This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10901–10903 10901

Cite this: Chem. Commun., 2012, 48, 10901–10903

Metal-free direct amination/aromatization of 2-cyclohexenones

to iodo-N-arylanilines and N-arylanilines promoted by iodinew

M. Teresa Barros,aSuvendu S. Dey,

aChristopher D. Maycock*

bcand Paula Rodrigues

b

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 occur-

rence and application of N-arylated amines in various fields,2

the synthesis of these compounds, especially the N-aryl-

anilines, is often difficult without metal catalysis. During the

last decade, some transition metal free syntheses of N-phenyl-

anilines 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 synthesis-

ing 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 knowl-

edge, iodine catalyzed direct amination/aromatization of 2-cyclo-

hexenones 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,cHerein we report a

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 mole-

cular 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-fluoro-

aniline 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-bromo-

4-fluoro-N-(4-iodophenyl)aniline (1) and 2-bromo-4-fluoro-

N-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 usingN-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 electron-

withdrawing and electron-donating substituents on the aryl ring of

the anilines were tolerated. Importantly, functional groups such as

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

a Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa,Monte da Caparica, Portugal

b Instituto de Tecnologia Quımica e Biologia, Universidade Nova deLisboa, 2780-157, Oeiras, Portugal. E-mail: maycock@itqb.unl.pt

c Departamento de Quımica e Bioquımica, Faculdade de Ciencias,Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugalw Electronic supplementary information (ESI) available. See DOI:10.1039/c2cc35801h

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10902 Chem. Commun., 2012, 48, 10901–10903 This journal is c The Royal Society of Chemistry 2012

I, Cl, Br, F, CF3, were compatible with the optimal reaction

conditions, hence providing a means for additional modifica-

tions at the halogenated positions. A variety of substituted

2-cyclohexenones also underwent aromatization, followed by

iodination, efficiently producing the predicted products in

good yields. In accordance with previous reports7 para-

iodination dominated and in most cases substitution took

place regioselectively at the ring corresponding to the cyclo-

hexenone 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- ormeta-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 corre-

sponding 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 ortho-

substituted 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

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, 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.

Table 2 Substrate scope for the preparation of 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.Dow

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10901–10903 10903

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 hetero-

atoms 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 andN-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 Fundacao para a Ciencia e

Tecnologia, Portugal for grants (BPD/66763/2009) and SFRH/

BD/27423/2006). This work has been supported by Fundacao

para a Ciencia 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

(REDE/1517/RMN/2005), is supported by POCI 2010 and

Fundacao para a Ciencia e a Tecnologia.

Notes and references

1 The RawMaterials Initiative –Meeting our critical needs for the growthand jobs in Europe, Commission of the European Communities,Brussels COM 2008, 699.

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Scheme 3 N-arylation of 3-aminopyridine derivatives.

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