Tetrahedron Letters 52 (2011) 3805–3809

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Tetrahedron Letters

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One step synthesis of azo compounds from nitroaromatics and anilines

Rui Zhao a,c, Chunyan Tan c, Yonghua Xie a,c, Chunmei Gao c, Hongxia Liu c, Yuyang Jiang b,c,⇑a Department of Chemistry, Tsinghua University, Beijing 100084, PR Chinab School of Medicine, Tsinghua University, Beijing 100084, PR Chinac Guangdong Provincial Key Laboratory of Chemical Biology, Graduate School of Shenzhen, Tsinghua University, Shenzhen 518055, PR China

a r t i c l e i n f o

Article history:Received 5 March 2011Revised 6 May 2011Accepted 13 May 2011Available online 19 May 2011

Keywords:Nitro compoundsAnilineAromatic azo compoundAsymmetricRedox reaction

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.05.054

⇑ Corresponding author. Tel.: +7 552 603 6017; faxE-mail address: jiangyy@sz.tsinghua.edu.cn (Y. Jian

a b s t r a c t

A general and efficient method for synthesis of both symmetric and asymmetric aromatic azo compoundsin one single step has been developed. The nitro compounds were reduced and the substituted anilineswere oxidized by each other without any metal in the base condition. Various azo compounds with hal-ogen, methyl and methoxy functional group were obtained by using available, cheap nitro compoundsand substituted anilines. In addition, the electronic effect and substituent effect of the compounds havebeen discussed.

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Aromatic azo compounds are widely used in various fields. Forexample, the azo compounds are used as organic dyes,1 indicators,2

radical reaction initiators,3 and therapeutic4 and drug deliveryagents.5 They are also important units in the area of nonlinearoptics,6 optical storage media,7 chemo sensors,8 photochemicalswitches9 and electronic devices.10 Therefore, synthesis of aromaticazo compounds has attracted great attention. Preparation ofsymmetric aromatic azo compounds are often performed by theoxidation of aromatic amines using stoichiometric amounts ofoxidants including transition metals11 (permanganate, lead tetra-acetate or other metal-containing compounds) and halo oxo acids12

(Eq. 1 in Fig. 1), or by the reduction of nitro aromatics using equiv-alent amounts of metals (Eq. 2 in Fig. 1).13 Recently, several oxida-tion and reduction methods using novel metal catalysts have beendeveloped.14 Examples include a gold-catalyzed oxidation ofanilines and reduction of nitroaromatics,14c,14d reduction of nitro-aromatics by nano-sized iron,14b and Cu-catalyzed oxidation of ani-lines. For synthesis of asymmetric aromatic azo compounds, thecoupling of aryl diazonium salts with electron-rich aromatics is acommon strategy.15 This coupling requires the in situ preparationof a diazonium salt from the oxidation of corresponding aromaticamine with nitrous acid.16 Although these methods above are effec-tive for synthesis of aromatic azo compounds, they do not meet thesustainable and environmentally benign conditions because of useof environmentally unfriendly transition metals or hazardous

ll rights reserved.

: +7 552 603 6018.g).

nitrous acid. Herein, we report a transition metal-free mediatedapproach to aromatic azo compounds via direct couplings of readilyavailable nitroaromatics and substituted anilines (Eq. 3 in Fig. 1).

In order to optimize reaction conditions, 1-chloro-2-nitroben-zene (1c) and 2-methoxybenzenamine (2h) were chosen as themodel substrates, and the effects of bases, solvents and tempera-tures were investigated under nitrogen atmosphere. As shown inTable 1, five bases (10 equiv) (relative to the amount of 1-chloro-2-nitrobenzene) were tested in toluene at 110 �C (entries 1–5),KOH and NaOH provided (E)-1-(2-chlorophenyl)-2-(2-methoxy-phenyl) diazene (3l) in 45% and 25% yields, respectively (entries1 and 2), whereas only trace amount of target product was affordedfor other bases, K2CO3, Cs2CO3 and Et3N (entries 3–5). We alsoscreened different solvents in the presence of KOH (entries 6–10), and DMF gave better yield (44%) (entry 6). Interestingly, theyield was greatly improved to 85% when reaction temperaturewas raised to 150 �C (entry 11), which implied that high tempera-ture could promote the formation of the aromatic azo product.Trace amount of target product was observed in the absence ofbase (entry 12), which means strong base is important. Therefore,the optimal reaction condition for synthesis of aromatic azo com-pounds is as follows: couplings of nitro aromatics and substitutedanilines were carried out at 150 �C under nitrogen atmospherewith 10 equiv of KOH as the base and DMF as the solvent.

We investigated the scope of couplings of nitro aromatics andsubstituted anilines under the optimized condition above. Asshown in Table 2, most of the examined substrates provided goodto excellent yields. The nitroaromatics containing electron-deficient groups showed higher reactivity than those containing

R1

NN

R1R1

NH2

R1

H2N+oxidation

symmetricthe previous method

(1)

R1

NN

R1R1

NO2

R1

O2N+reduction

symmetricthe previous method

(2)

R1

NN

R1R2

NO2

R2

H2N+one step

symmetric and asymmetricour method

(3)

Figure 1. The previous methods (Eq. 1 and 2) and our method (Eq. 3) for synthesis of aromatic azo compounds.

Table 1Optimization of conditions for the synthesis of azo compounda

NO2

Cl1c

H2N

H3CO

2h

base, solventtemp., N2, 16h

+ NN

Cl3l

H3CO

Entry Base Solventb Temp. (�C) Yieldc (%)

1 KOH Toluene 110 452 NaOH Toluene 110 253 K2CO3 Toluene 110 Trace4 Cs2CO3 Toluene 110 Trace5 Et3N Toluene 110 Trace6 KOH DMF 110 447 KOH Dioxane 101 428 KOH DMSO 110 219 KOH H2O 100 0

10 KOH THF 66d 4011 KOH DMF 150 8512 — DMF 150 Trace

a Reaction condition: 1-chloro-2-nitrobenzene (1 mmol), 2-methoxybenzen-amine (3 mmol), base (10 mmol), solvent (5 mL) under nitrogen atmosphere.

b DMSO = dimethylsulfoxide. THF = tetrahydrofuran. DMF = N,N-dimethylform-amide.

c Isolated yield.d Under the reflux of THF (bp 66 �C).

Table 2Synthesis of aromatic azo compoundsa

NO2 H2N+

KOH

150°

1 2

12 -

R1 R2

Entry 1 2 3

1

NO2

OCH3 1a

H2N2a

2 1aH2N

H3C

2b

3806 R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809

electron-rich groups. For example, 1-chloro-2-nitrobenzene (1c),1-chloro-3-nitrobenzene (1d) and 1-iodo-4-nitrobenzene (1e) pro-vided higher yields (more than 74%) (entries 12–20), while 1-methoxy-2-nitrobenzene (1a) and nitrobenzene (1b) gave loweryields (50–79%) (entries 1–11). For the substituted anilines, elec-tronic variation in the substrates, including electron-withdrawing,neutral and electron-donating effects, did not obviously affect theefficiency of the reactions. Aniline gave better yields than thesubstituted anilines when reacting with the same nitroaromaticcompound. Specifically, anilines with methoxy (entries 7, 8 and10), methyl (entry 9) and fluoro groups (entry 11) provided thesimilar yields in the range of 55–70%, whereas the nonsubstitutedaniline which reacted with the same nitrobenzene provided theyield at 90% (Table 2, entry 6). Similar effects can be seen in thereactions with methoxyl-nitrobenzene (entry 1 vs entries 2–5).The coupling reactions could tolerate functional groups includinghalo- (entries 5, 11–20), methyl- (entries 2–4 and 9) and meth-oxy-substitutions (entries 1–5, 7, 8, 10, 12 and 16) in the sub-strates. In addition, the synthesized aromatic azo compoundsshowed most trans-forms, which were identified by NMR spectros-copy, and the trans–cis transformation of some selective com-pounds under UV/Vis was discussed (see Supplementary data).

In order to explore the reaction mechanism for synthesis of aro-matic azo compounds, we performed the following control exper-iments under our standard condition as shown in Scheme 1. As a

NN

, DMF

C, N2

3

48 h

R1

R2

Reaction time (h) Yieldb (%)

NN

OCH3 3a

36 68

NN

OCH3

H3C

3b

32 60

Table 2 (continued)

Entry 1 2 3 Reaction time (h) Yieldb (%)

3 1aH2N

CH3

2c NN

OCH3

CH3

3c

32 50

4 1a

H2N CH32d N

N

OCH3

CH3

3d

30 50

5 1aH2N

F

2e NN

OCH3

F

3e

28 56

6NO2

1b 2a NN

3f12 90

7 1b H2N

OCH3

2f NN

OCH3

3g

24 55

8 1bH2N OCH3

2g NN OCH3

3h24 70

9 1b 2bNN

H3C

3i

24 56

10 1b H2N

H3CO

2h NN

H3CO

3j

24 70

11 1b H2N

F

2i NN

F

3k

18 65

12

NO2

Cl 1c 2h NN

Cl

H3CO

3l

16 85

13 1c 2i NN

Cl

F

3m

14 88

14 1cH2N

Cl

2j NN

Cl

Cl

3n

14 93

15 1c

H2N OCF3 2k N

N

Cl

OCF3

3o

12 95

(continued on next page)

R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809 3807

Table 2 (continued)

Entry 1 2 3 Reaction time (h) Yieldb (%)

16 1c 2f NN

Cl

OCH3

3p

18 88

17 1cH2N

Br

2l NN

Cl

Br

3q

14 90

18

NO2

Cl 1d 2i NN

F

Cl 3r

12 92

19 1c H2N

HNO

2mNN

Cl

NH2

3s

14 74

20NO2I

1eH2N I

2n NN I

I3t

16 80

a Reaction condition: reaction temperature (150 �C), nitroaromatic (1 mmol), aniline (3 mmol), KOH (10 mmol), DMF (5 mL) under nitrogen atmosphere.b Isolated yields.

NN

O-

yield < 10%

++

NNNO H2N+

KOH, DMF

150 °C, N2

150 °C, N2

5 2a 3f16 h

NN

KOH, DMF

3f16h

H2N

4 2a

yield 96%

(1)

(2)

Scheme 1. Reactions of (4) or (5) with aniline (2a) under the standard condition.

H2O

KOH

R1

NN

R1R2

N

1

3

O

O-+

R2

H2N

2

R1

NO

OH

HN

R2I

R1

NO

HOHN

R2

III

R2

H2N

2

R1

NOH

R2

NH

IV

II

Scheme 2. Possible mechanism for the synthesis of aromatic azo compounds.

3808 R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809

result, reaction of azoxybenzene (4) with aniline only producedsmall amount of 1,2-diphenyldiazene (3f) (less than 10% yield)(Eq. 1 in Scheme 1), while coupling of nitrosobenzene (5) with ani-line provided the corresponding azo product (3h) in 96% yield (Eq.2 in Scheme 1). This indicated that nitrosobenzene intermediate

could appear during reactions of nitroaromatics and substitutedanilines under the standard condition.

Furthermore, we used GC–MS to analyze the mixture of reac-tion solution from coupling of nitrobenzene with aniline, and amass spectral peak at m/z 107 corresponding to the molecular

R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809 3809

ion of nitrosobenzene was observed (see Supplementary data).Therefore, a possible mechanism for synthesis of both aromaticazo compounds is suggested in Scheme 2. Nucleophilic attack ofamino group on the aniline (2) to nitro group on the nitroaromatic(1) firstly formed intermediate I in the presence of base (KOH), andcleavage of I under heating produced nitroso compound III in thesimilar fashion reported before.17 The coupling of nitrosobenzeneand aniline then provided the target product (3) by nucleophilic at-tack to form intermediate IV and dehydration.

In summary, we have developed a simple, general and efficientKOH-promoted method for synthesis of both symmetric and asym-metric aromatic azo compounds via direct couplings of readilyavailable nitroaromatics and substituted anilines, and the corre-sponding target products were obtained in good to excellent yields.The method is of tolerance toward functional groups in the sub-strates. It avoids the use of environmentally unfriendly transitionmetals and hazardous nitrous acid. Therefore, this convenientand practical approach is anticipated to attract much attention.

Acknowledgments

We would like to thank the financial support which was pro-vided by the Ministry of Science and Technology of China(2009ZX09501-004), the National Natural Science Foundation ofChina (Grant No. 20872077 and 90813013) and Shenzhen Sci. &Tech. Bureau.

Supplementary data

Supplementary data (experimental procedures and full spectro-scopic data for all compounds) associated with this article can befound, in the online version, at doi:10.1016/j.tetlet.2011.05.054.

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