One step synthesis of azo compounds from nitroaromatics and anilines
Transcript of One step synthesis of azo compounds from nitroaromatics and anilines
Tetrahedron Letters 52 (2011) 3805–3809
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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: [email protected] (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
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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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