Palladium-catalyzed regioselective halogenation of aromatic azo compounds

Article abstract of DOI:10.1002/adsc.201200902

A highly regioselective halogenation reaction of symmetrical and unsymmetrical aromatic azo compounds has been developed at room temperature or at 50 °C. In the presence of 5 mol% palladium diacetate and 0.5 equiv. of p-toluenesulfonic acid, a range of symmetrical aromatic azo compounds smoothly undergo monobromination with N-bromosuccinimide to give the corresponding unsymmetrical aromatic azo compounds in good to excellent yields with >99:1 ortho-selectivity. This chemistry has been successfully extended to unsymmetrical aromatic azo compounds, whose electronricher aryl groups prefer to be monobrominated. Moreover, replacing N-bromosuccinimide with Niodosuccinimide in the reaction allows the synthesis of monoiodinated aromatic azo compounds with >99:1 regioselectivity.

Full text of DOI:10.1002/adsc.201200902

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DOI: 10.1002/adsc.201200902
Palladium-Catalyzed Regioselective Halogenation of Aromatic
Azo Compounds
Xian-Tao Maa and Shi-Kai Tiana,b,*
a
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, Peopleꢀs Republic of China
Fax : (+86) 0551-3601592; e-mail: tiansk@ustc.edu.cn
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: October 8, 2012; Revised: December 3, 2012; Published online: January 25, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200902.
Abstract: A highly regioselective halogenation reac-
tion of symmetrical and unsymmetrical aromatic
azo compounds has been developed at room tem-
perature or at 508C. In the presence of 5 mol% pal-
ladium diacetate and 0.5 equiv. of p-toluenesulfonic
acid, a range of symmetrical aromatic azo com-
pounds smoothly undergo monobromination with
N-bromosuccinimide to give the corresponding un-
symmetrical aromatic azo compounds in good to
excellent yields with >99:1 ortho-selectivity. This
chemistry has been successfully extended to unsym-
metrical aromatic azo compounds, whose electron-
richer aryl groups prefer to be monobrominated.
Moreover, replacing N-bromosuccinimide with N-
iodosuccinimide in the reaction allows the synthesis
of monoiodinated aromatic azo compounds with
>99:1 regioselectivity.
amines[4] have recently been developed for the syn-
thesis of unsymmetrical aromatic azo compounds,
they require high temperature, high pressure, excess
reactants/reagents, and/or strong bases, and moreover,
suffer from a narrow substrate scope.
Since symmetrical aromatic azo compounds are
readily accessible, their monofunctionalization would
constitute a promising strategy for the synthesis of un-
symmetrical aromatic azo compounds. Early studies
have shown that treatment of aromatic azo com-
pounds with a stoichiometric amount of palladium
leads to the formation of carbon-palladium bonds,
which can be further transformed into carbon-carbon
and carbon-heteroatom bonds.[5] Although in recent
years palladium,[6] ruthenium,[7] and rhodium[8] have
been found to catalyze the monofunctionalization of
two symmetrical aromatic azo compounds, diphenyl-
diazene and diACHTUNTRGNEUNG(m-tolyl)diazene, the reactions require
Keywords: aromatic azo compounds; bromination;
iodination; palladium; regioselectivity
a temperature equal or higher than 1008C and the
yields are unsatisfactory (ꢀ62%). Particularly,
a single example for the monoiodination of diACHTUNGTRENNUNG(m-tol-
yl)diazene has been reported by Sanford and co-
workers to proceed at 100–1208C and give the ortho-
iodinated product in 41% yield.[6b] Here we report an
Owing to their unique structure, aromatic azo com- efficient palladium-catalyzed regioselective halogena-
pounds are able to serve as food additives, therapeutic tion reaction of symmetrical and unsymmetrical azo
agents, indicators, dyes, pigments, and light-responsive compounds at room temperature or at 508C.[9] Impor-
functional materials.[1] In this context, much attention tantly, this study provides an easy access to function-
has been paid to the synthesis of aromatic azo com- alized unsymmetrical azo compounds from readily ac-
pounds. In general, symmetrical aromatic azo com- cessible starting materials under mild reaction condi-
pounds are readily accessible through reduction of ni- tions.
troarenes and oxidation of aromatic amines, and the
unsymmetrical ones are prepared by diazo coupling (1a) with N-bromosuccinimide (NBS) did not occur in
and the Mills reaction, which, however, require reac- the presence of 5 mol% Pd(OAc)2 in acetonitrile at
Initially, the model reaction of diphenyldiazene
AHCTUNGTRENNUNG
tive intermediates (diazonium salts and nitroso com- room temperature (Table 1, entry 1). We attempted to
pounds) and suffer from a narrow substrate scope due promote the reaction with Brønsted acids that were
to their intrinsic reaction mechanisms.[2] Although the reported previously to be capable of changing the
oxidative cross-dimerization of aromatic amines[3] and electrophilicity of the palladium(II) catalyst[10] and
the cross-coupling of nitroarenes with aromatic render NBS a more effective source of Br+ via proto-
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337

Xian-Tao Ma and Shi-Kai Tian
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Regioselective monobromination of aromatic azo
compounds.[a]
[a]
Reaction azo
conditions:
aromatic
compound
1 (0.30 mmol), NBS (0.36 mmol), PdACHTUNTGREN(NUGN OAc)2 (5 mol%),
TsOH (0.15 mmol), acetonitrile (1.0 mL), room tempera-
ture, 10 h.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
The reaction was run at 508C.
[a]
The reaction was run in toluene at 508C.
The reaction was run in 1,2-dichloroethane for 20 h.
The reaction was run with 1.0 equiv of NBS in nitrome-
thane.
Reaction conditions: aromatic azo compound 1a
(0.30 mmol), NBS (0.36 mmol), Pd source (5 mol%), acid
(if any, 0.5 equiv.), solvent (1.0 mL), room temperature,
10 h.
[b]
Isolated yield.
nation of the carbonyl group.[9h,11] Indeed, the reaction yields with >99:1 ortho-selectivity (determined by
was dramatically affected by the structure of the 1H NMR spectroscopic analysis) (Table 2, entries 1–
Brønsted acids (Table 1, entries 2–5) and, to our de- 10). It is noteworthy that the reaction tolerated a vari-
light, the use of p-toluenesulfonic acid (0.5 equiv.) led ety of functional groups such as fluoro, chloro, bromo,
to the formation of aromatic azo compound 2a as and ester. In a few cases acetonitrile was replaced
a single regioisomer in 90% yield (Table 1, entry 5). with 1,2-dichloroethane, toluene, and nitromethane in
Since Pd
MeCN) could be formed as the actual catalyst from matic azo compounds (Table 2, entries 4–6 and 10).
Pd
(OAc)2 and excess p-toluenesulfonic acid,[9h,l,12] we Relatively lower yields were obtained in some cases
examined this palladium source and found that the re- owing to dibromination (Table 2, entries 4, 5, 7, 9, and
action gave comparable yield (89%, Table 1, 10). This chemistry was successfully extended to un-
entry 6). In sharp contrast to Pd(OAc)2, Pd(OTs)2 symmetrical aromatic azo compounds, whose elec-
ACHTUNGTRENNUNG(OTs)2 (with two solvent molecules of order to provide better solubility for the starting aro-
ACHTUNGTRENNUNG
a
A
ACHTUNGTRENNUNG
itself was capable of catalyzing the reaction in the ab- tron-richer aryl groups preferred to undergo mono-
sence of p-toluenesulfonic acid to give the desired bromination with >99:1 regioselectivity. For example,
product in 72% yield (Table 1, entry 7). Replacing the phenyl group in unsymmetrical aromatic azo com-
Pd
[Pd
or even resulted in no desired product at all (Table 1, (Table 2, entry 11).
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
entries 8–10). Moreover, no better yield was obtained
The regioselectivity could be switched when
by employing a common organic solvents other than a strong electron-donating group was introduced into
acetonitrile (Table 1, entries 11–18).
the aromatic ring of an aromatic azo compound. For
In the presence of 5 mol% Pd(OAc)2 and 0.5 equiv. example, the 4-methoxyphenyl group in unsymmetri-
AHCTUNGTRENNUNG
of p-toluenesulfonic acid, a range of symmetrical aro- cal aromatic azo compound 1l was preferentially mon-
matic azo compounds smoothly underwent monobro- obrominated to give product 3 as a single regioisomer
mination with NBS in acetonitrile at room tempera- in 72% yield (Scheme 1).[13] A control experiment was
ture or at 508C to give the corresponding unsymmet- performed without Pd
ACHTUNGRTEN(NUNG OAc)2 and the same product
rical aromatic azo compounds in good to excellent was obtained in 78% yield. These results indicate that
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Palladium-Catalyzed Regioselective Halogenation of Aromatic Azo Compounds
Scheme 1. Monobromination of aromatic azo compound 1l.
the methoxy group in substrate 1l completely over-
rides the azo group with regard to the ability to direct
monobromination under the standard reaction condi-
tions.
Replacing NBS with N-iodosuccinimide (NIS) in
the aforementioned reaction allowed us to obtain
Scheme 2. Proposed catalytic cycle.
a range of monoiodinated aromatic azo compounds in
good to excellent yields with >99:1 ortho-selectivity
(Table 3).[14] A variety of functional groups such as p-toluenesulfonic acid results in the formation of the
fluoro, chloro, and ester could be introduced into the actual catalyst, PdACHTNUGRTNEUNG
(OTs)2,[12a] which is attacked by aro-
unsymmetrical aromatic azo compounds. Moreover, matic azo compound 1 to give palladacycle 5. Oxida-
the monoiodination with an unsymmetrical aromatic tive addition of NBS (or NIS), activated by p-toluene-
azo compound occurred readily at the unsubstituted sulfonic acid,[9h,11] to palladacycle 5 leads to the forma-
phenyl ring rather than at the phenyl ring bearing an tion of Pd(IV) complex 6,[9c,15] which undergoes reduc-
electron-withdrawing substitutent (Table 3, entries 7 tive elimination to give product 2 (or 4) and mean-
and 8).
while release Pd(II) species 7. Displacement of Pd(II)
by p-toluenesulfonic acid regenerates
(OTs)2 to continue the catalytic cycle.
In summary, we have provided an easy access to
Based on our results and previous studies on the species
7
palladium-catalyzed ortho-halogenation of aromatic PdACHTUNGTRENNUNG
compounds,[6b,9c,i,l] we propose the catalytic cycle de-
picted in Scheme 2 for the ortho-halogenation of aro- functionalized unsymmetrical aromatic azo com-
matic azo compounds. Displacement of PdACTHUNGTRENNUNG
AHCTUNGTRENNUNG
Table 3. Regioselective monoiodination of aromatic azo
acid, a range of symmetrical aromatic azo compounds
smoothly undergo monobromination with N-bromo-
succinimide at room temperature or at 508C to give
the corresponding unsymmetrical aromatic azo com-
pounds in good to excellent yields with >99:1 ortho-
selectivity. This chemistry has been successfully ex-
tended to unsymmetrical aromatic azo compounds,
whose electron-richer aryl groups prefer to be mono-
brominated. Moreover, replacing N-bromosuccin-
compounds.[a]
AHCTUNGTREGiNNUN mide with N-iodosuccinimide in the reaction allows
the synthesis of monoiodinated aromatic azo com-
pounds with>99:1 regioselectivity.
Experimental Section
[a]
Reaction azo
conditions:
aromatic
compound
1 (0.30 mmol), NIS (0.36 mmol), PdACHTUNTGREN(NUGN OAc)2 (5 mol%),
TsOH (0.15 mmol), acetonitrile (1.0 mL), room tempera-
ture, 20 h.
General Procedure for the Palladium-Catalyzed
Regioselective Halogenation of Aromatic Azo
Compounds
[b]
[c]
[d]
Isolated yield.
The reaction was run at 508C.
The reaction was run in nitromethane at 508C.
A mixture of aromatic azo compound 1 (0.30 mmol),
PdACTHNUTRGEN(NUG OAc)2 (3.4 mg, 0.015 mmol), NXS (X=Br or I,
Adv. Synth. Catal. 2013, 355, 337 – 340
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339

Xian-Tao Ma and Shi-Kai Tian
COMMUNICATIONS
0.36 mmol), and TsOH·H2O (28.5 mg, 0.15 mmol) in aceto-
nitrile (1.0 mL) was stirred at room temperature or 508C for
10 or 20 h as specified in Table 2 and Table 3. The mixture
was purified by flash column chromatography on silica gel,
eluting with ethyl acetate/petroleum ether (0~10:1), to give
compound 2 or 4.
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We are grateful for the financial support from the National
Natural Science Foundation of China (21232007, 21172206,
and 20972147), the National Basic Research Program of
China (973 Program 2010CB833300), and the Program for
Changjiang Scholars and Innovative Research Team in Uni-
versity (IRT1189).
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