Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Transition-Metal-Free Regiospecific Aroylation of Nitroarenes Using Ethyl Arylacetates at Room Temperature Promod Kumar, Anup Kumar Sharma, Tirumaleswararao Guntreddi, Rahul Singh, and Krishna Nand Singh* Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi-221005, India S Supporting Information *
ABSTRACT: A novel regiospecific C(sp3)−C(sp2) coupling between ethyl arylacetates and nitroarenes has been developed to deliver biaryl ketones in excellent yields. The protocol is metal-free, mild, and compatible with a number of functional groups on both of the reacting partners.
T
Scheme 1. Recent Reports and Our Contribution
ransition-metal-catalyzed coupling reactions have transformed the construction of carbon−carbon and carbon− heteroatom bonds in contemporary organic synthesis. Extensive research in this rapidly evolving field has traversed well beyond organic synthesis up to biology, materials science, and engineering.1 Nevertheless, the current challenge in the field of coupling reactions remains the development of innovative protocols under transition-metal-free conditions.2 Biaryl ketones constitute an important class of organic compounds, which are prevalent in biologically active molecules, photosensitizers, advanced organic materials, and natural products.3 Traditionally, such ketones are synthesized by a Friedel−Crafts type reaction of active arenes with acyl halides in the presence of a Lewis acid,4 or by using threecomponent cross-coupling of aryl halides (or pseudohalides), organometallic reagents, and carbon monoxide (CO) in the presence of transition metal catalysts.5 In this course, some fine contributions involving Pd/Cu/Ag-catalyzed decarboxylative cross-coupling of α-oxocarboxylic acids with aryl halides or arylboronic acids have lately appeared.6 Recently, some important reactions involving directing group assisted orthoacylation using α-oxocarboxylic acids or aldehydes or toluene derivatives have also been described.7 Recently, Szostak et al. have accomplished the synthesis of biaryl ketones using Suzuki−Miyaura cross-coupling of amides via site selective N−C bond cleavage by synergistic catalysis of a Lewis base and palladium,8a whereas Newman et al. have reported the NHCbased Pd catalyzed synthesis of ketone containing products by coupling of the aryl esters with aryl boronic acids (Scheme 1).8b Although these metal catalyzed transformations represent a powerful tool in organic synthesis, they suffer from the use of expensive or toxic transition metals and ligands, high temperature, prolonged reaction time, and generation of metal waste. Also, certain functional groups are intolerant to the transition metal systems, which limit their potential applications. Therefore, the development of practical protocols to achieve the synthesis of biaryl ketones without using transition metal catalysts is demanding and challenging.9 © XXXX American Chemical Society
Nitroarenes are versatile and common aromatic building blocks in organic synthesis10 and can be readily obtained by nitration of the parent arenes. They readily undergo nucleophilic substitution mediated by strong bases, in which the NO2 group serves as an activator.11 In light of the above and as a part of our ongoing interest in metal-free reactions12 we disclose herein an efficient KOtBu mediated regiospecific aroylation of nitroarenes using ethyl arylacetates to afford the biaryl ketones at room temperature (Scheme 1). In order to optimize the reaction conditions, a model reaction using ethyl phenylacetate (1A) and nitrobenzene (2a) was investigated in detail by varying different parameters, and the findings are summarized in Table 1. The study commenced with the reaction of equivalent quantities (1.0 mmol) of 1A and 2a in the presence of KOtBu (2.0 equiv) in DMSO at room temperature for 3 h, which led to the formation of the desired product (4-nitrophenyl)(phenyl) methanone (3Aa), albeit in Received: December 13, 2017
A
DOI: 10.1021/acs.orglett.7b03882 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Scope and Versatility of the Reactiona
entry
base
solvent
temp (°C)
yieldb 3Aa (%)
1 2 3 4 5 6 7 8 9 10
KOtBu − KOtBu KOtBu KOtBu KOtBu KOtBu LiOtBu NaOtBu other basese
DMSO DMSO DMF CH3CN toluene EtOH benzene benzene benzene benzene
rt rt rt rt rt rt rt rt rt rt
20c 0 10c 18c 30d 0 75 62 54 0
a
Conditions: 1A (1.0 mmol), 2a (1.0 mmol), base (2.0 mmol), solvent (4.0 mL), 3 h. bIsolated yield. c4Aa as major product. d5Aa as a major product (47%) in accordance with an earlier observation13a concerned with the α-C−H hydroxylation of α-substituted carbonyl compounds. e Other bases: Na2CO3, K2CO3, Cs2CO3, CH3COONa, KOH, NaOH, DBU, DABCO.
low yield (20%; Table 1, entry 1). The role of KOtBu was found to be critical, as the reaction did not proceed at all in its absence (entry 2). In an attempt to improve the product yield, several solvents and bases were then screened at different temperatures. Changing the solvent from DMSO to DMF and acetonitrile diminished the formation of 3Aa (entries 3 and 4) and facilitated the α-C−H arylation giving rise to the product 4Aa (50% in DMSO, 44% in DMF and 39% in CH3CN). The use of toluene as solvent, however, furnished a mixture of products 3Aa (30%) and 5Aa (47%), whereas use of EtOH remained completely futile (entries 5 and 6). However, use of benzene as solvent increased the desired product 3Aa yield (75%, entry 7). Other bases such as LiOtBu and NaOtBu afforded the product 3Aa in 62% and 54% yields respectively (entries 8 and 9). The effect of bases such as Na2CO3, K2CO3, Cs2CO3, CH3COONa, KOH, NaOH, DBU, and DABCO in benzene at room temperature was also examined, however did not afford any product (entry 10). Having identified KOtBu/benzene as the preferred combination, other parameters such as the change in the ratio of the reactants, base, and temperature was studied. The optimized reaction conditions were found to include the use of KOtBu (2.0 equiv) in benzene employing equivalent quantities (1.0 mmol) of the reactants 1A and 2a at room temperature for 3 h (entry 7). With the established conditions in hand (Table 1, entry 7), the scope and versatility of the reaction were then examined by using different ethyl arylacetates 1A−M and nitroarenes 2a−e as coupling partners (Scheme 2). Ethyl arylacetates 1 bearing a halogen substituent such as 2Cl (1C), 4-Cl (1D), 3,5-dichloro (1E), 2,4-dichloro (1F), 4-Br (1G), and 4-F (1H), when reacted with nitrobenzene (2a), gave the corresponding products 3Ca, 3Da, 3Ea, 3Fa, 3Ga, and 3Ha in good yields. Ethyl arylacetates having an electron-rich substituent at different positions such as 4-OMe (1I), 2-OMe (1J), 2-Me (1K), and 4-Me (1L) also underwent smooth aroylation with 2a affording the corresponding products 3Ia, 3Ja, 3Ka, and 3La in 64−80% yield. Ethyl 1-(naphthalen-1yl)acetate (1M) also worked well leading to the formation of
a Conditions: 1 (1.0 mmol), 2 (1.0 mmol), KOtBu (2.0 mmol), benzene (4.0 mL). bDMSO (4.0 mL). cDMF (4.0 mL). dCH3CN (4.0 mL). eToluene (4.0 mL).
the product 3Ma in 72% yield. The adaptability of the reaction on the nitroarene component having a substituent such as 2-Cl (2b), 3-Me (2c), 3-Br (2d), and 2-CN (2e) was also checked with various ethyl arylacetates to give the corresponding biaryl ketones 3Ib, 3Db, 3Ic, 3Lc, 3Dc, 3Hc, 3Dd, 3Gd, and 3De in 57−75% yields. More importantly, the reaction is highly regiospecific, as para-aroylation of nitroarenes is exclusively observed. Employing different para-substituted nitroarenes, viz. 1-fluoro-4-nitrobenzene, 1-chloro-4-nitrobenzene, and 1-iodo4-nitrobenzene, in the reaction under the optimized reaction conditions failed to give the desired products or any ortho functionalized products. In order to gain insight into the reaction mechanism, some control experiments (Scheme 3) were performed using esters B
DOI: 10.1021/acs.orglett.7b03882 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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Scheme 3. Control Experiments
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03882. Experimental procedures and spectroscopic data for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected];
[email protected]. ORCID
Krishna Nand Singh: 0000-0001-9147-5463 Notes
other than ethyl phenylacetate, viz. methyl phenylacetate and iso-propyl phenylacetate, with 2a resulting in the same product 3Aa with marginal difference in yields. When ethyl phenylacetate was allowed to react under the optimized reaction conditions without nitrobenzene, it furnished potassium 2phenylacetate, which eventually failed to give the desired product on addition of nitrobenzene. This suggests that the reaction proceeds with α-C−H aroylation followed by the decarboxylation step. In order to ascertain the role of atmospheric oxygen, the reaction was also performed under an inert atmosphere which failed to produce any significant conversion to the desired product. Based on isolated products, control experiments, and existing literature,11,13 a plausible pathway is outlined in Scheme 4.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are thankful to the SERB, New Delhi (File No. EMR/ 2016/000750) for financial assistance. P.K. thanks UGC, New Delhi for the award of a DSK−Postdoctoral Fellowship (Award Letter No. F.4-2/2006 (BSR)/CH/13-14/0165).
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REFERENCES
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Scheme 4. Plausible Pathway for Formation of 3
Potassium tert-butoxide abstracts a proton from ethyl arylacetate (1A−M) to provide carbanion I which attacks the para-position of the nitroarene (2a−e) to afford the resonance stabilized intermediate II. The intermediate II in the presence of a base and aerial oxygen undergoes oxidative elimination to afford the intermediate III, which is subsequently transformed to the intermediate IV. The α-hydroperoxy intermediate IV eventually undergoes hydrolytic decarboxylation along with loss of a hydroxide ion to give the desired product 3. In summary, a practical and convenient approach to synthesize biaryl ketones from nitroarenes and ethyl arylacetate is presented under metal-free conditions. C
DOI: 10.1021/acs.orglett.7b03882 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.7b03882 Org. Lett. XXXX, XXX, XXX−XXX
