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Synlett 2016; 27(20): 2774-2782
DOI: 10.1055/s-0036-1588085
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© Georg Thieme Verlag Stuttgart · New York

Research on the Conversion of α-Hydroxy Ketones into 1,2-Diketones and Subsequent Transformations

Hanbing Liang
a   School of Chemical Engineering, Shandong University of Technology, 266 West Xincun Road, Zibo 255049, P. R. of China
,
Hui Liu*
a   School of Chemical Engineering, Shandong University of Technology, 266 West Xincun Road, Zibo 255049, P. R. of China
,
Xuefeng Jiang*
b   Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, Shanghai 200062, P. R. of China   Email: xfjiang@chem.ecnu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 07 August 2016

Accepted after revision: 05 October 2016

Publication Date:
27 October 2016 (online)

 
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Abstract

1,2-Diketone derivatives are valuable molecules which are widely applied in organic synthesis. In this account, we discuss our recent research progress on the construction of 1,2-diketone derivatives and their subsequent transformations, including the synthesis of ynediones, the dicarbonylation of indoles and the preparation of heterocyclic hemiketals from ynediones. In addition, mechanistic investigations on the dicarbonylation of α-hydroxy ketones are described and plausible mechanisms are proposed. Furthermore, the synthesis of 3(2H)-furanones and 3(2H)-thienones from ynediones are also described.

1 Introduction

2 A Copper-Catalyzed One-Pot Approach Toward Ynediones

3 Copper-Catalyzed Aerobic Oxidative Dicarbonylation of Indoles

4 Synthesis of Heterocyclic Hemiketals from Ynediones

5 Conclusion


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Key words

dicarbonylation - ynediones - α-hydroxy ketones - furanone - thienone - indole

Biographical Sketches

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Hanbing Liang was born in Zibo, P. R. of China in 1981. He graduated from the College of Chemistry and Chemical Engineering of OUC in 2000. He served as an assistant to the Project Executive of the research institute of Shandong Xinhua Pharmaceutical Co., Ltd from 2000 to 2007. Subsequently, he pursued his M.S. degree with Professor Xianjin Yu at Shandong University of Technology between 2007 and 2010. He held the post of R&D Engineer at Zibo Riken Mountain Coated Abrasive Co., Ltd from 2010 to 2015. Since 2015, he has been pursuing his Ph.D. studies with Professor Yunhui Dong and Professor Hui Liu at Shandong University of Technology. His studies are directed toward the development of palladium-catalyzed methodology.

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Hui Liu was born in Shandong, P. R. of China. He received his B.Sc. degree from Qufu Normal University (P. R. of China) in 2006, and then pursued his Ph.D. studies with Professor Limin Wang and Professor Xiaofeng Tong at East China University of Science and Technology. After postdoctoral research with Professor Xuefeng Jiang at East China Normal University, Professor Fréd Taran at CEA (France) and Professor Véronique Gouverneur at Oxford University from 2012 to 2014, he joined Shandong University of Technology. His research interests involve the development of transition-metal-catalyzed methodologies and applications in synthesis.

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Xuefeng Jiang received his B.S. degree from Northwest University (P. R. of China) in 2003, and pursued his Ph.D. studies with Professor Shengming Ma at the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences. From 2008 to 2011, he was a postdoctoral researcher under the guidance of Professor K. C. Nicolaou at The Scripps Research Institute (TSRI) in the field of natural product total synthesis. He is currently a professor at East China Normal University and his research interests are in methodology-oriented total synthesis.

1

Introduction

1,2-Diketones appear frequently in biologically active compounds and are important precursors for various organic transformations, in particular, for the synthesis of heterocyclic compounds.[1] One of the most straightforward methods to prepare 1,2-diketone derivatives is via the direct oxidation of properly substituted alkynes.[2] Alternatively, 1,2-diketones can be obtained by the oxidation of alkenes.[3] A novel aminocatalytic cross-coupling approach with wide substrate scope for the generation of 1,2-diketones via iminium ion activation was reported in 2014.[4a] In the past few years, a number of synthetic methodologies for the dicarbonylation of indoles have been realized. In 2013, Tang et al. developed a selective C–N bond oxidative cleavage method to construct 3-acylated indoles by means of palladium-catalyzed oxidative cross-coupling of indoles with α-amino ketones.[4b] Meanwhile, the same group established a one-pot synthesis of 3-acylated indoles from 2-ethynylanilines and α-amino carbonyl compounds.[4b] In 2015, Yang et al. reported a copper-catalyzed aerobic oxidative dicarbonylation of indoles employing α-carbonyl aldehydes to construct C-3 indole-substituted 1,2-diketones under mild conditions.[4c] In addition, Yan et al. demonstrated a one-pot tandem reaction of indole and β-carbonyl nitriles to generate dicarbonyl indoles, which provided a new method for the synthesis of functional dicarbonyl indoles under simple conditions.[4d] In our group, we have been interested in developing new transformations from α-hydroxy ketones.[5] Some strategies toward the synthesis of diketone derivatives have been developed. In this account, we highlight our achievements in the area of 1,2-diketone construction and transformations.


# 2

A Copper-Catalyzed One-Pot Approach Toward Ynediones

When studying the aerobic oxidative carbon–carbon bond cleavage of α-hydroxy ketones, our group observed that the α-position was easily activated by oxygen.[5] This inspired us to establish a method for dicarbonylation[6] involving this stable and readily available structure by utilizing its extremely active α-position combined with oxygen[7] [8] and copper(I) catalysis.

Ynediones are special alkynes containing a 1,2-dione motif and have a unique, densely electrophilic structure. Based on the above characteristics, ynediones can be easily converted into a variety of valuable heterocyclic precursors.[9] In multicomponent syntheses of pharmaceutical heterocycles and in natural product research, ynediones have received significant attention.[10] As a result of this wide range of applications, convenient and highly efficient synthetic methods for their construction are very desirable.

Reports on the preparation of ynediones are rare. Most of the described methods have employed the Castro–Stephens coupling[11] to obtain ynediones from the reactions of glyoxylyl chlorides and terminal alkynes. Müller[10] and Zhang’s groups[12] have developed a more convenient method by using the glyoxylation of electron-rich heteroaromatic nucleophiles and α-keto carboxylic acids with oxalyl chloride. In 2012, our group developed a procedure for the carbon–carbon cleavage of α-hydroxy ketones by using K2CO3­ and O2; some special properties of α-hydroxy ketones were found from this system. A direct and efficient approach to ynediones had been established involving the oxidative coupling of α-hydroxy ketones and terminal alkynes, which avoided Glaser coupling[13] in this transformation (Scheme [1]).

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Scheme 1 Synthesis of ynediones

Using the optimized conditions,[14] a series of α-hydroxy ketones 1 was explored (Scheme [2]). In particular, when the quantity of 2-hydroxy-1-phenylethan-1-one (1a) was increased to 2 mmol (272 mg), a good yield was obtained. Even when the reaction was performed on a 10 mmol (1.36 g) scale of 1a, the yield reached 62%. With electron-donating and electron-withdrawing groups, α-hydroxy ketones could be successfully converted into the corresponding ynediones 2a–h in moderate to excellent yields. The α-hydroxy ketones did not show any distinct effects resulting from steric hindrance when a methyl substituent was present at the o-, m-, or p-position on the aryl ring. Whether using copper-catalyst activation or not, halogen-substituted substrates provided good yields of the expected products 2i–l. Furthermore, this method could be adapted to polycyclic and heterocyclic α-hydroxy ketone substrates, such as those possessing naphthalene, furan, thiophene, benzofuran, 2,3-dihydrobenzofuran and benzothiophene moieties (2m–t).

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Scheme 2 Scope of the α-hydroxy ketones
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Scheme 3 Scope of the alkynes

Having examined numerous α-hydroxy ketones, different functionalized terminal alkynes were investigated in reactions with 2-hydroxy-1-phenylethan-1-one (1a) (Scheme [3]). As a matter of fact, both arynes and alkylacetylenes worked very well. Arynes with methyl and methoxy groups afforded moderate to excellent yields of the ynediones 3a and 3b. Long-chain alkyl-substituted alkynes, such as hex-1-yne and oct-1-yne, also offered moderate yields via the addition of p-benzoquinone to accelerate this oxidative process.[8f] [15] Cycloalkane-substituted alkynes (cyclopropyl and cyclohexyl acetylenes) were converted into the desired products 3e and 3f in 69% and 50% yield, respectively. Alkynes bearing different hydroxy protecting groups, such as TBS, TBDPS, Bn, THP, and allyl, were compatible in this transformation, affording the desired products 3g–k in good yields. Phenyl, phthalimide, chlorine, TES, and ester groups were well tolerated in this reaction system (3l–p). When a disubstituted terminal alkyne substrate was tested, only one of the alkyne groups reacted to afford the ynedione 3q. Alkyl acetylenes possessing phenyl or heterocyclic groups linked via an ester also produced the desired products 3r–t.

There are two feasible routes for the oxidation of the hydroxy group (Scheme [4]). In path A, the copper alkoxide produced binuclear copper(II) peroxide 4b in the presence of oxygen. Homolytic cleavage followed by hydrogen atom abstraction offered the hydroxy copper(I) species 4d. After exchange between the hydroxy ligand and alcohol 1a, the copper alkoxide 4a was regenerated following the loss of a water molecule.[16] In path B, the hydroxy phenylethanone 1a tautomerized into an enediol ligand to coordinate to copper(II). Following direct electron transfer, dicarbonyl compound 4f and copper(I) were formed. Next, the oxygen oxidized copper(I) to copper(II). Besides, there was an equilibrium between dicarbonyl compound 4f and its monohydrate 4g in the system. After ethynylbenzene was added, alkynyl copper species 4i was formed. Addition of the alkynyl copper species 4i to phenylglyoxal could afford intermediate 4j, which is then oxidized to dimer 4k. Further oxidation then produces 1,4-diphenylbut-3-yne-1,2-dione (2a).

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Scheme 4 Plausible mechanisms for the formation of ynediones
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Scheme 5 Dicarbonylation of indoles

# 3

Copper-Catalyzed Aerobic Oxidative Dicarbonylation of Indoles

In continuation of this work, the copper-catalyzed aerobic oxidative dicarbonylation was extended to indoles.

Series of substituted indoles and α-hydroxy ketones were investigated in this dicarbonylation reaction[17] (Scheme [5]). Indoles substituted with different electron-neutral and electron-donating groups, including methyl, allyl, benzyl, and p-methoxybenzyl, under nitrogen, were transformed into the desired products 6a–d in moderate to excellent yields. The reaction of an unprotected indole also offered a good yield of the corresponding product 6e. A variety of electron-rich substituents on the indole proved to be highly suitable for this transformation affording products 6f–i. Besides indoles, an unprotected pyrrole also afforded the expected product 6j in good yield. N-Methylindoles with a chloro substituent at the C-4, C-5, or C-6 positions were compatible and afforded the corresponding products 6k–m. A more sensitive bromo group was able to tolerate the standard conditions to produce compound 6n. When substituents such as methoxy, fluoro, chloro, bromo, methyl formyl, and trifluoromethyl were located on the aromatic ring of the α-hydroxy ketone, the corresponding products 6o–t were obtained. Moreover, this method was adapted to diverse condensed rings and heterocycles (such as naphthalene, benzofuran, benzothiophene, and thiophene), which provided the possibility to construct highly conjugated multiheterocyclic structures 6u–z and 6aa with potential fluorescent properties.

With control experiments explored, a plausible mechanism was investigated (Scheme [6]). Both CuTC and O2 were necessary for this transformation (Schemes 6a and 6b). Notably, phenylglyoxal monohydrate (1aa) was subjected to the optimized conditions and product 6a was successfully obtained (Scheme [6c]). The initial oxidation of 1a by an associated effect of oxygen and the copper catalyst results in the desired ketoaldehyde 1aa, which went through a Friedel–Crafts-type reaction to produce 5ba (Scheme [6d]). Finally, oxidation of 5ba with oxygen and the copper catalyst afforded the desired product 6a (Scheme [6e]).


# 4

Synthesis of Heterocyclic Hemiketals from Ynediones

When we explored the applications of the ynedione derivatives, we found that they were considered as being appropriate synthetic precursors of heterocyclic hemiketal-containing α,β-unsaturated ketones. Examples include 3(2H)-furanones and 3(2H)-thienones, this series of α,β-unsaturated ketones being present in certain antitumor and antibiotic pharmaceuticals, and also serve as important synthetic precursors.[18] Most of the previous synthetic methods involve complicated starting materials which need multiple-step syntheses.[19] [20] Therefore, a simple and efficient method to prepare the 3(2H)-furanone and 3(2H)-thienones appeared to be particularly important. During our development of efficient methods for the synthesis of chalcogen-containing compounds, we established one-step methods for the preparation of series of 3(2H)-furanone and 3(2H)-thienone products.

As shown in Scheme [7, 3](2H)-furanones 8 and 3(2H)-thienones 9 were obtained from ynedione substrates with various functional groups. Electron-donating and electron-neutral groups, such as methyl, methoxy, and phenyl, were well tolerated in the conversions. Ynediones with different halide substituents were converted into the expected products in high yields. In addition, this strategy was adapted to different types of condensed rings and heterocycles, such as naphthalene, thiophene, benzothiophene, benzofuran, and furan, to afford excellent yields of the corresponding hemiketals. A 3(2H)-thienone with a nitro group (9h) was also obtained easily. Furthermore, the transformation also proceeded smoothly when the alkynyl-connected phenyl group was replaced with a substituted aryl, alkyl, or even a cyclopropane group.

A plausible mechanism has been put forward to account for the synthesis of the heterocyclic 3(2H)-furanone hemiketal-containing α,β-unsaturated ketones (Scheme [8]). The synthesis of the 3(2H)-furanone began with activation of the carbonyl of the ynedione by silver(I). Subsequently, the 2-hydroxy-2,5-diphenylfuran can be produced by ring-closing from the hydroxy adding to the carbonyl group.

On the other hand, the synthesis of the 3(2H)-thienones may have occurred by one of two pathways (Scheme [9]). One plausible route is to start from the addition of thiourea, followed by the dissociation of cyanamide to generate 7d and 7g. The second route is via condensation between the ynedione and thiourea to form imine 7e. Next, the addition of sulfur to the activated alkyne forms the six-membered ring intermediate 7f, followed by cyanamide liberation to form 7g. Finally, cyclization affords the desired 2-hydroxy-2,5-diphenylthiophene product.

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Scheme 6 Control experiments for the dicarbonylation of indoles. NR = no reaction

# 5

Conclusion

Based on the investigation of α-hydroxy ketones, our group has developed two methodologies in this field. The preparation of ynediones has been achieved via a one-pot strategy employing a copper catalyst. The wide compatibility with various functional groups makes it a quite useful strategy. Profiting from the mild and convenient system, the dicarbonylation of indoles was investigated. We had already explored some applications of the ynediones, and the synthesis of heterocyclic hemiketal-containing α,β-unsaturated ketones has been realized by employing water and thiourea. Diverse structure-sensitive 3(2H)-furanones and 3(2H)-thienones have been constructed, with the processes demonstrating excellent tolerance of a wide range of functional groups. Further research on the dicarbonylation will be reported in the future.

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Scheme 7 Synthesis of various substituted 3(2H)-furanones and 3(2H)-thienones
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Scheme 8 A plausible mechanism for the synthesis of 3(2H)-furanones
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Scheme 9 Plausible mechanisms for the synthesis of the 3(2H)-thienones

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Acknowledgment

Financial support was provided by NBRPC (973 Program, 2015CB856600), NSFC (21472050, 21272075, 21302057), the Fok Ying Tung Education Foundation (141011), the Young Talents Joint Fund of Shandong Province (ZR2015JL005), CPSF (2016M590736) and the Special Funding for Postdoctoral Innovation Project of Shandong Province (201501002), the program for Shanghai Rising Star (15QA1401800), the Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the Changjiang Scholar and Innovative Research Team in University.



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Scheme 1 Synthesis of ynediones
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Scheme 2 Scope of the α-hydroxy ketones
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Scheme 3 Scope of the alkynes
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Scheme 4 Plausible mechanisms for the formation of ynediones
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Scheme 5 Dicarbonylation of indoles
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Scheme 6 Control experiments for the dicarbonylation of indoles. NR = no reaction
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Scheme 7 Synthesis of various substituted 3(2H)-furanones and 3(2H)-thienones
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Scheme 8 A plausible mechanism for the synthesis of 3(2H)-furanones
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Scheme 9 Plausible mechanisms for the synthesis of the 3(2H)-thienones