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Synlett 2021; 32(04): 387-390
DOI: 10.1055/s-0040-1707246
cluster
Radicals – by Young Chinese Organic Chemists
© Georg Thieme Verlag Stuttgart · New York

Direct Deoxygenative Intramolecular Acylation of Biarylcarboxylic Acids

Yantao Li
a   State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. of China   Email: cjzhu@nju.edu.cn   Email: xie@nju.edu.cn
,
Wentao Xu
a   State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. of China   Email: cjzhu@nju.edu.cn   Email: xie@nju.edu.cn
,
Chengjian Zhu∗
a   State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. of China   Email: cjzhu@nju.edu.cn   Email: xie@nju.edu.cn
b   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. of China
,
Jin Xie∗
a   State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. of China   Email: cjzhu@nju.edu.cn   Email: xie@nju.edu.cn
› Author Affiliations

We thank the National Natural Science Foundation of China (Grant Nos. 21971108, 21971111, 21702098, 21732003 and 21672099), the Natural Science Foundation of Jiangsu Province (Grant No. BK20190006), the Fundamental Research Funds for the Central Universities (Grant No. 020514380176), Jiangsu Six Peak Talent Project, and start-up funds from Nanjing University for financial support.
Further Information

Publication History

Received: 23 June 2020

Accepted after revision: 19 July 2020

Publication Date:
21 August 2020 (online)

 
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Published as part of the Cluster Radicals – by Young Chinese Organic Chemists

Abstract

A photocatalyzed intramolecular cyclization is developed for the synthesis of fluorenones. In this photoredox reaction, triphenylphosphine is used as an inexpensive and effective deoxygenative reagent for biarylcarboxylic acids to give acyl radicals, which quickly undergo intramolecular radical cyclization. Reactions in the presence of air and continuous flow photoredox technology demonstrate the generality and practicality of this process.


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Key words

photocatalytic - deoxygenation - triphenylphosphine - radical cyclization - flow chemistry

Fluorenone is a cornerstone in photoelectric materials and biologically active molecules (Figure [1]).[1] Recently, fluorenones have been successfully applied as hydrogen atom transfer (HAT) catalysts in organic synthesis.[2] Hence, the construction of the fluorenone skeleton is of significant importance and has gained considerable attention. They are typically prepared via the classical Friedel–Crafts acylation of the corresponding acids,[3] however, the method suffers from the use of strong and excess acids, poor functional group tolerance and incompatibility with electron-rich arenes. Recently, when using strong oxidants as HAT reagents, such as K2S2O4 and t-BuOOH, aldehydes and α-keto acids have been found to undergo dehydrogenation or decarboxylation to generate nucleophilic acyl radicals, triggering the desired transformation.[4] Alternatively, cycloaddition reactions,[5] oxidation of fluorenones or fluorenes[6] and cyclocarbonylation[7] can also be used to prepare fluorenones. However, high temperatures and the use of excess oxidants are disadvantages of these processes.

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Figure 1 The application of fluorenone derivatives

Carboxylic acids are abundant in nature and have been successfully used as acyl precursors.[8] In 2014, a rhodium-catalyzed intramolecular acylation of 2-aryl acids was developed to synthesize fluorenones through an acylrhodium species at a temperature of 160 °C (Scheme [1, a]).[9] During the last decade, photoredox catalysis has proven to be a valuable and powerful method for the development of new chemical reactions that involve single-electron transfer (SET) processes.[10] Previously, our group developed a photoredox catalytic decarboxylation of anhydrides generated from biarylcarboxylic acids and dimethyl dicarbonate (DMDC).[11] Recently, our group disclosed the first direct and practical deoxygenation of acids (as acyl sources) with triphenylphosphine.[12] This powerful strategy has been applied in direct deoxygenative ketone synthesis, deoxygenative deuteration and deoxygenative arylation. Similar deoxygenative pathways were also applied in organic transformations by Doyle[13] and others.[14] As ongoing research, we report a photoredox intramolecular cyclization of biarylcarboxylic acids using cheap and stable Ph3P as a deoxygenation reagent (Scheme [1, b]). This study provides a practical and straightforward protocol for the preparation of fluorenone scaffolds under air conditions, and further enhances its utility in synthetic applications utilizing continuous flow synthesis.

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Scheme 1 Recent representative work on the synthesis of fluorenones

We started our investigations on the direct deoxygenative acylation with 2-phenylbenzoic acid (1a) as a model substrate. The optimized reaction conditions were determined to be Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) as the photocatalyst, PPh3 (3.0 equiv) as the deoxygenative reagent, together with K2CO3 (0.75 equiv) as the inorganic base in DCE under blue LEDs at room temperature (Table [1], entry 1). The target product, 9H-fluoren-9-one (2a), was obtained in 70% isolated yield. Replacing Ph3P with Ph2POMe or P(OEt)3 resulted in none of the desired product being detected (entries 2 and 3). Other inorganic base led to lower yields (entries 4 and 5). A lower oxidation potential photocatalyst, Ir[dF(Me)ppy]2(dtbbpy)PF6 [1/2 E red (*IrIII/IrII) = +0.97 V vs SCE; τ = 1.2 μs],[15] resulted in a slightly decreased yield (entry 6). Control experiments showed that PPh3, air, light and the photocatalyst all play a crucial role in the reaction (entries 7–9).

Table 1 Optimization of the Reaction Conditionsa

Entry

Deviation from standard conditions

Yieldb

1

none

70%

2

Ph2POMe instead of Ph3P

nd

3

P(OEt)3 instead of Ph3P

nd

4

K2HPO4 instead of K2CO3

40%

5

K3PO4 instead of K2CO3

45%

6

Ir[dF(Me)ppy]2(dtbbpy)PF6

55%

7

no Ph3P

nd

8

under Ar

nd

9

in the dark

nd

a Standard reaction conditions: 1a (0.1 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%), Ph3P (3.0 equiv), K2CO3 (0.75 equiv), DCE (2 mL), 2 blue LEDs (45 W), 24 h, rt, under air.

b Isolated yield; nd = not detected.

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Figure 2 Substrate scope. a Regioselectivity determined by GC.

With optimized reaction conditions in hand, the scope of the reaction was investigated. The versatility of this cyclization reaction with different substrates and the generality of the strategy is demonstrated by the examples shown in Figure [2].[16] Acids 1 with substituents on the Ar2 ring were initially examined in this cyclization reaction and they can afford the desired products (2a–2o) in moderate to good yields. Substrates with electron-donating substituents [methyl (1b), methoxy (1c) and tert-butyl (1d)] or with an electron-withdrawing trifluoromethyl substituent (1h) were found to undergo efficient intramolecular acylation to give the corresponding products 2b–d,h. Biarylcarboxylic acids with halogen substituents (1e–g,n) also reacted in good yields. Two disubstituted substrates (1i,j) also showed good activity, whilst acid 1k with an ortho-Cl substituent was also compatible. When a halogen was located at the meta-position of the Ar2 ring (1n), the reaction proceeded smoothly with good regioselectivity to afford product 2n. In addition, an acid with an electron-withdrawing group (1l) on the Ar1 ring gave a higher yield of the corresponding product 2l compared with an acid possessing an electron-donating group (1m) on the same aryl ring. Heteroaromatic acid 1o was converted into the desired fluorenone 2o in an acceptable 64% yield.

Continuous flow technology has attracted more and more attention in recent years,[17] and shows some significant advantages over conventional batch reactions, including the in situ formation and direct use of reaction intermediates, convenience of temperature control, increased reaction contact area, and ease of amplification. Hence, the model reactant 1a was used to study this intramolecular cyclization reaction under continuous flow conditions. The direct deoxygenative intramolecular acylation can be scaled up to 1 mmol with lower loading of the photocatalyst by the use of continuous micro-tubing reactors,[18] which leads to enhanced utility in synthetic applications (Scheme [2]).

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Scheme 2 Continuous flow transformations. Conditions: 1a (1.0 equiv, 1.0 mmol), PPh3 (3.0 equiv, 3.0 mmol), K2CO3 (0.5 equiv, 0.5 mmol, 120 mesh), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%, 0.01 mmol), DCE (30 mL), 2 blue LEDs (45 W), rt, under air.

To gain further insight into the cyclization, a radical-trapping experiment was conducted (Scheme [3]). In the presence of the radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), the reaction was completely inhibited and none of the desired product 2a was observed. Moreover, the corresponding acyl radical was trapped by TEMPO, which indicates that this transformation may involve radical intermediates.

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Scheme 3 Radical-trapping experiment

Based on previous work[4c] [f] [12a] and the radical-trapping experiment with TEMPO, a plausible reaction mechanism is proposed (Scheme [4]). Under irradiation, the photoexcited catalyst *Ir[dF(CF3)ppy]2(dtbbpy)PF6 [E 1/2 red (*IrIII/IrII) = +1.21 V vs SCE)] goes through a single-electron transfer (SET) process with PPh3 to give the radical cation 4, which quickly reacts with carboxylate anion 5 to produce the phosphoryl radical 6. Next, β-selective C(acyl)–O bond cleavage results in triphenylphosphine oxide being released. Subsequent cyclization then leads to the formation of intermediate 7. Under air, O2 can oxidize [IrII] to its ground state and close the photocatalytic cycle. The resulting O2 •– species would then oxidize 7 to give the final product 2a.

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Scheme 4 The proposed mechanism

In summary, a green, mild and simple method to access fluorenone derivatives is described. A number of substituted fluorenones[17] have been synthesized via this process, which may have potential as luminescent materials. Continuous flow chemistry[18] was successfully applied in this deoxygenative intramolecular acylation, showing the potential for scale-up and possible industrialization of the process. Further studies on the cyclization of aliphatic carboxylic acids are underway in our laboratory.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707246.
  • Supporting Information


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Zoom Image
Figure 1 The application of fluorenone derivatives
Zoom Image
Scheme 1 Recent representative work on the synthesis of fluorenones
Zoom Image
Figure 2 Substrate scope. a Regioselectivity determined by GC.
Zoom Image
Scheme 2 Continuous flow transformations. Conditions: 1a (1.0 equiv, 1.0 mmol), PPh3 (3.0 equiv, 3.0 mmol), K2CO3 (0.5 equiv, 0.5 mmol, 120 mesh), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%, 0.01 mmol), DCE (30 mL), 2 blue LEDs (45 W), rt, under air.
Zoom Image
Scheme 3 Radical-trapping experiment
Zoom Image
Scheme 4 The proposed mechanism