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Metal-free direct amination/aromatization of 2-cyclohexenones to iodo-N-arylanilines and N-arylanilines promoted by iodinew M. Teresa Barros,a Suvendu S. Dey,a Christopher D. Maycock*bc and Paula Rodriguesb Received 10th August 2012, Accepted 12th September 2012 DOI: 10.1039/c2cc35801h An iodine mediated aromatization leading to a one-pot synthesis of iodo-N-arylanilines and N-arylanilines is reported. This highly regioselective aliphatic–aromatic transformation can be performed with various combinations of 2-cyclohexenones and anilines. The presence of a directing group is crucial for achieving high yields. Problems such as waste management, the limited supply of expensive transition metals and metal salts1 and the difficulties faced by pharmaceutical companies to separate these metals or metal salts from the final products, challenge chemists to find new synthetic methods that employ readily available metal catalysts, or even metal-free alternatives for organic transformations. Despite the simple structure and wide occurrence and application of N-arylated amines in various fields,2 the synthesis of these compounds, especially the N-arylanilines, is often difficult without metal catalysis. During the last decade, some transition metal free syntheses of N-phenylanilines have been achieved through aromatic C–N coupling reactions.3 However few examples are mentioned for the synthesis of N-arylamines using an aliphatic to aromatic transformation,4 most of which are less efficient for synthesising N-arylanilines. The metal free strategies4d,g which require either an electrophile or a leaving group for aromatization, are limited in substrate scope. In order to avoid these limitations development of methods to make N-arylaniline-derivatives easily and economically, particularly for industrial use, is still an imperative. Iodo-N-arylanilines are also required as the precursors of various important compounds. Although there are many examples of aromatic halogenations, iodination remains a difficult transformation to facilitate.5a To the best of our knowledge, iodine catalyzed direct amination/aromatization of 2-cyclohexenones in the presence of anilines leading to iodo-N-arylanilines or N-diarylamines has not yet been reported. We considered that after formation of a dienamine oxidation by iodine could occur with formation of the aromatic ring. The use of DMSO could recycle the hydrogen iodide formed to iodine.5b,c Herein we report a a

Faculdade de Cieˆncias e Tecnologia, Universidade Nova de Lisboa, Monte da Caparica, Portugal b Instituto de Tecnologia Quı´mica e Biologia, Universidade Nova de Lisboa, 2780-157, Oeiras, Portugal. E-mail: [email protected] c Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal w Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cc35801h

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c

The Royal Society of Chemistry 2012

Scheme 1 Synthesis of iodo-N-arylanilines and N-arylanilines.

simple metal-free one-pot synthesis of iodo-N-arylanilines and N-arylanilines from 2-cyclohexenones using a variety of anilines using stoichiometric and substoichiometric molecular iodine in dimethylsulfoxide (DMSO) in the presence of catalytic amount of p-toluenesulfonic acid monohydrate (p-TsOH) (Scheme 1). Optimization studies were carried out with the amination/ aromatization of cyclohex-2-en-1-one with 2-bromo-4-fluoroaniline as a model reaction (Table SA, see ESIw). The use of different amounts of iodine in different solvents at different temperatures was explored. Iodine itself was responsible for the progress of the reaction. An optimal yield of 2-bromo4-fluoro-N-(4-iodophenyl)aniline (1) and 2-bromo-4-fluoroN-phenylaniline (2) was obtained at 90 1C by using 110 mol% (Table SA, entry 2, ESIw) and 50 mol% (Table SA, entry 3, ESIw) of iodine respectively in DMSO with 10 mol% p-TsOH. Iodide coupled with an oxidizing reagent is typically employed to generate an electrophilic iodinium species.6 We tested the model reaction using N-iodosuccinamide (NIS) instead of iodine and found that it required 2.2 equiv. of NIS (Table SA, entry 15, ESIw) to obtain 2-bromo-4-fluoro-N-(4-iodophenyl)aniline (1). This study also suggested that for this transformation, the low electrophilicity of iodine was advantageous with respect to NIS which readily iodinated the aniline without the need for the oxidative process (Scheme 2). With an optimized catalytic system in hand, the generality of this aliphatic–aromatic transformation protocol was examined. As shown in Tables 1 and 2, all the reactions proceeded smoothly and afforded moderate to excellent yields of the corresponding iodo-N-arylanilines and N-arylanilines respectively. Both electronwithdrawing and electron-donating substituents on the aryl ring of the anilines were tolerated. Importantly, functional groups such as Chem. Commun., 2012, 48, 10901–10903

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Table 2 Substrate scope for the preparation of N-arylanilinesa

Scheme 2

Comparison between the use of NIS and I2.

Table 1 Substrate scope for the preparation of mono-iodo-N-arylanilinesa

a

Solution of 0.33 mmol of ketone and 0.25 mmol of amine in 0.5 ml of DMSO with I2 and 10 mol% of p-TsOH 90 1C. b Isolated Yield.

a

Solution of 0.33 mmol of ketone, 0.25 mmol of amine in 0.5 ml of DMSO with I2 and 10 mol% of p-TsOH, 90 1C. b Isolated Yield. c Separated by preparative TLC.

I, Cl, Br, F, CF3, were compatible with the optimal reaction conditions, hence providing a means for additional modifications at the halogenated positions. A variety of substituted 2-cyclohexenones also underwent aromatization, followed by 10902

Chem. Commun., 2012, 48, 10901–10903

iodination, efficiently producing the predicted products in good yields. In accordance with previous reports7 paraiodination dominated and in most cases substitution took place regioselectively at the ring corresponding to the cyclohexenone used. When the para-positions of both aryl-rings were blocked, iodination took place at the ortho-position of the less substituted ring (1m, 1n and 1o). Interestingly 4-iodoaniline, 4-methylaniline when treated with 2-cyclohexenone under these conditions, afforded low yields of the corresponding iodo-N,N-diarylamines (1c, 1j). Aniline and anisidines did not produce the corresponding iodo-products with 2-cyclohexenone. It also demonstrated that the presence of groups such as –Cl, –Br-, –I, –COOEt at the ortho- or meta-position of the aryl amine or nearer to the in situ formed enamine group (2a, 2b, 2c, 2d, 1f, 1q) proved to be crucial in order to achieve high yields of products. Hagemann’s ester reacted with aniline to afford the corresponding N-arylaniline (2m), although with a lower yield than for the ortho-substituted anilines. Comparing the yields of 1j and 1p, it may be concluded that anilines without orthosubstituted groups coupled more efficiently with Hagemann’s ester than with simple substituted 2-cyclohexenones. This may be explained by rapid aromatization of Hagemann’s ester This journal is

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(REDE/1517/RMN/2005), is supported by POCI 2010 and Fundaçaõ para a Cieˆncia e a Tecnologia.


Notes and references

Scheme 3

N-arylation of 3-aminopyridine derivatives.

after imine formation. At this time the exact reason behind the unexpected directive nature of functionalized anilines is not known. 3-Aminopyridine derivatives could also be synthesized using the present protocol (Scheme 3) showing that other heteroatoms were also tolerated. In conclusion this study has demonstrated a novel, atom economical, efficient, oxidative aromatization method for the synthesis of N,N-diarylamines and iodo-N,N-diarylamines. Iodination being a viable option for arene derivatization, this method provides the precursors for a host of compounds via transition metal-catalyzed cross-coupling reactions. The mild reaction conditions, operational simplicity and use of readily available reagents, affords a convenient metal-free N-arylation method with utility in medicinal chemistry and for the synthesis of natural product containing nitrogen heterocycles and N-diaryl moieties. Further studies on the applications of this reaction will be disclosed in due course. S.S.D. and P.R. are grateful to Fundaçaõ para a Cieˆncia e Tecnologia, Portugal for grants (BPD/66763/2009) and SFRH/ BD/27423/2006). This work has been supported by Fundaçaõ para a Cieˆncia e a Tecnologia through grants no. PEst-OE/ EQB/LA0004/2011 and PEst-C/EQB/LA0006/2011 and project PTDC/QUI-QUI/104056/2008. The National NMR Network

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