Aerobic Oxidation of Alkyl 2-Phenylhydrazinecarboxylates Catalyzed by CuCl and DMAP

Article abstract of DOI:10.1021/acs.joc.7b03119

Recently, various fruitful organic reactions such as a catalytic Mitsunobu reaction were reported by virtue of alkyl 2-phenylazocarboxylates, however, the synthesis of alkyl 2-phenylazocarboxylates largely depended on the stoichiometric use of toxic oxidants. In this manuscript, an environment-friendly aerobic oxidative transformation of alkyl 2-phenylhydrazinecarboxylates to alkyl 2-phenylazocarboxylates is disclosed. The use of CuCl and DMAP system efficiently catalyzed the aerobic oxidation of alkyl 2-phenylhydrazinecarboxylates under mild conditions. The reaction rate of the present Cu-catalysis was much faster than that of the previously reported Fe-catalysis, and a variety of azo products were synthesized within 3 h. The present protocol was effective on larger scale. It was observed that the produced azo compound could undergo various reactions without isolation through one-pot sequential protocols.

Full text of DOI:10.1021/acs.joc.7b03119

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Note
Aerobic Oxidation of Alkyl 2-
Phenylhydrazinecarboxylates Catalyzed by CuCl and DMAP
Min Hye Kim, and Jinho Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03119 • Publication Date (Web): 11 Jan 2018
Downloaded from http://pubs.acs.org on January 11, 2018
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Aerobic Oxidation of Alkyl 2ꢀ
Phenylhydrazinecarboxylates Catalyzed by CuCl
and DMAP
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Min Hye Kim and Jinho Kim*
Department of Chemistry, and Research Institute of Natural Sciences, Incheon National University, 119
Academyꢀro, Yeonsuꢀgu, Incheon 22012, Republic of Korea
jinho@inu.ac.kr
Abstract
Recently, various fruitful organic reactions such as a catalytic Mitsunobu reaction were reported by virtue
of alkyl 2ꢀphenylazocarboxylates, however, the synthesis of alkyl 2ꢀphenylazocarboxylates largely
depended on the stoichiometric use of toxic oxidants. In this manuscript, an environmentꢀfriendly aerobic
oxidative transformation of alkyl 2ꢀphenylhydrazinecarboxylates to alkyl 2ꢀphenylazocarboxylates was
disclosed. The use of CuCl and DMAP system efficiently catalyzed the aerobic oxidation of alkyl 2ꢀ
phenylhydrazinecarboxylates under mild conditions. The reaction rate of the present Cuꢀcatalysis was
much faster than that of the previously reported Feꢀcatalysis, and a variety of azo products were
synthesized within 3 hours. The present protocol was effective on larger scale. It was observed that the
produced azo compound could undergo various reactions without isolation through oneꢀpot sequential
protocols.
Azo compounds have been used in multifarious area due to their unique property and reactivity, which
could be tuned by the substituent at nitrogenꢀnitrogen double bond.1 Azobenzene derivatives, which
contain phenyl groups at both nitrogens, have played an important role in dyes and pigments for a long
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time.2 In addition, their interesting E/Z isomerization by the light was utilized in the molecular switches
and machines.3 Dialkyl azodicarboxylates, which contain alkoxy carbonyl groups at both nitrogens, have
been employed in the various organic reactions.4 Mitsunobu reaction, the representative utilization of the
dialkyl azodicarboxylates such as diethyl azodicarboxylate (DEAD), is widely used in pharmaceutical and
synthetic chemistry, because the Mitsunobu reaction provides a facile route for the inversion of the chiral
secondary alcohols.5 Additionally, dialkyl azodicarboxylates have been employed in electrophilic
aminations,6 [4+2] cycloadditions,7 oxidative couplings of tertiary amine,8 hydrazination,9 and
dehydrations.10
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Alkyl 2ꢀphenylazocarboxylates are unsymmetrical azo compounds, which contain a phenyl group at
one nitrogen and an alkoxy carbonyl group at the other. They recently received much attention from
synthetic chemists, because these azo compounds showed distinct reactivity from symmetrical azo
compounds. In CꢀN bond formation, they reacted with various organometallic reagents as well as
enamines and showed the high regioselectivity at the phenyl substituted nitrogen position.11 Heinrich et al.
revealed that paraꢀsubstituted alkyl 2ꢀphenylazocarboxylates could be used in nucleophilic substitutions
and radical reactions.12 In addition, they reported that the treatment of alkyl 2ꢀphenylazocarboxylates with
tetrabutyl ammonium hydroxide (Bu4NOH) generated phenylazocarboxylate salts and these salts could be
utilized in cycloaddition and MizorokiꢀHeck reaction.13 They also achieved [3+2] cycloaddition of alkyl
2ꢀphenylazocarboxylates for the synthesis of 1,3,5ꢀtrisubstituted 1,2,4ꢀtriazoles.14 Taniguchi group
developed catalytic Mitsunobu reaction with the exquisite tunings of alkyl 2ꢀphenylazocarboxylates in the
Fe(Pc) catalyzed aerobic oxidation conditions.15 It was reported that alkyl 2ꢀphenylazocarboxylates
reacted with acrylates to produce indoline derivatives through rhodium catalyzed CꢀH bond activation.16
The synthesis of alkyl 2ꢀphenylazocarboxylates largely depends on the oxidations of the corresponding
hydrazine compounds with stoichiometric oxidant such as MnO2, ceric ammonium nitrate (CAN), NaNO2,
NBS, and Pb(OAc)4.11d,11g,12a,12b,17 In terms of green and sustainable chemistry, molecular oxygen is an
attractive oxidant which is readily accessible and produces water as byproduct.18 However, only few
aerobic oxidation methods for alkyl 2ꢀphenylazocarboxylates were reported.19
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The oxidation potential of azo compound varied by the substituents at each nitrogen atom.20 For
example, the oxidation potential of diꢀtertꢀbutyl hydrazodicarboxylate (DBADꢀH2), which have strong
electron withdrawing groups at both nitrogen atoms, is 1.62 V and higher than that of 1,2ꢀ
diphenylhydrazine (0.68 V). The oxidation potential of tertꢀbutyl 2ꢀphenyl hydrazinecarboxylate is
between them (1.02 V). Recently, our group reported that the combination of Cu and DMAP could
catalyze aerobic oxidation of DBADꢀH2.21 On the basis of our observation and related references,22 we
envisioned that Cu/DAMP system would catalyze the aerobic oxidation of alkyl 2ꢀ
phenylhydrazinecarboxylates efficiently due to their lower oxidation potential. Zhang et al. reported the
preliminary result of the Cuꢀcatalyzed aerobic oxidation of alkyl 2ꢀphenylhydrazinecarboxylates.23
However, they focused on the development of crossꢀcoupling
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Table 1. Optimization for Cuꢀcatalyzed aerobic oxidation of ethyl 2ꢀphenylhydrazinecarboxylate.a
Entry
Cu
Additive
DMAP
DMAP
DMAP
DMAP
DMAP
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Yield (%)b
1
CuI
18
89
95
80
69
94
75
84
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86
84
2
CuBr
CuCl
CuBr2
CuCl2
3
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6
Cu(OAc)2 DMAP
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CuCl
CuCl
CuCl
CuCl
CuCl
pyridine
DBU
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9
1,10ꢀphen CH2Cl2
10
11
DMAP
DMAP
CH3CN
DMF
aReaction conditions: 1a (0.5 mmol), Cu (5 mol %), additive (10 mol %), and solvent (2 mL) in 50 mL roundꢀbottom flask
b
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under air at room temperature for 1 h (stirring rate : 900 rpm). Yield determined by H NMR spectroscopy (internal standard:
1,1,2,2ꢀtetrachloroethane).
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reaction using hydrazines such as N’ꢀphenylbenzoylhydrazide and the reaction parameters as well as
substrate scope for aerobic oxidation of alkyl 2ꢀphenylhydrazinecarboxylates were not investigated
sufficiently. Herein, we describe an efficient aerobic oxidative synthesis alkyl 2ꢀphenylazocarboxylates
catalyzed by CuCl/DMAP system.
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To prove our hypothesis, we screened copper catalyst with ethyl 2ꢀphenylhydrazinecarboxylate 1a as a
model substrate (Table 1). The use of CuI/DMAP system, the optimized conditions in the aerobic
oxidation of DBADꢀH2, gave poor conversion and yield in dichloromethane media (entry 1). It was
revealed that several Cu sources such as CuCl, Cu(CH3CN)4PF6, and Cu(OAc)2, showed full conversion
and excellent yield (entries 2–6).24 However, we decided to choose CuCl for the optimal catalyst,25
because it showed wide substrate scope. The use of pyridine, DBU, or 1,10ꢀphenanthroline, instead of
DMAP, produced ethyl 2ꢀphenylazocarboxylate 2a in lower yields (entries 7–9). It was revealed that the
reactivity of the developed method was not affected by the choice of solvents, however, chlorinated
solvents such as chloroform, dichloroethane, and dichloromethane exhibited better reactivities in general
(entries 10 and 11). Control reactions revealed that CuCl, DMAP, and air are essential for oxidation of
1a.26 It was revealed that the reaction vessel size affected on the reactivity of the developed oxidation
under air, however, the oxidation under oxygen showed better reactivity than under air as well as no
significant difference of the reaction rate upon reaction vessel size. These observations indicated that
mass transfer of oxygen is crucial for the present oxidation under air. In consideration of reactivity,
reproducibility, and practicality, we decided to carry out the present oxidation in 50 mL roundꢀbottom
flask with a constant stirring rate (900 rpm) under air.
With the optimized conditions in hands (Table 1, entry 3), we investigated the substrate scope of the
present aerobic oxidation (Table 2). Although good yields were generally obtained within 1 h, the
prolonged reaction time increased the product yield above 90%.27 Various paraꢀsubstituted 2ꢀ
phenylhydrazinecarboxylates underwent the present oxidation efficiently regardless of the electronic
nature (2a–2i). The aerobic oxidation of metaꢀsubstituted as well as orthoꢀsubstituted 2ꢀphenyl
hydrazinecarboxylates produced the corresponding azo compound in good to excellent yields (2j–2o).
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Disubstituted 2ꢀphenylhydrazinecarboxylates such as 1p and 1q were employed and full conversions and
high yields were observed in 3 h. The aerobic oxidation of 1r was sluggish in the optimized conditions
(45% conversion and 36% yield), however, the replacement of DMAP with 4ꢀmethoxypyridine gave a
quantitative yield of 2r in 3 h. It is presumably due to the facile coordination of electron deficient 2r to
Cu in 4ꢀmethoxypyridine, which has weaker interaction with Cu than DMAP.28 Other alkyl 2ꢀ
phenylhydrazinecarboxylates having tertꢀbutyl (2s–2x), benzyl (2y), or trichloroethyl (2z), instead of
ethyl group, were also tested in the present conditions, and good to high yields were observed.
Interestingly, the aerobic oxidation of benzoylꢀ2ꢀphenylhydrazine took place smoothly to provide
benzoylazobenzene (2aa).
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Table 2. Substrate scope of Cuꢀcatalyzed aerobic oxidation of alkyl 2ꢀphenylhydrazinecarboxylate.a
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aReaction conditions: 1 (0.5 mmol), CuCl (5 mol %), DMAP (10 mol %), and CH2Cl2 (2 mL) in 50 mL roundꢀbottom flask
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under air at room temperature f or 1 h (stirring rate : 900 rpm). bFor 3 h. cInstead of DMAP, 4ꢀmethoxypyridine was used.
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We have compared the reaction rate of our developed Cu catalysis with that of Taniguchi’s Fe(Pc)
system,19b and observed that Cu catalysis is much faster than Fe(Pc) catalysis (Fig. 1). The present aerobic
oxidation was effective on a larger scale (Scheme 1). Cuꢀcatalyzed aerobic oxidation of 1a (1.1 g, 6
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mmol) was carried out in 200 mL beaker, the azo product 2a was obtained in 87% yield.
CuCl (5 mol %)
DMAP (10 mol %)
or
Fe(Pc) (5 mol %)
O
O
H
N
N
N
OEt
N
OEt
H
CH2Cl2 (2 mL)
air, rt, time
2a
1a
(0.5 mmol)
Figure 1. Comparison reaction rate of CuCl/DMAP catalysis with Fe(Pc) catalysis in the aerobic
oxidation of 1a.
CuCl (5 mol %)
DMAP (10 mol %)
O
O
H
N
N
N
H
OEt
N
OEt
CH2Cl2 (20 mL)
air, rt, 1 h
2a
87 %
1a
1.1 g (6 mmol)
Scheme 1. The Cuꢀcatalyzed aerobic oxidation on a gram scale.
1) CuCl (5 mol %)
DMAP (10 mol %)
DMF, air, rt, 1 h
A.
O
O
H
F
N
N
N
OtBu
N
H
OtBu
2) 4-fluorophenol (1.2 equiv)
Cs2CO3 (5 equiv), 1.5 h
O
O2N
1x
3, 78%
1) CuCl (5 mol %)
DMAP (10 mol %)
DMF, air, rt, 1 h
B.
O
O
N
H
N
OtBu
N
N
H
OtBu
2) morpholine (5 equiv)
K2CO3 (5 equiv), 5 h
N
F
O
1w
4
, 70%
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Scheme 2. Oneꢀpot sequential aerobic oxidation and nucleophilic substitution.
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Recently, Heinrich et al. demonstrated that 2x underwent the nucleophilic substitution with phenol
derivatives to generate diphenyl ethers.12 We examined a domino reaction consisting of aerobic oxidation
and nucleophilic substitution with 1x in the presence of CuCl, DMAP, 4ꢀfluorophenol, and Cs2CO3.
However, the conversion of 1x was poor and the desired product was obtained in only 38% yield without
2x. The control experiment revealed that the nucleophilic substitution of 1x with 4ꢀfluorophenol did not
occur. These results indicated that the poor yield of diphenyl ether was caused by the suppression of the
aerobic oxidation of 1x in the presence of 4ꢀfluorophenol and Cs2CO3. To address this issue, we
employed oneꢀpot sequential strategy. After initial aerobic oxidation of 1x in DMF for 1h, we added the
solution of 4ꢀfluorophenol and Cs2CO3 in DMF. After 1.5 h, the desired diphenyl ether 3 was isolated in
78% yield (Scheme 2, A). Similarly, 4 was synthesized by the addition of morpholine and K2CO3 after
Cuꢀcatalyzed aerobic oxidation of 1w (Scheme 2, B).29
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Scheme 3. Other oneꢀpot sequential reactions with 1x.
We also investigated other utilizations of 1x using oneꢀpot sequential strategy (Scheme 3). After the
aerobic oxidation of 1x with the developed Cuꢀcatalysis, the addition of phenyl boronic acid gave
hydrazine 5 in good yield,11d,23a or the addition of TFA generated aryl radical species.12 We could utilized
the inꢀsitu generated aryl radical for the preparation of arylated (6, 58%) and iodinated compounds (7,
81%).
In summary, we demonstrated CuCl/DMAP was able to catalyze the aerobic oxidation of alkyl 2ꢀ
phenylazocarboxylates efficiently. A variety of alkyl 2ꢀphenylazocarboxylates were converted into the
corresponding azo compounds in high to excellent yields within 3 h. The reaction rate of the developed
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Cu catalysis was much faster than the previously reported Fe catalysis. The present method was effective
even in larger scale. In addition, several oneꢀpot sequential reactions consisting of Cuꢀcatalyzed aerobic
oxidation and other reactions were achieved.
9
Experimental Section
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General considerations: All commercially available compounds and solvents were purchased and used
as received, unless otherwise noted. Analytical thin layer chromatography (TLC) was performed on
precoated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm)
and treatment with phosphomolybdic acid stain followed by heating. Flash chromatography was
1
performed using Silica gel (particle size 40ꢀ63 um, 230ꢀ400 mesh). H, 13C, and 19F NMR spectra were
recorded on 400 MHz NMR (400 MHz for 1H, 101 MHz for 13C, 376 MHz for 19F). Chemical shift values
1
13
are given in parts per million relative to internal TMS (0.00 ppm for H) or CDCl3 (77.06 ppm for C).
The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s
= singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = double of doublet, dt =
double of triplet, td = triple of doublet. Coupling constants, J, were reported in hertz unit (Hz). High
resolution mass spectra were obtained from the Korea Basic Science Institute (Daegu) by using FAB
method and magnetic sector mass analyzer.
Optimization for Cu-catalyzed aerobic oxidation of 1a (Table 1): To a 50 mL round bottom flask
equipped with a magnetic stir bar, 1a (0.5 mmol), copper catalyst (5 mol %, 0.025 mmol), additive (10
mol %, 0.05 mmol), and solvent (2.0 mL) were added. The reaction mixture was stirred at room
temperature under air (stirring rate : 900 rpm). After 1 h, the reaction mixture was diluted by adding
CH2Cl2 and quenched with a saturated aqueous solution of NH4Cl. Two layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The 1H NMR yield of the desired product was determined by integration using
an internal standard (1,1,2,2ꢀtetrachloroethane).
Preparation for alkyl 2-phenylhydrazinecarboxylates
Preparation for 1a-r, 1z, 1aa17b
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To a 100 mL round bottom flask equipped with a magnetic stir bar, phenylhydrazine or appropriate
phenylhydrazine hydrochloride (5.0 mmol), pyridine (1.1 equiv, 5.5 mmol, 0.45 mL), and CH3CN (5.0
mL) were added. The solution was cooled to 0 oC and ethyl chloroformate (1.1 equiv, 5.5 mmol, 0.52 mL)
was added dropwise. The reaction mixture was stirred for 1 h at room temperature. The reaction was
diluted by adding CH2Cl2 and washed with 4 M HCl aqueous solution. Two layers were separated, and
the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered,
and concentrated on rotary evaporator. The residue was purified by recrystallization using CH2Cl2 and
hexane to give alkyl 2ꢀphenylhydrazinecarboxylates.
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Preparation for 1s-x30
A 100 mL flameꢀdried round bottom flask, which was equipped with a magnetic stir bar and charged with
phenylhydrazine or appropriate phenylhydrazine hydrochloride (5.0 mmol), was evacuated and back
filled with N2. After 3.0 mL of CH3CN was added Et3N (1.5 equiv, 7.5 mmol, 1.0 mL), diꢀtertꢀbutyl
dicarbonate (4.0 equiv, 20 mmol, 4.4 g), and CH3CN (2.0 mL) were added in sequence. The reaction
mixture was stirred for 1 h at room temperature. The reaction was diluted by adding CH2Cl2 and washed
with a saturated aqueous solution of NaHCO3. Two layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and concentrated on
rotary evaporator. The residue was purified by recrystallization using CH2Cl2 and hexane to give alkyl 2ꢀ
phenylhydrazinecarboxylates. The hydrazine 1x was purified by column chromatography and
recrystallization.
Preparation for 1y31
To a 100 mL round bottom flask equipped with a magnetic stir bar, phenylhydrazine (5.0 mmol), pyridine
o
(1.1 equiv, 5.5 mmol, 0.45 mL), and CH2Cl2 (5.0 mL) were added. The solution was cooled to 0 C and
benzoyl chloride (1.0 equiv, 5.0 mmol, 0.62 mL) was added dropwise. The reaction mixture was stirred
for 5 h at room temperature. The reaction was diluted by adding CH2Cl2 and washed with 4 M HCl
aqueous solution. Two layers were separated, and the aqueous layer was extracted with CH2Cl2. The
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combined organic layer was dried over MgSO4, filtered, and concentrated on rotary evaporator. The
residue was purified by recrystallization using CH2Cl2 and hexane to give a benzoyl phenylhydrazine, 1y.
General procedure for Cu-catalyzed aerobic oxidation of alkyl 2-phenylhydrazinecarboxylates
(Table 2): To a 50 ml round bottom flask equipped with a magnetic stir bar, alkyl 2ꢀ
phenylhydrazinecarboxylate (0.5 mmol), CuCl (5 mol %, 0.025 mmol, 2.5 mg), DMAP (10 mol %, 0.05
mmol, 6.2 mg), and CH2Cl2 (2.0 mL) were added. The reaction mixture was stirred for 1 or 3 h at room
temperature under air (stirring rate : 900 rpm). The reaction was diluted by adding CH2Cl2 and quenched
with a saturated aqueous solution of NH4Cl. Two layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography to give azo products.
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Ethyl 2-phenylazocarboxylate19b (2a); 95% (85 mg), orange oil, EA/hexane=1:5, H NMR (400 MHz,
CDCl3) δ 7.93 (d, 2H), δ 7.61ꢀ7.49 (m, 3H), δ 4.52 (q, J = 7.1 Hz, 2H), δ 1.47 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 163.4, 152.8, 135.0, 130.4, 124.9, 65.6, 15.3.
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Ethyl 2-(4-methoxyphenyl)azocarboxylate19b (2b); 97% (110 mg), red oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), δ 7.00 (d, J = 8.9 Hz, 2H), δ 4.50 (q, J = 7.1, Hz, 2H), δ
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3.89 (s, 3H), δ 1.46 (t, J = 7.1 Hz 3H); C{1H} NMR (101 MHz, CDCl3) δ 164.1, 161.6, 145.6, 125.9,
114.0, 63.7, 55.2, 13.7.
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Ethyl 2-(4-methylphenyl)azocarboxylate19b (2c); 90% (86 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3); δ 7.84 (d, J = 8.1 Hz, 2H), δ 7.32 (d, J = 8.0 Hz, 2H), δ 4.51 (q, J = 7.1 Hz, 2H), δ
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2.44 (s, 3H), δ 1.46 (t, J = 7.1 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 161.7, 149.3, 144.7, 129.5,
123.4, 63.9, 21.2, 13.7.
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Ethyl 2-(4-bromophenyl)azocarboxylate19b (2d); 87% (112 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 8.6 Hz, 2H), δ 7.67 (d, J = 8.6 Hz, 2H), δ 4.52 (q, J = 7.1 Hz, 2H), δ
1.47 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.4, 149.8, 132.2, 128.4, 124.6, 64.1, 13.7.
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Ethyl 2-(4-chlorophenyl)azocarboxylate19b (2e); 91% (103 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.85 (d, J = 8.7Hz, 2H), δ 7.47 (d, J = 8.7 Hz, 2H), δ 4.49 (q, J = 7.1 Hz, 2H), δ
1.44 (t, J = 7.1 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.4, 149.4, 139.7, 129.2, 154.5, 64.1, 13.7.
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Ethyl 2-(4-fluorophenyl)azocarboxylate19b (2f); 96% (94 mg), orange oil, EA/hexane=1:5, H NMR
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(400 MHz, CDCl3) δ 7.97 (dd, J = 8.0, 5.3 Hz, 2H), δ 7.21 (t, J = 8.5 Hz, 2H), δ 4.52 (q, J = 7.1 Hz, 2H),
δ 1.47 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.6 (d, J = 256.6 Hz), 161.5, 147.7 (d, J
= 2.9 Hz), 125.7 (d, J = 9.6 Hz), 116.0 (d, J = 23.2 Hz), 64.0, 13.6.; 19F NMR (376 MHz, CDCl3) δ –
104.2.
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Ethyl 2-(4-cyanophenyl)azocarboxylate19b (2g); 93% (94 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), δ 7.81 (d, J = 8.4 Hz, 2H), δ 4.51 (q, J = 7.1 Hz, 2H), δ
1.44 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.2, 152.6, 132.9, 123.5, 117.3, 116.2,
64.5, 13.7.
Ethyl 2-(4-nitrophenyl)azocarboxylate19b (2h); 93% (104 mg), red solid, EA/hexane=1:5, 1H NMR (400
MHz, CDCl3) δ 8.40 (d, J = 8.9 Hz, 2H), δ 8.06 (d, J = 8.9 Hz, 2H), δ 4.56 (q, J = 7.1 Hz, 2H), δ 1.49 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.1, 153.8, 149.8, 124.3, 123.7, 64.5, 13.6.
Ethyl 2-(4-(trifluoromethyl)phenyl)azocarboxylate11g (2i); 97% (119 mg), orange oil, EA/hexane=1:5,
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 2H), δ 7.80 (d, J = 8.2 Hz, 2H), δ 4.54 (q, J = 7.1 Hz,
2H) , δ 1.48 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 157.3, 138.8 (q, J = 32.8 Hz),
130.6 (q, J = 3.7 Hz), 127.9, 127.6 (q, J = 272.7 Hz), 68.9, 18.2; 19F NMR (376 MHz, CDCl3) δ –63.0.
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Ethyl 2-(3-methoxyphenyl)azocarboxylate19b (2j); 85% (88 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.60 (d, J = 7.7 Hz, 1H), δ 7.47ꢀ7.40 (m, 2H), δ 7.14 (d, J = 8.3 Hz, 1H), δ 4.52 (q,
J = 7.1 Hz, 2H), δ 3.85 (s, 3H), δ 1.47 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1,
160.3, 152.7, 130.0, 121.0, 118.7, 105.3, 64.5, 55.5, 14.1.
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Ethyl 2-(3-methylphenyl)azocarboxylate19b (2k); 91% (87 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.78ꢀ7.73 (m, 2H), δ 7.45ꢀ7.38 (m, 2H), δ 4.52 (q, J = 7.1, Hz 2H), δ 2.43 (s, 3H), δ
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121.7, 64.4, 21.2, 14.1.
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Ethyl 2-(3-chlorophenyl)azocarboxylate19b (2l); 92% (98 mg), orange oil, EA/hexane=1:5, H NMR
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(400 MHz, CDCl3) δ 7.91ꢀ7.82 (m, 2H), δ 7.51 (dt, J = 15.8, 7.9 Hz, 2H), δ 7.48 (t, J = 7.9 Hz, 1H), δ
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4.53 (q, J = 7.2 Hz, 2H), δ 1.47 (t, J = 7.1 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 161.3, 151.8,
135.0, 132.9, 129.9, 122.8, 121.8, 64.2, 13.7.
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Ethyl 2-(3-fluorophenyl)azocarboxylate (2m); 96% (94 mg), red solid, EA/hexane=1:5, H NMR (400
MHz, CDCl3) δ 8.00ꢀ7.94 (m, 2H), δ 7.24ꢀ7.18 (m, 2H), δ 4.52 (q, 2H), δ 1.47 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 166.1 (d, J = 256.6 Hz), 161.9, 148.1 (d, J = 3.0 Hz), 126.2 (d, J =
9.6 Hz), 116.6, 116.3, 64.5, 14.1; 19F NMR (376 MHz, CDCl3) δ –104.2; HRMS (FAB) m/z calcd. for
C9H10FN2O2 [M+H]+: 197.0726, found 197.0723.
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Ethyl 2-(2-methoxyphenyl)azocarboxylate (2n); 95% (99 mg), orange oil, EA/hexane=1:5, H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 1H), δ 7.55 (t, J = 7.8 Hz, 1H), δ 7.10 (d, J = 8.5 Hz, 1H), δ
6.98 (t, J = 7.7 Hz, 1H), δ 4.49 (q, J = 7.2 Hz, 2H), δ 4.02 (s, 3H), δ 1.45 (t, J = 7.1 Hz, 3H); C{1H}
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NMR (101 MHz, CDCl3) δ 161.8, 158.2, 140.4, 135.5, 120.1, 116.1, 112.5, 63.8, 55.7, 13.7; HRMS
(FAB) m/z calcd. for C10H13N2O3 [M+H]+: 209.0926, found 209.0929.
Ethyl 2-(2-chlorophenyl)azocarboxylate19b (2o); 99% (105 mg), orange oil, EA/hexane=1:5, H NMR
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(400 MHz, CDCl3) δ 7.59 (dd, J = 12.4, 8.2 Hz, 2H), δ 7.49 (t, J = 7.6 Hz, 1H), δ 7.33 (t, J = 7.7 Hz, 1H),
δ 4.52 (q, J = 7.1 Hz, 2H), δ 1.46 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.0, 147.8,
137.2, 134.4, 131.1, 127.3 , 117.1, 64.6, 14.1.
Ethyl 2-(3,4-dichlorophenyl)azocarboxylate19b (2p); 91% (120 mg), red solid, EA/hexane=1:5, H
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NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), δ 7.77 (d, J = 8.5 Hz, 1H), δ 7.59 (d, J = 8.5 Hz, 1H), δ 4.49 (q,
J = 7.1 Hz, 2H), δ 1.44 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.1, 149.8, 137.6,
133.5, 130.7, 124.1, 123.0, 64.3, 13.9.
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Ethyl 2-(3,5-dichlorophenyl)azocarboxylate19b (2q); 90% (111 mg), orange oil, EA/hexane=1:5, H
NMR (400 MHz, CDCl3) δ 7.80 (s, 2H), δ 7.55 (s, 1H), δ 4.53 (q, J = 7.2 Hz, 2H), δ 1.47 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.0, 151.9, 135.5, 132.4, 121.6, 64.4, 13.6.
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Ethyl 2-(2,3,4,5,6-pentafluorophenyl)azocarboxylate19b (2r); 99% (133 mg), orange oil,
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EA/hexane=1:5, H NMR (400 MHz, CDCl3) δ 4.54 (q, J = 7.2 Hz, 2H), δ 1.49 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 160.7, 145.0–144.7 (m), 143.3–143.1 (m), 142.4–142.1 (m), 140.6–
140.4 (m), 139.4–139.1 (m), 136.8–136.6 (m), 126.8–126.6 (m), 65.16, 13.96; 19F NMR (376 MHz,
CDCl3) δ –146.7, –161.1.
tert-Butyl 2-phenylazocarboxylate19b (2s); 94% (97 mg), orange oil, EA/hexane=1:5, H NMR (400
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MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), δ 7.58ꢀ7.47 (m, 3H), δ 1.66 (s, 9H); C{1H} NMR (101 MHz,
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CDCl3) δ 161.3, 151.6, 133.4, 129.2, 123.5, 85.0, 27.9.
tert-Butyl 2-(4-methylphenyl)azocarboxylate16 (2t); 72% (79 mg), yellow solid, EA/hexane=1:5, H
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NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.1 Hz, 2H), δ 7.30 (d, J = 8.0 Hz, 2H), δ 2.43 (s, 3H), δ 1.66 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.4, 150.9, 145.7, 131.0, 124.8, 75.3, 29.0, 22.8.
tert-Butyl 2-(4-bromophenyl)azocarboxylate16 (2u); 89% (127 mg), yellow solid, EA/hexane=1:5, H
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NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), δ 7.66 (d, J = 8.5 Hz, 2H), δ 1.66 (s, 9H); C{1H}
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NMR (101 MHz, CDCl3) δ 165.1, 154.4, 136.7, 132.4, 129.1, 89.4, 31.9.
tert-Butyl 2-(4-chlorophenyl)azocarboxylate16 (2v); 89% (107 mg), yellow solid, EA/hexane=1:5, H
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NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H), δ 7.48 (d, J = 8.6 Hz, 2H), δ 1.66 (s, 9H); C{1H}
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NMR (101 MHz, CDCl3) δ 162.1, 151.1, 140.7, 130.7, 125.9, 75.3, 29.0.
tert-Butyl 2-(4-fluorophenyl)azocarboxylate16 (2w); 88% (99 mg), orange oil, EA/hexane=1:5, 1H NMR
(400 MHz, CDCl3) δ 7.99ꢀ7.87 (m, 2H), δ 7.22ꢀ7.16 (m, 2H), δ 1.66 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 165.8 (d, J = 255.7 Hz), 160.98, 148.1 (d, J = 2.9 Hz), 125.9 (d, J = 9.5 Hz), 116.3 (d, J = 23.1
Hz), 85.0, 27.8; 19F NMR (376 MHz, CDCl3) δ –105.1.
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tert-Butyl 2-(4-nitrophenyl)azocarboxylate12b (2x); 97% (122 mg), orange oil, EA/hexane=1:5, H
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.9 Hz, 2H), δ 8.03 (d, J = 8.9 Hz, 2H), δ 1.68 (s, 9H); C{1H}
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NMR (101 MHz, CDCl3) δ 160.5, 154.4, 150.1, 124.7, 124.1, 86.1, 27.8.
Benzyl 2-phenylazocarboxylate19b (2y); 94% (113 mg), orange oil, EA/hexane=1:5, 1H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), δ 7.59ꢀ7.54 (m, 1H), δ 7.53ꢀ7.46 (m, 4H), δ 7.43ꢀ7.35 (m, 3H), δ 5.46
(s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1, 151.6, 134.4, 134.0, 129.3, 128.9, 128.8, 128.7, 123.8,
69.9.
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2,2,2,-Trichloroethyl 2-phenylazocarboxylate19b (2z); 86%, (121 mg), orange oil, EA/hexane=1:5, H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 2H), δ 7.64 (t, J = 7.3 Hz, 1H), δ 7.59ꢀ7.53 (m, 2H), δ
5.07 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.6, 160.6, 151.6, 134.5, 129.4, 124.1, 29.7
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Benzoylazobenzene19b (2aa); 75% (79 mg), orange oil, EA/hexane=1:5, H NMR (400 MHz, CDCl3) δ
8.06 (d, J = 7.2 Hz, 2H), δ 7.99 (d, J = 7.4 Hz, 2H), δ 7.64 (t, J = 7.4 Hz, 1H), δ 7.57 (t, J = 7.7 Hz, 3H),
δ 7.60ꢀ7.47 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.6, 106.6, 89.2, 88.0, 85.4, 85.1, 84.0, 83.5,
78.2.
Procedure for Cu-catalyzed aerobic oxidation of 1a on gram scale (Scheme 1): To a 200 mL beaker
equipped with a magnetic stir bar, 1a (6.0 mmol, 1.07 g), CuCl (5 mol %, 0.3 mmol, 30 mg), DMAP (10
mol %, 0.6 mmol, 73 mg), and CH2Cl2 (20 mL) were added. After covering the beaker with a perforated
parafilm, reaction mixture was stirred for 1 h at room temperature under air (stirring rate : 900 rpm). The
reaction was diluted by adding CH2Cl2 and quenched with a saturated aqueous solution of NH4Cl. Two
layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column
chromatography to give 2a.
Procedure for one-pot sequential nucleophilic substitution (Scheme 2): To a 50 mL round bottom
flask equipped with a magnetic stir bar, 1x (0.5 mmol), CuCl (5 mol %, 0.025 mmol, 2.5 mg), DMAP (10
mol %, 0.05 mmol, 6.2 mg), and DMF (2.0 mL) were added (stirring rate : 900 rpm). After 1 h, 4ꢀ
fluorophenol (1.2 equiv, 0.6 mmol, 67 mg), Cs2CO3 (5.0 equiv, 2.5 mmol, 800 mg), and DMF (4.0 mL)
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were added for 3 or morpholine (5 equiv, 2.5 mmol, 0.21 mL), K2CO3 (5.0 equiv, 2.5 mmol, 346 mg), and
DMF (2.0 mL) were added for 4. The reaction mixture was stirred for 1.5 h or 5 h for the synthesis of 3 or
4, respectively. The reaction was diluted by adding EtOAc and quenched with a saturated aqueous
solution of NH4Cl. Two layers were separated, and the aqueous layer was extracted with EtOAc. The
combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography to give 3 (EA/hexane=1:5) or 4 (EA/hexane=1:2)
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tert-Butyl 2-(4-(4’-fluorophenoxy)phenyl)azocarboxylate12a (3); 78% (123 mg), orange oil,
EA/hexane=1:5, 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.9 Hz, 2H), δ 7.14ꢀ7.04 (m, 4H), δ 7.02 (d, J
= 8.9 Hz, 2H), δ 1.66 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.6, 161.1, 159.6 (d, J = 243.7 Hz),
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151.0 (d, J = 2.7 Hz), 147.0, 126.0, 121.9 (d, J = 8.4 Hz), 117.3, 116.7 (d, J = 23.4 Hz), 84.7, 27.8; F
NMR (376 MHz, CDCl3) δ –117.8.
tert-Butyl 2-(N’-(4-Morpholin-4-yl-phenyl))azocarboxylate12a (4); 70% (102 mg), orange solid,
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EA/hexane=1:5, H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 9.0 Hz, 2H), δ 6.90 (d, J = 9.0 Hz, 2H), δ
3.86 (dd, J = 6.4, 3.0 Hz, 4H), δ 3.39 (dd, J = 6.5, 2.9 Hz, 4H), δ 1.66 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 161.1, 154.9, 144.2, 126.5, 113.4, 83.8, 66.4, 47.2, 27.9.
Procedure for one-pot sequential arylation with boronic acid (Scheme 3): After 1 h of Cuꢀcatalyzed
aerobic oxidation of 1x in the developed conditions, CH2Cl2 was evaporated and phenylboronic acid (1.8
equiv, 0.9 mmol, 110 mg) and MeOH (2.0 mL) was added. The reaction mixture was stirred for 40 min.
The reaction was diluted by adding EtOAc and quenched with a saturated aqueous solution of NH4Cl.
Two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column
chromatography to give 5. (EA/hexane=1:5)
tert-Butyl 2-(4-nitrophenyl)-2-phenylhydrazinecarboxylate11d (5); 90% (148 mg), yellow oil,
EA/hexane=1:5, 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 2H), δ 7.48ꢀ7.25 (m, 6H), δ 6.91 (d, J
= 7.2 Hz, 2H), δ 1.45/1.35 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.3, 152.5, 143.5, 140.4, 129.8,
125.6, 124.9, 113.3, 82.2, 28.2.
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Procedure for the synthesis of 6 and 7 (Scheme 3): After 1 h of Cuꢀcatalyzed aerobic oxidation of 1x in
the developed conditions, CH2Cl2 was evaporated and benzene (50 equiv, 25 mmol, 2.2 mL) and TFA (10
equiv, 5 mmol, 0.4 mL) were added for 6 or iodine (10 equiv, 5.0 mmol, 2.5 g), TFA (10 equiv, 5.0 mmol,
0.4 mL), and CH3CN (2.0 mL) were added for 7. The reaction mixture was stirred at 80 oC for 0.5 h (6) or
4 h (7). The reaction was diluted by adding EtOAc and quenched with a saturated aqueous solution of
NH4Cl. Two layers were separated, and the aqueous layer was extracted with EtOAc. The combined
organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by
column chromatography to give 6 (EA/hexane=1:5) or 7 (hexane)
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1-Phenyl-4-nitrobenzene12a (6); 57% (57 mg), brown solid, EA/hexane=1:5, H NMR (400 MHz,
CDCl3) δ 8.29 (d, J = 8.9 Hz, 2H), δ 7.73 (d, J = 8.9 Hz, 2H), δ 7.62 (d, J = 8.0 Hz, 2H), δ 7.53ꢀ7.43 (m,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 147.6, 147.0, 138.7, 129.1, 128.9, 127.8, 127.4, 124.1.
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1-Iodo-4-nitrobenzene12a (7); 80% (100 mg), white solid, hexane, H NMR (400 MHz, CDCl3) δ 8.02ꢀ
7.84 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 147.7, 138.6, 124.8, 102.7.
Author Information
Corresponding Authors
* Eꢀmail: jinho@inu.ac.kr
Notes
The authors declare no competing financial interest.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRFꢀ
2015R1C1A1A02037185). This work was also supported by the Incheon National University Research
Grant in 2016.
Associated Content
1
Supporting Information: Copies of H, 13C, and 19F NMR spectra are included. This material is
available free of charge via the Internet at http://pubs.acs.org/.
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