A practical synthesis of azobenzenes through oxidative dimerization of aromatic amines using tert-butyl hypoiodite

Article abstract of DOI:10.1055/s-0032-1318388

A straightforward, convenient, and efficient synthetic method of azobenzenes through oxidative dimerization of aromatic amines using a unique and cost-effective iodinating reagent is described. This new method allows for easy access to both of symmetrical and unsymmetrical azobenzenes under extremely mild conditions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1318388

PRACTICAL SYNTHETIC PROCEDURES
▌1029
pAracPticarlasycntthiecticaplroSceydunresthesis of Azobenzenes through Oxidative Dimerization of
Aromatic Amines Using tert-Butyl Hypoiodite
A Practical Synthesis of Azobenzenes
Youhei Takeda,a,b Sota Okumura,b Satoshi Minakata*b
a
Frontier Research Base for Young Researchers, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871,
Japan
b
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1,
Suita, Osaka 565-0871, Japan
Fax +81(6)68797402; E-mail: minakata@chem.eng.osaka-u.ac.jp
PSP
Received: 22.01.2013; Accepted after revision: 15.02.2013
No247
Abstract: A straightforward, convenient, and efficient synthetic method of azobenzenes through oxidative dimerization of aromatic amines
using a unique and cost-effective iodinating reagent is described. This new method allows for easy access to both of symmetrical and un-
symmetrical azobenzenes under extremely mild conditions.
Key words: amines, azo compounds, dimerization, iodine, oxidation
procedure 1: synthesis of symmetrical azobenzenes
t-BuOCl (2.0 equiv)
NH2
R
NaI (2.0 equiv)
N
R
N
–20 °C to r.t.
19 examples, 44–97%
R
procedure 2: synthesis of unsymmetrical azobenzenes
t-BuOCl (4.0 equiv)
R2
NH2
R2
NaI (4.0 equiv)
N
R1
+
N
H2N
R1
–20 °C to r.t.
15 examples, 47–72%
Scheme 1 General procedures for the synthesis of symmetrical (Procedure 1) and unsymmetrical (Procedure 2) azobenzenes from anilines
coupling6 and the Mills reaction7 have been extensively
Introduction
used. Nevertheless, in these reactions, explosive or toxic
Aromatic azo compounds, namely, azobenzenes consti- starting materials must be prepared from commercially
tute a large class of organic dyes in industry.1 Additionally, available compounds. More specifically, the main issue
light-sensitivity of azobenzenes (i.e., photoisomerization lies in the substrate scope, which is exclusively restricted
between trans- and cis-isomers)2 offers the opportunities to the combination of electron-rich and -deficient aromat-
for the creation of photoresponsive soft materials such as ic substrates. In this regard, recently, two catalytic oxida-
smart polymers, liquid crystals, and photoswitches in bio- tive dimerization reactions of aromatic amines have been
logical systems.3 From a synthetic viewpoint, among the independently developed by García8 and Jiao groups.9 Al-
conventional methods used for symmetrical azoben- though both methods succeeded in preparing a series of
zenes,4 the oxidative homodimerization of aromatic unsymmetrical azobenzenes, there still remains consider-
amines is a straightforward approach and advantageous in able room for improving the reaction conditions, such as
terms of availability of starting materials. However, these lowering the reaction temperature or reducing the use of
methods suffer from the use of environmentally unfriendly excess amounts of reagents. As a part of our program to
heavy-metal salts as an oxidant, such as BaMnO4,5a develop efficient synthetic methods of nitrogen-contain-
Pb(OAc)4,5b and HgO.5c On the other hand, for the prepa- ing compounds by utilizing a unique iodinating reagent,
ration of unsymmetrical azobenzenes, diazonium tert-butyl hypoiodite (t-BuOI),10 we have recently report-
ed an efficient, less-energy-consuming, and metal-free
synthetic method of azobenzenes through oxidative di-
SYNTHESIS 2013, 45, 1029–1033
Advanced online publication: 07.03.2013
merization of aromatic amines (Scheme 1).11 The method
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318388; Art ID: SS-2013-Z0070-PSP
© Georg Thieme Verlag Stuttgart · New York
allows for synthesizing not only symmetrical azoben-

1030
Y. Takeda et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Synthesis of Symmetrical Azobenzenes 2a (continued)
zenes (Procedure 1 in Scheme 1) but also unsymmetrical
types in a selective manner (Procedure 2 in Scheme 1).
Herein we wish to describe our practical procedures for
preparing a series of azobenzenes using the combination
of inexpensive and easy to handle reagents, tert-butyl hy-
pochlorite (t-BuOCl) and NaI as the precursors of t-BuOI.
Entry
7
ArNH2 1
1g FG = I
Conditions
Product 2 Yield (%)b
Et2O
–20 °C, 12 h
2gg
2hh
2ii
88
95
91
89
79
Et2O
25 °C, 3 h
8
1h FG = CO2Et
1i FG = Ac
Scope and Limitations
Et2O
–20 °C, 12 h
9
A typical procedure for the homodimerization (Procedure
1 in Scheme 1) of aromatic amines is as follows: t-BuOCl
(1.0 mmol) was added to a solution of aromatic amine (0.5
mmol) and NaI (1.0 mmol), and the resulting mixture was
stirred for the time indicated in Table 1. The simplest aro-
matic amine, aniline (1a), was efficiently converted into
azobenezne (2aa) in one hour at room temperature (entry
1). Symmetrical azobenzenes bearing the 4,4′-difunction-
alities were synthesized in high to excellent yields from
para-substituted anilines 1b–1k, regardless of their elec-
tronic structures (entries 2–11). It should be noted that
aromatic iodination did not occur, even though electroni-
cally rich aniline 1c was used in the presence of iodonium
cation (I+) equivalent reagent. Anilines that have a meta-
substituent 1l and 1m also afforded the corresponding
azobenzenes 2ll and 2mm in high yields (Table 1, entries
12 and 13). Remarkably, aniline 1n bearing a sterically
demanding substituent at the ortho-position was also con-
verted into the corresponding azobenzene 2nn, albeit in
moderate yield (entry 14). Using this method, a variety of
symmetrical azobenzenes 2oo–2rr were successfully pre-
pared in high yields (entries 15–18). Notably, heteroaro-
matic amine 1s also served as a substrate for the oxidative
homodimerization to afford the multiple heteroatom-in-
corporated azo product 2ss in 72% yield (entry 19).
THF
25 °C, 12 h
10
11c
1j FG = CN
1k FG = NO2
2jj
THF
25 °C, 6 h
2kk
FG
NH2
acetone
25 °C, 3 h
12
13
1l FG = Cl
2ll
86
78
THF
–20 °C, 12 h
1m FG = NO2
2mm
FG
NH2
Et2O
–20 °C, 36 h
14
15
1n FG = Ph
2nn
2oo
44
73
Et2O
25 °C, 24 h
1o FG = CN
NH2
Et2O
25 °C, 1 h
16
17
2pp
2qq
89
94
1p
F3C
NH2
Table 1 Synthesis of Symmetrical Azobenzenes 2a
Entry
1
ArNH2 1
Conditions
Product 2 Yield (%)b
THF
25 °C, 12 h
CF3
NH2
1q
F
MeCN
25 °C, 1 h
2aa
95
F
NH2
F
1a
Et2O
25 °C, 12 h
NH2
18
19
2rr
2ss
67
72
F
F
S
FG
1r
Et2O
25 °C, 1 h
NH2
2
3
4
5
6
1b FG = Me
2bb
2cc
2dd
2ee
2ff
97
87
95
96
83
N
MeCN
25 °C, 48 h
MeCN
25 °C, 0.25 h
1c FG = OMe
1d FG = F
acetone
25 °C, 6 h
1s
a Reaction conditions: aromatic amine 1 (0.5 mmol), t-BuOCl (1.0
mmol), NaI (1.0 mmol), and solvent (3 mL).
b Isolated yield.
Et2O
–20 °C, 12 h
1e FG = Cl
1f FG = Br
c t-BuOCl (2 mmol) and NaI (2 mmol) were used.
acetone
25 °C, 3 h
Synthesis 2013, 45, 1029–1033
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Practical Synthesis of Azobenzenes
1031
Table 2 Synthesis of Unsymmetrical Azobenzenes 2a
To demonstrate the power of this synthetic method, a
large-scale preparation of azobenzene 2hh was performed
(Scheme 2). From a 10 mmol (1.65 g) of ethyl 4-amino-
benzoate (1h), the desired product 2hh was successfully
synthesized in gram-scale (1.51 g, 93%) without any sig-
nificant loss of reaction efficiency, compared with the
small-scale (0.5 mmol) preparation (Table 1, entry 8,).
Entry 1
Condi-
tions
Product 2
Yield
(%)b
CO2Et
NO2
Ac
THF
6 h
N
N
1
1b + 1h 0 °C
62
CO2Et
t-BuOCl (20 mmol)
NaI (20 mmol)
NH2
2bh
2bk
N
Et2O (60 mL)
25 °C, 3 h
N
EtO2C
THF
N
EtO2C
0 °C, 3 h
then 25 °C,
1 h
N
1h
(10 mmol, 1.65 g)
2hh
(1.51 g, 93%)
2
1b + 1k
64
58
Scheme 2 Large-scale synthesis of 2hh
The notable feature of this oxidative dimerization method
is the feasibility of selective synthesis of unsymmetrical
azobenzenes (Procedure 2 in Scheme 1). The scope of the
cross-dimerization of aromatic amines is shown in Table
2. When an equimolar THF solution of p-toluidine (1b;
0.25 mmol) and ethyl 4-aminobenzoate (1h; 0.25 mmol)
was treated with t-BuOCl (1.0 mmol) in the presence of
NaI (1.0 mmol) at 0 °C, cross-dimerized product 2bh was
formed in a selective manner (62%) over the homodimers
2bb and 2hh (Table 2, entry 1).12 These azobenzenes were
easily separated by silica gel column chromatography.
Cross-dimerization of 1b with anilines bearing electron-
deficient functionalities proceeded smoothly, affording
unsymmetrical azobenzenes 2bk–2bq in good yields (en-
tries 2–6). Notably, this method allowed for the efficient
access to unsymmetrical azobenzenes possessing elec-
tron-deficient moieties on the phenyl ring that are other-
wise difficult to prepare by conventional method (entries
7–14). Furthermore, unsymmetrical azobenzenes that has
a heteroaromatic component was also selectively synthe-
sized in moderate yield (entry 15). In the case of the com-
bination of electron-rich anilines, cross-dimerization
failed, and homodimers were the major products. Al-
though the precise mechanism of the oxidative dimeriza-
tion is unclear at present, a tentative mechanism is as
follows: 1) the electronically richer aniline is doubly N-io-
dinated through the agency of halogen bonding between
t-BuOI and Ar1NH2; 2) nucleophilic substitution on the N-
center of Ar1NI2 by the remaining Ar2NH2 proceeds to
form the N–N single bond; 3) then HI is eliminated from
the resulting N,N′-diarylhydrazine to give azo products.
The limitation in the cross-dimerization of electron-rich
anilines might be ascribed to the existence of equilibrium
between ArNH2 and ArNI2, leading to the scrambling of
homo-dimers.
N
N
N
THF
1b + 1i –20 °C
N
N
N
3c
24 h
2bi
acetone
1b + 1l 0 °C
3 h
Cl
4
5
52
60
2bl
THF
1b + 1m –20 °C
24 h
NO2
2bm
CF3
THF
1b + 1q 25 °C
12 h
N
6
7
66
54
N
CF3
2bq
Ac
N
THF
1a + 1i 25 °C
12 h
N
2ai
NO2
N
MeCN
1i + 1k –20 °C
24 h
N
8
9
72
61
Ac
2ik
Ac
DME
1d + 1i 25 °C
3 h
N
N
F
2di
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1029–1033

1032
Y. Takeda et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Synthesis of Unsymmetrical Azobenzenes 2a (continued)
challenge for a long time. Moreover, the practical utility
of the method was further demonstrated by gram-scale
synthesis.
Entry 1
Condi-
tions
Product 2
Yield
(%)b
Ac
Melting points were determined on a Stanford Research Systems
MPA100 OptiMelt Automated Melting Point System. IR spectra
were recorded on a Shimadzu IR Affinity-1 FT-IR spectrometer. 1H
and 13C NMR spectra were recorded on a Jeol FT-NMR JNM EX
270 spectrometer (1H NMR, 270 MHz; 13C NMR, 68 MHz) using
TMS as an internal standard. 19F NMR spectra were recorded on a
Bruker Avance III 400 spectrometer (19F NMR, 376 MHz) using
benzotrifluoride as an internal standard. Mass spectra were obtained
on a Jeol JMS-DX303HF mass spectrometer. High-resolution mass
spectra were obtained on a Jeol JMS-DX303HF mass spectrometer.
Products were purified by chromatography on silica gel BW-300
(Fuji Silysia Chemical Ltd.) or Al2O3 (Merck, 90 active stage I,
0.063–0.200 mm). Analytical TLC was performed on pre-coated
silica gel glass plates (Merck silica gel 60 F254, 0.25 mm thickness).
Compounds were visualized with UV lamp or treatment with an
ethanolic solution of phosphomolybdic acid followed by heating.
MeCN
18 h
N
N
10
1e + 1i 0 °C
65
Cl
2ei
Ac
N
DME
1f + 1i –20 °C
24 h
N
11
12
58
53
Br
2fi
Ac
N
THF
1g + 1i 25 °C
12 h
N
(E)-1,2-Diphenyldiazene (2aa); Typical Procedure for Symmet-
rical Azobenzenes (Procedure 1 in Scheme 1)
I
To a mixture of aniline (1a; 46.6 mg, 0.5 mmol) and NaI (150.0 mg,
1.0 mmol) in MeCN (3 mL) was added t-BuOCl (108.6 mg, 1.0
mmol) under the N2 atmosphere at 25 °C. The mixture was stirred
for 1 h, quenched with aq Na2S2O3 (1.0 M, 10 mL), and extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
(Na2SO4) and concentrated under vacuum to give the crude product.
Purification by flash column chromatography on silica gel (eluent:
hexane–EtOAc, 99:1) gave 2aa9 (43.0 mg, 95%) as a yellow solid;
mp 67–68 °C; Rf = 0.53 (hexane–EtOAc, 9:1).
2gi
CF3
MeCN
1i + 1q –20 °C
24 h
N
13
63
N
N
CF3
Ac
IR (ATR): 1580, 1481, 1450, 1298, 1068, 926, 773 cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.41–7.53 (m, 6 H), 7.89–7.94 (m,
2iq
NO2
4 H).
MeCN
N
13C NMR (68 MHz, CDCl3): δ = 122.7, 129.0, 130.9, 152.5.
MS (EI, 70 eV): m/z (%) = 182 (57, [M]+), 77 (100), 105 (26).
HRMS (EI): m/z [M]+ calcd for C12H10N2: 182.0844; found:
14d 1h + 1k 0 °C
66
47
24 h
EtO2C
2hk
182.0841.
S
Ethyl (E)-(p-Tolyldiazenyl)benzoate (2bh); Typical Procedure
for Unsymmetrical Azobenzenes (Procedure 2 in Scheme 1)
To a mixture of p-toluidine (1b; 26.8 mg, 0.25 mmol), ethyl 4-ami-
nobenzoate (1h; 41.3 mg, 0.25 mmol), and NaI (150.0 mg, 1.0
mmol) in THF (3 mL) was added t-BuOCl (108.6 mg, 1.0 mmol)
under the N2 atmosphere at 0 °C. The mixture was stirred for 6 h,
quenched with aq Na2S2O3 (1.0 M, 10 mL), and extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
(Na2SO4) and concentrated under vacuum to give the crude product.
Purification by flash column chromatography on silica gel (eluent:
hexane–EtOAc, gradient from 99:1 to 70:30) gave 2bh9 (41.3 mg,
62%) as a yellow solid; mp 100–101 °C; Rf = 0.43 (hexane–EtOAc,
9:1).
MeCN
N
N
15e 1b + 1s 25 °C
N
12 h
2bs
a Reaction conditions: two different aromatic amines 1 (0.25 mmol for
each), t-BuOCl (1.0 mmol), NaI (1.0 mmol), and the solvent (3 mL).
b Isolated yield.
c Anilines 1b (0.5 mmol) and 1i (0.25 mmol), t-BuOCl (1.5 mmol),
and NaI (1.5 mmol) were used.
d Anilines 1h (0.25 mmol) and 1k (0.5 mmol), t-BuOCl (1.5 mmol),
and NaI (1.5 mmol) were used.
e Anilines 1b (0.5 mmol) and 1s (0.5 mmol), t-BuOCl (2.0 mmol), and
NaI (2.0 mmol) were used.
IR (ATR): 2922, 1715, 1601, 1265, 1103, 1094, 1008, 866, 822,
773, 709 cm–1.
1H NMR (270 MHz, CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 2.45 (s,
3 H), 4.42 (q, J = 7.0 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.87 (d, J =
8.4 Hz, 2 H), 7.92 (d, J = 8.6 Hz, 2 H), 8.19 (d, J = 8.6 Hz, 2 H).
13C NMR (68 MHz, CDCl3): δ = 14.4, 21.6, 61.2, 122.4, 123.1,
129.7, 130.4, 131.8, 142.3, 150.6, 155.1, 165.9.
MS (EI, 70 eV): m/z (%) = 268 (53, [M]+), 91 (100), 119 (33), 149
(25).
HRMS (EI): m/z [M]+ calcd for C16H16N2O2: 268.1212; found:
268.1214.
In summary, a straightforward, efficient, and cost-effec-
tive synthetic procedure of azobenzenes has been devel-
oped. The method was successfully applied to a wide
variety of readily available aromatic amines. Further-
more, by using this method, unsymmetrical azobenzenes
were selectively synthesized over homodimerized prod-
ucts under mild conditions, which has been a synthetic
Synthesis 2013, 45, 1029–1033
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Acknowledgment
A Practical Synthesis of Azobenzenes
1033
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This research was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’ from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan. One of the au-
thors (Y.T.) would like to acknowledge the support from the
Frontier Research Base for Global Young Researchers, Osaka Uni-
versity, based on the Program of MEXT.
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Supporting Information for this article is available online at
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n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1029–1033