reactivity toward even rather weak nucleophiles, and these additions were successfully applied for construction of various carbon−carbon and carbon− heteroatom bonds. All these transformations provide a wide range of carbo- and heterocyclic systems including, for example, cyclopentane,3 furan,4 pyrrole,5 indole,6,7 benzofuran,8 imidazole,9 pyrazine,10 quinoxaline,10 triazines,11 and isoquinoline.12 Several examples of applications of VTCs in the total synthesis of natural products have been reported.1,13 Furthermore, vicinal tricarbonyl amides (α,β-diketoamides) and their hemiketal forms were identified in biologically active natural macrolide compounds including elastase inhibitors14 and immunosuppressants such as rapamycin15 and tacrolimus.16 Conventional routes to VTCs include oxidation of βdicarbonyl compounds17−22 or their α-mono(di)substituted derivatives23,24 (Scheme 1a) and oxidative cleavage of the C=C, C=N, C=S, C=P, and C=I double bonds of αfunctionalized β-dicarbonyls1,25 (Scheme 1b). One of the most convenient and frequently used methods leading to VTCs is the oxidation of diazo derivatives of β-dicarbonyls (X = N2) by t-BuOCl,3,26 DMDO,27 epoxides,28 or pyridine Noxides.29 However, the dangerous nature of highly energetic and, consequently, potentially explosive diazo compounds substantially limits the scope of these synthetic methods.30,31 In the past decade, catalytic reactions involving gold α-oxo carbenes have found application in organic synthesis.32−38 Transformations of these highly electrophilic intermediates (Scheme 2) comprise an excellent synthetic alternative to the reactions of α-diazo carbonyl compounds.39 Gold α-oxo carbenes can be easily generated under mild conditions in the presence of gold complexes40 from readily available © XXXX American Chemical Society

Scheme 2. Generation of Gold α-Oxo Carbenes

acetylenes and safe oxygen carriers, namely, pyridine Noxides.41,42 Herein we report on the gold(I)-catalyzed oxidation of COR-functionalized internal alkynes (acyl acetylenes)43,44 to VTCs by 2,6-dichloropyridine N-oxide. Various VTCs (α,β-diketoesters, 1,2,3-triketones, α,β-diketoamides) were obtained under mild conditions in high yields. In Received: April 14, 2019

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DOI: 10.1021/acs.orglett.9b01297 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

when the reaction time increased up to 4 h. In summary, the best results were obtained with 2.5 equiv of 2,6-dichloropyridine N-oxide and 5 mol % of Ph3PAuNTf2 in DCM at rt for 1 h (Entry 11). With optimal conditions at hand, the substrate scope of the developed method was examined (Scheme 3). Initially, various

addition, this oxidative method was integrated into a one-pot reaction sequence delivering a range of useful azaheterocyclic compounds. A few examples of the syntheses of VTCs based on transformations of alkynes have been reported.45−47 These methods are not free from significant drawbacks, which include a quite limited scope of starting alkynes (only a few acyl ynamides were employed)45,47 and the usage of aggressive and highly toxic oxidants such as, for instance, HOF46 or O3.47 Recently, we found that ethyl 2,3-dioxo-3-phenylpropanoate is generated as a byproduct of the AuI-catalyzed reaction between ethyl 3-phenylpropiolate and 2-chloropyridine N-oxide to achieve ethyl 2-methyl-5-phenyloxazole-4-carboxylate as the target compound.48 In order to develop a useful approach to the synthesis of VTCs, we began to study the reaction of gold(I)-catalyzed oxidation of propiolates to α,β-diketoesters. Ethyl 3-(4-fluorophenyl)propiolate (1a) was chosen as a model substrate because of easy monitoring of the reaction by 19 F NMR (Table 1).

Scheme 3. Gold-Catalyzed Synthesis of VTCsa−c

Table 1. Optimization of the Reaction Conditionsa

a

entry

N-oxide

solvent

t, °C

time, h

yield,b %

1 2 3 4 5 6 7 8 9 10 11 12 13

3a 3b 3c 3d 3d 3d 3d 3d 3d 3d 3d 3d 3d

PhCl PhCl PhCl PhCl CHCl3 DCE THF PhCF3 DCM PhCF3 DCM DCM DCM

60 60 60 60 60 60 60 60 40 80 20 20 20

3 3 3 3 3 3 3 3 3 3 1 2 4

30 27 52 91 80 84 35 93 93 89 96 96 83c

All reactions were carried out on a 0.1 mmol scale (0.5 M). NMR yield. c3 mol % of Ph3PAuNTf2 was employed.

b19

a

All reactions were carried out on a 0.2 mmol scale (0.5 M). bIsolated yield. cA mixture of the keto and hydrate forms was obtained for 5f (1:2), 5h (3:7), 5m (3:2), 5o (2:3), 5p (9:11), and 5q (10:3).

alkynyl esters were tested in the oxidation. Both methyl- and ethyl-3-arylpropiolates were efficiently transformed to corresponding VCTs 5a−d that were isolated in excellent (84− 92%) yields. A number of electron-donating and electronwithdrawing groups at the ortho (5e,f), para (5g−k), or meta (5l) positions were tolerated well. The reaction conditions were also found applicable to the preparation of α-naphthyland α-thienyl-substituted esters 5m,n. The alkynyl ketones 4o,p were transformed to desired triketo products 5o,p (76− 80%). Mono- and di-N-substituted alkynyl amides 4q,r were also examined, and the corresponding VCTs were obtained in good to excellent (72−92%) yields. Also, we scaled the oxidation of 4c up to 1 mmol, and the isolated yield of 5c was 89%. It is noteworthy that ester and ketone products were isolated as hydrate forms 5′ or as mixtures of keto and hydrate forms with a predominance of the latter; in the cases of the amide products, keto form 5 prevails.

F

Initially, the well-defined complex Ph3PAuNTf2 (5 mol %)49 was chosen as the catalyst, and the reaction was carried out in PhCl at 60 °C for 3 h. Screening of pyridine N-oxides commonly used for nucleophilic oxygenation of alkynes50 (Entries 1−4) revealed that bulky and electron-deficient 2,6dichloropyridine N-oxide 2d is the most effective oxidant. Next, the best results were obtained using nonpolar inert solvents (DCM, PhCl, PhCF3), and more volatile DCM was chosen for the further study. Increasing the reaction temperature to 80 °C reduced the efficiency of the oxidation. However, carrying out the reaction at rt led to almost complete conversion of the starting propiolate during 1 h. Using 3 mol % catalyst loading leads to lower efficiency of the reaction even B

DOI: 10.1021/acs.orglett.9b01297 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters To the best of our knowledge, isolation of aliphatic VTCs is often complicated probably because of easy side aldol condensations.17,21 Our attempts to obtain alkyl-substituted products of satisfactory purity failed. Hence, more stable heterocyclic derivatives of aliphatic VTCs were chosen for characterization. The one-pot synthesis of quinoxalines 6 was carried out in a sequential way by oxidation of alkyl-substituted alkynes 4r,s under the optimized conditionswhen PhCF3 was taken as a solventfollowed by the condensation with ophenylenediamine;51 quinoxaline derivatives 6 were isolated in good overall yields (63−75%; Scheme 4). These experiments indicate that alkyl-substituted alkynes can also be used as precursors of VTCs.

Scheme 6. Control Experiment

Scheme 7. Plausible Mechanism for Generation of 5

Scheme 4. One-Pot Synthesis of Quinoxalines 6

Motivated by the success of the quinoxalines synthesis, we decided to apply our methodology for the construction of other scaffolds based on alkynes as convenient building blocks. This approach has been successful for the synthesis of useful acyl-substituted heterocycles (Scheme 5) such as indole,52 pyrazine,53 and benzo[b][1,4]oxazine.54

gold−alkyne complex A gives intermediate B, which then transforms to gold-based α,α′-dioxo carbene C. Next, the nucleophilic addition of another N-oxide to C followed by the loss of pyridine provides tricarbonyls 5, whereas the catalyst is regenerated. In conclusion, we have developed a facile and direct gold(I)catalyzed method for the transformation of internal alkynes (alkynyl esters, ketones, and amides) to corresponding vicinal tricarbonyl compounds. The methodology carries a number of substantial advantages over the previously described routes to VTCs including the possibility of using readily available and safe alkynes as substrates, mild reaction conditions, good substituent tolerance, and good to excellent (59−92%) yields. Furthermore, our oxidation method can be integrated into a one-pot synthesis of various important azaheterocyclic systems, and consequently, the approach can be useful for combinatorial medicinal chemistry.

Scheme 5. One-Pot Synthesis of Acyl-Substituted Heterocycles 7−9

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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.9b01297. Experimental procedures and analytical data of all compounds; 1H NMR, 13C NMR, and HRMS (ESI) spectra (PDF)

To clarify the alkyne oxidation mechanism, a control experiment was carried out (Scheme 6). An excess of styrene was used to trap the presumed gold carbene, and besides tricarbonyl product 5d, cyclopropane 11 was detected by NMR and HRMS (ESI) as a minor product. The cyclopropanation of Rh α,α′-dioxo55 and Au α-oxo carbenes56 derived from diazo compounds is known. On the basis of these data, we suggest a plausible mechanism57 of the gold-catalyzed generation of VTCs (Scheme 7). First, addition−elimination of N-oxides 3 to

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (A.Yu.D.) *E-mail: [email protected] (V.Yu.K.) C

DOI: 10.1021/acs.orglett.9b01297 Org. Lett. XXXX, XXX, XXX−XXX

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Alexey Yu. Dubovtsev: 0000-0001-6576-814X Dmitry V. Dar’in: 0000-0002-0413-7413 Vadim Yu. Kukushkin: 0000-0002-2253-085X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.Yu.D thanks the Russian Science Foundation for support of these studies (grant 18-73-00026). We are much obliged to the Center for Magnetic Resonance and Center for Chemical Analysis and Material Research (both belonging to Saint Petersburg State University) for physicochemical measurements.

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DOI: 10.1021/acs.orglett.9b01297 Org. Lett. XXXX, XXX, XXX−XXX