Oxidative dehydrogenative couplings of pyrazol-5-amines selectively forming azopyrroles

Article abstract of DOI:10.1021/jo5004967

New oxidative dehydrogenative couplings of pyrazol-5-amines for the selective synthesis of azopyrrole derivatives have been described. The former reaction simultaneously installs C-I and N-N bonds through iodination and oxidation, whereas the latter involved a copper-catalyzed oxidative coupling process. The resulting iodo-substituted azopyrroles were employed by treatment with various terminal alkynes through Sonogashira cross-coupling leading to new azo compounds.

Full text of DOI:10.1021/jo5004967

Article
pubs.acs.org/joc
Oxidative Dehydrogenative Couplings of Pyrazol-5-amines
Selectively Forming Azopyrroles
Bo Jiang,*,† Yi Ning,† Wei Fan,† Shu-Jiang Tu,*,† and Guigen Li‡,§
†School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou 221116, P. R. China
‡Institute of Chemistry & Biomedical Sciences, Nanjing University, Nanjing 210093, P. R. China
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: New oxidative dehydrogenative couplings of pyrazol-5-amines for the selective synthesis of azopyrrole derivatives
have been described. The former reaction simultaneously installs C−I and N−N bonds through iodination and oxidation,
whereas the latter involved a copper-catalyzed oxidative coupling process. The resulting iodo-substituted azopyrroles were
employed by treatment with various terminal alkynes through Sonogashira cross-coupling leading to new azo compounds.
(I2) with copper catalyst and tert-butyl hydroperoxide
(TBHP)11 as an oxidant (Scheme 1). To the best of our
knowledge, this is the first catalytic approach to azopyrazole
compounds through iodination of pyrazol-5-amines using
TBHP as the oxidant.
INTRODUCTION
■
Aromatic azo compounds have been playing a pivotal role in
organic and biomedical sciences for several decades.1−5 They
serve as therapeutic agents, radical reaction initiators, food
additives, etc.1 and can be utilized in research on photochemical
molecular switches,2 self-assembly of liquid crystal materials,3
biomedical imaging,4 and light-driven molecular motors.5 Many
efforts have been devoted to the synthesis of azo derivatives,
which made it more powerful and applicable.6 Among them,
the oxidation of anilines has taken a dominant position,7 and
various stoichiometric oxidants such as manganese salts,7a lead
salts,7b,c mercury salts,7d,e ferrates,7f,g or N-chloroacetanilide7h
have been utilized for oxidation. The reduction of nitro
aromatic derivatives by stoichiometric amounts of metals was
previously reported.8,9 However, these catalytic procedures are
focused on the synthesis of aromatic azo compounds, and the
construction of heteroaryl azo derivatives was seldom
investigated. Salaheldin and co-workers have developed a
protocol for the oxidation of pyrazol-5-amines to pyrazolyl azo
derivatives using NBS as the oxidant, but narrow substrate
scopes and the employment of environmentally malignant
oxidants has limited its application.10 Therefore, the develop-
ment of alternative step-economical routes to azo derivatives by
minimizing waste and byproducts continues to be of great
interest and importance. Herein, we demonstrate a novel
method for the construction of azo compounds from
inexpensive and commercially available pyrazol-5-amines
under mild conditions using readily available molecular iodine
Scheme 1. Selective Formation Azopyrrole Derivatives
RESULTS AND DISCUSSION
■
The use of iodine and TBHP as a catalytic system to construct
active molecules has attracted considerable attention.12 Our
investigation began with the reaction of pyrazol-5-amines (1a)
in the presence of 1.1 equiv of iodine and TBHP (4.0 equiv).
The results were summarized in Table 1. First, the solvent
Received: March 2, 2014
Published: April 14, 2014
© 2014 American Chemical Society
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corresponding yield was improved to 86% from 62%. A further
increase in the amount of iodine to 1.3 equiv failed to improve
the yield of desired product 2a. Moreover, without TBHP, the
reaction of 1a with 1.1 equiv of iodine in the presence of
K2CO3 (1.5 equiv) did not proceed at 50 °C, using ethanol as a
solvent (see the control experiment). The structure of 2a was
determined by X-ray diffraction analysis (see the Supporting
Information). It was shown that in this reaction iodine behaved
as both Lewis acid catalyst and iodination reagent for this
oxidative dehydrogenative coupling.
With these optimized reaction conditions in hand, the scope
of pyrazol-5-amines in the direct oxidative dehydrogenative
coupling of iodine with a variety of pyrazol-5-amines was
investigated. The results were summarized in Scheme 2. As
aniticipated, the substituents on the aromatic ring of pyrazol-5-
amines 1 did not hamper the reaction process. Reactions of
methyl- (1f,g), chloro- (1h), or bromophenyl-substituted (1k)
pyrazol-5-amines proceeded efficiently to afford the desired
products in good to excellent yields. Variation of nitrogen-
tethered substituents on the pyrazole ring 1 including methyl
cyclopropyl, ethyl, and tert-butyl groups afforded heteroaryl azo
compounds in moderate to good yields through oxidative
dehydrogenative coupling and iodination using TBHP as the
oxidant. Importantly, iodination of heteroaromatics is an
electrophilic substitution reaction, which has immense synthetic
and industrial value.14
Table 1. Optimization for the Synthesis of Product 2a
a
entry
I2 (equiv)
solvent
temp (°C)
yield (%)
1
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.3
toluene
CHCl3
DMF
40
40
40
reflux
40
rt
trace
38
22
46
67
42
86
79
62
84
3
4
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
5
6
7
50
60
50
50
8
9
10
a
Isolated yield.
effect was examined in this reaction. It was found that the
reaction cannot proceed in toluene. When CHCl3 or DMF was
employed as solvent, low yields of the desired product were
isolated. The identical reaction in CH2Cl2 under refluxing
conditions afforded 2a in slightly higher yield (46%).13 The
best yield of 67% was obtained when the reaction was
performed in EtOH. We then examined the effect of different
reaction temperatures on the reaction. This reaction worked
more efficiently in EtOH at an enhanced temperature of 50 °C,
leading to the corresponding product 2a in 86% yield (entry 7).
With substrate 1a, a lower yield of the product was obtained
when the reaction was performed at lower (rt) or higher (60
°C) reaction temperature (entries 6 and 8). Finally, the effect of
different amounts of iodine was examined. When the amount of
iodine was changed to 1.1 equiv from 1.0 equiv, the
After the above reactions were accomplished, we then turned
our attention toward examining the oxidative dehydrogenative
coupling of pyrazol-5-amines without iodination. We envisaged
that the above oxidative iodination is occurring due to excess
usage of iodine (1.1 equiv) and examined whether the products
2 or 3 can be obtained with the decrease in the amount of
iodine to 0.1 equiv. On the basis of this analysis, oxidative
dehydrogenative coupling of pyrazol-5-amines 2a was attemp-
ted using 0.1 equiv of iodine as catalyst and 3.0 equiv of TBHP
Scheme 2. Synthesis of Azopyrrole Derivatives 2
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as the oxidant, and the reaction was performed in EtOH.
However, the product 2 was still obtained. Without iodine, this
coupling reaction proceeds with no desired product obtained.
We then planned to use the copper(I) reagent as a catalyst to
succeed in this oxidative dehydrogenative coupling. The
coupling reaction of pyrazol-5-amines 1a was carried out in
EtOH using CuI (10 mol %) as a catalyst without any additive,
but no desired product 3a was detected. When pyridine was
used as a ligand in this reaction, product 3a was obtained in
18% yield (Table 2, entry 1), which indicated that ligand is the
other reaction parameters, 10 mol % of CuI and 30 mol % of
1,10-phenanthroline in CH2Cl2 at room temperature under air
were found to be the best conditions for this reaction affording
the product in 56% yield (Table 2, entry 3).
With the optimized conditions in hand, we next explored its
scope using various readily available pyrazol-5-amines. A series
of substituted pyrazol-5-amines 1 were successfully transformed
into the corresponding heteroaryl azo compounds 3 through
oxidative dehydrogenative coupling, and the results are
summarized in Scheme 3. It should be noted that the reaction
of pyrazol-5-amines 1i−j gave the corresponding product 3h−i
in lower yields, respectively, due to its relatively lower reactivity.
It should be noted that the iodination of aryl ring is special and
useful in the formation of carbon−carbon bonds through
Sonogashira cross-coupling.15 To further expand the scope of
this reaction and construct new azo compounds, the coupling
of the resulting azopyrroles 2a with various terminal alkynes 4
was performed with a palladium catalyst and a copper(I)
cocatalyst, using Et3N as base at 50 °C under argon. The
expected coupling products 5 were isolated in 28−51%
chemical yields (Scheme 4). 4-Methyl- and 4-t-butyl-substituted
arylalkynes showed higher reactivity than those substituents in
the meta position, therefore providing better yields. Hex-1-yne
was suitable for this Sonogashira cross-coupling. The structure
of 5b was determined by X-ray diffraction analysis (see the
Supporting Information).
As a probe to the mechanism (Scheme 5), when the mixture
of pyrazol-5-amines 1a with 1.1 equiv of iodine and TBHP (4.0
equiv) was treated in the presence of radical scavenger TEMPO
(4 equiv), the reaction gave complex mixtures and the desired
product 2a was not observed, indicating the possibility of a
radical mechanism (eq 1). As a further support to the radical
path of the mechanism, the reactions were carried out
independently with I2 and CuI under air conditions without
the use of aq TBHP. The desired products 2a and 3a were not
Table 2. Optimization for the Synthesis of Product 3a
a
entry
cat. (mol %)
additive (mol %)
solvent
yield (%)
1
2
3
4
5
CuI (10)
CuI (10)
CuI (10)
CuI (5)
pyridine (30)
pyridine (30)
1,10-phen (30)
1,10-phen (15)
1,10-phen (60)
EtOH
18
45
56
42
56
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CuI (20)
a
Isolated yield.
key for this efficient transformation. Encouraged by the above
results, we then investigated the effect of different solvents:
poor yields of product 3a were obtained in CHCl3 (30%) and
DMF (35%), respectively. After optimization, CH2Cl2 was
found to be the best solvent for this reaction, affording the
product in 45% yield. Attempts to employ other metal catalysts
such as CuBr (27%), CuCl (25%), and AuCl (trace) were
unsuccessful. Further studies indicated that the efficiency of this
transformation was improved when 1,10-phenanthroline was
used as a ligand (Table 2, entry 3). After extensive screening of
Scheme 3. Synthesis of Azopyrrole Derivatives 3
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a
of azopyrroles 3e did not give the desired azopyrrole product
2e (eq 5). These controlled experiments suggest that TBHP is
essential for this transformation and the iodination occurred
prior to coupling step. To determine the oxidative dehydrogen-
ation process, the reaction of 4-iodopyrazoles 6a in the
presence of 1.1 equiv of iodine was performed, which did not
provide the desired azopyrrole 2a (eq 6). It was shown that
iodine cannot promote the coupling of the NH2 group. Thus,
we reasoned that in situ generated tert-butoxy radical from
TBHP catalyzed by I2 may take part in the oxidative
dehydrogenation process.
Scheme 4. Application of Azopyrroles 2a
On the basis of literature reports17 and from the observations
of the control experiments, a mechanism analogous to the one
recently proposed18 was envisaged for these reactions. Since
peroxides are the most common source of spontaneously
induced free radicals, which was in combination with I211or
copper salt19 to serve as a single-electron oxidant, it was
proposed that a single-electron transfer (SET) process might be
involved in the dehydrogenative coupling. The proposed
mechanism for forming azopyrroles 2 and 3 is depicted in
Scheme 6. In the former reaction, the single-electron oxidation
of pyrazol-5-amines 1,19 mediated by TBHP in the presence of
I2, results in radical cation A, followed by resonance to radical
cation A′, which was subjected with molecular iodine to form
iodo-substituted imine cation B. Then, the imine cation B
underwent tautomerization to give iodo-substituted enamines
C mediated by TBHP in the presence of I2, forming the
corresponding radical cation D. Subsequent coupling of D with
C gives a three-electron σ bond E,6a,19 which consecutively
donates two protons and one electron providing hydrazine F.
Hydrazine F is further converted into the corresponding
aromatic azo product 2 mediated by in situ generated tert-
butoxy radical from TBHP catalyzed by I2. Peroxides
spontaneously induced by copper(I) catalyst are the most
common source of free radicals,20 and the copper(II) catalyst,
generated by the initiator peroxides, oxidizes arylamino group
into arylamino radical cation by single-electron transfer (SET)
process.18 Similar to the former, the latter involves a single-
electron oxidation mediated by copper(II) catalyst generated by
the initiator TBHP (1 to A), intermolecular coupling (A to G),
and oxidization (G to H) to give aromatic azo product 3
(Scheme 6).
a
Conditions: (Ph3P)2PdCl2 (5 mol %), CuI (10 mol %), Et3N (4.0
mL), 50 °C, 12 h.
Scheme 5. Control Experiments
In conclusion, we have developed a novel oxidative
dehydrogenative coupling strategy of pyrazol-5-amines for the
selective formation of highly functionalized heteroaromatic azo
compounds by controlling the catalytic system. The former
reaction simultaneously installs C−I and N−N bonds through
intermolecular iodination and oxidation, showing that the
synthetic route allows us to build blocks of iodo-substituted
azopyrroles 2 with a wide diversity in substituents. The latter
involved a copper-catalyzed oxidative coupling of pyrazol-5-
amines, which were directly converted into azopyrroles 3. The
mild reaction conditions, selective modification of pyrrole
skeleton, and high bond-forming efficiency (BFE) make this
oxidative coupling strategy highly viable for future applications.
A detailed study of this oxidative dehydrogenative mechanism
and the application of this reaction are currently in progress.
observed in either of these reactions (eqs 2 and 3). These
control experiments suggest that neither I2 nor CuI alone is
sufficient to form the radical cation and the radical initiator
TBHP is essential for this transformation. Furthermore, to
further confirm the iodination sequence, the reaction of 4-
iodopyrazoles was carried out to generate the desired
azopyrrole product 2a in 89% yield (eq 4),16 but the reaction
EXPERIMENTAL SECTION
■
General Methods. HRMS (APCI or ESI) was measured with a
miroTOF HRMS instrument.
Example for the Synthesis of 2a. (E)-1,2-Bis(4-iodo-3-methyl-1-
phenyl-1H-pyrazol-5-yl)diazene. 3-Methyl-1-phenyl-1H-pyrazol-5-
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Scheme 6. Proposed Mechanisms for the Direct Transformation
amine (1a, 1 mmol, 173 mg) was introduced in a 25 mL reaction flask,
and I2 (1.1 mmol, 279.4 mg), K2CO3 (1.5 mmol, 207 mg), and EtOH
(3.0 mL) as well as aq TBHP (TBHP 70% solution in water, 0.2 mL,
2.0 mmol) were then successively added and the mixture stirred at 50
°C for 3 h. After completion of the reaction (monitored by TLC), the
reaction mixture was then cooled to room temperature and diluted
29.2; HRMS (APCI) m/z calcd for C26H28I2N6 679.0543 [M + H]+,
found 679.0543.
(E)-1,2-Bis(4-iodo-3-methyl-1-p-tolyl-1H-pyrazol-5-yl)diazene
(2f): red solid, 0.200 g; yield 64%; mp 201−203 °C; IR (KBr, ν, cm−1)
1
1559, 1542, 1509, 1457, 1173, 1037, 816, 780, 669; H NMR (400
MHz, CDCl3) (δ, ppm) 7.48 (d, J = 7.4 Hz, 4H, ArH), 7.37−7.09 (m,
4H, ArH), 2.42 (s, 6H, CH3), 2.38 (s, 6H, CH3); 13C NMR (100
MHz, CDCl3) (δ, ppm) 153.4, 149.6, 138.1, 136.6, 129.4, 125.6, 52.6,
21.2, 14.5; HRMS (APCI) m/z calcd for C22H22I2N6 625.0074 [M +
H]+, found 625.0089.
(E)-1,2-Bis(4-iodo-1-phenyl-3-p-tolyl-1H-pyrazol-5-yl)diazene
(2g): orange red solid, 0.310 g, yield 83%; mp 142−144 °C; IR (KBr,
ν, cm−1) 1595, 1499, 1422, 1299, 1200, 962, 822, 688; 1H NMR (400
MHz, CDCl3) (δ, ppm) 7.79−7.71 (m, 4H, ArH), 7.65 (d, J = 7.9 Hz,
3H, ArH), 7.51 (d, J = 5.8 Hz, 2H, ArH), 7.49−7.38 (m, 7H, ArH),
7.29 (s, 2H, ArH), 2.42 (s, 3H, CH3), 2.41 (s, 3H,CH3); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 149.9, 129.7, 129.4, 129.3, 129.2, 129.0,
128.9, 128.6, 128.5, 126.0, 124.9, 21.4; HRMS (APCI) m/z calcd for
C32H24I2N6 747.0230 [M + H]+, found 747.0252.
(E)-1,2-Bis(3-(4-chlorophenyl)-4-iodo-1-methyl-1H-pyrazol-5-yl)-
diazene (2h): yellow solid, 0.277 g, yield 89%; mp 146−147 °C; IR
(KBr, ν, cm−1) 1596, 1508, 1432, 1397, 1089, 981, 830; 1H NMR (400
MHz, CDCl3) (δ, ppm) 7.83−7.70 (m, 4H, ArH), 7.45 (d, J = 7.8 Hz,
4H, ArH), 4.31 (s, 6H, CH3); 13C NMR (100 MHz, CDCl3) (δ, ppm)
151.6, 135.4, 129.9, 129.7, 129.6, 128.7, 128.6, 59.6, 42.3; HRMS
(APCI) m/z calcd for C20H15Cl2I2N6 662.8825 [M + H]+, found
662.8853.
with cold water (50 mL). The solid product was collected by Buchner
̈
filtration and was purified by flash column chromatography (silica gel,
mixtures of petroleum ether/EtOAc, 10:1, v/v) to afford the pure
product 2a: yellow solid, 0.255 g; yield 86%; mp 243−244 °C; IR
1
(KBr, ν, cm−1) 1595, 1504, 1458, 1422, 1035, 824, 768, 688, 648; H
NMR (400 MHz, CDCl3) (δ, ppm) 8.37−5.86 (m, 10H, ArH), 2.40
(s, 3H, CH3), 2.37 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) (δ,
ppm) 153.7, 138.9, 129.5, 129.3, 128.9, 128.2, 125.90, 125.0, 14.5;
HRMS (APCI) m/z calcd for C20H17I2N6 594.9604 [M + H]+, found
594.9599.
(E)-1,2-Bis(4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)diazene (2b): yel-
low solid, 0.155 g; yield 66%; mp 289−290 °C; IR (KBr, ν, cm−1)
1
1635, 1456, 1302, 1036, 882, 700; H NMR (400 MHz, CDCl3) (δ,
ppm) 4.21 (s, 6H, CH3), 2.34 (s, 6H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 152.4, 148.9, 55.9, 40.1, 14.7; HRMS (APCI) m/z
calcd for C10H12I2N6: 470.9291 [M + H]+, found: 470.9291.
(E)-1,2-bis(3-cyclopropyl-4-iodo-1-methyl-1H-pyrazol-5-yl)-
diazene (2c). Yellow solid, 0.183 g, yield 70%; mp 248−250 °C; IR
1
(KBr, ν, cm−1) 3091, 1541, 1493, 1477, 1311, 1021, 832, 698; H
NMR (400 MHz, CDCl3) (δ, ppm) 4.16 (s, 6H, CH3), 1.99−1.79 (m,
2H, CH), 1.08−0.70 (m, 8H, CH2); 13C NMR (100 MHz, CDCl3) (δ,
ppm) 154.6, 147.7, 57.4, 49.2, 8.4, 6.6; HRMS (APCI) m/z calcd for
C14H17I2N6 522.9604 [M + H]+, found 522.9586.
(E)-1,2-Bis(3-cyclopropyl-4-iodo-1-phenyl-1H-pyrazol-5-yl)-
diazene (2d): orange red solid, 0.223 g; yield 69%; mp 91−92 °C; IR
(KBr, ν, cm−1) 1594, 1506, 1415, 1331, 1003, 833, 765, 692; 1H NMR
(400 MHz, CDCl3) (δ, ppm) 7.58−7.55 (m, 2H, ArH), 7.50−7.39 (m,
5H, ArH), 7.38−7.29 (m, 3H, ArH), 2.05−1.83 (m, 2H, CH), 1.09−
0.93 (m, 8H, CH2); 13C NMR (100 MHz, CDCl3) (δ, ppm) 129.4,
129.3, 128.8, 128.1, 125.9, 125.0, 52.5, 9.9, 9.6, 8.2, 7.9; HRMS
(APCI) m/z calcd for C24H21I2N6 646.9917 [M + H]+, found
646.9916.
(E)-1,2-Bis(3-tert-butyl-4-iodo-1-phenyl-1H-pyrazol-5-yl)diazene
(2e): red solid, 0.231 g; yield 68%; mp 186−189 °C; IR (KBr, ν, cm−1)
1542, 1507, 1458, 1418, 999, 756, 685, 669; 1H NMR (400 MHz,) (δ,
ppm) 8.47 (d, J = 8.3 Hz, 4H, ArH), 7.57 (t, J = 7.8 Hz, 4H, ArH),
7.39−7.16 (m, 2H, ArH), 1.72 (s, 18H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 153.1, 141.9, 139.9, 132.4, 129.2, 125.1, 119.4, 34.3,
(E)-1,2-Bis(4-iodo-1-methyl-1H-pyrazol-5-yl)diazene (2i): yellow
solid, 0.106 g; yield 48%; mp 99−101 °C; IR (KBr, ν, cm−1) 1541,
1
1436, 1329, 1023, 967, 876, 829; H NMR (400 MHz, CDCl3) (δ,
ppm) 7.62 (s, 2H, CH), 4.28 (s, 6H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 146.3, 144.9, 59.78, 42.3; HRMS (APCI) m/z calcd
for C8H9I2N6 442.8972 [M + H]+, found 442.8968.
(E)-1,2-Bis(1-ethyl-4-iodo-1H-pyrazol-5-yl)diazene (2j): red solid,
0.143 g; yield 61%; mp 179−181 °C; IR (KBr, ν, cm−1)1541, 1436,
1304, 1064, 993, 946, 842, 742, 679; 1H NMR (400 MHz, CDCl3) (δ,
ppm) 7.69 (s, 2H, CH), 4.69 (q, J = 7.2 Hz, 4H, CH2), 1.54 (t, J = 7.1
Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3) (δ, ppm) 147.7, 146.4,
47.0, 45.6, 15.8; HRMS (APCI) m/z calcd for C10H13I2N6 470.9286
[M + H]+, found 470.9287.
(E)-1,2-Bis(1-(4-bromophenyl)-4-iodo-3-phenyl-1H-pyrazol-5-yl)-
diazene (2k): orange red solid; 0.337 g; yield 77%; mp 173−174 °C;
IR (KBr, ν, cm−1) 1634, 1491, 1420, 1321, 1072, 1011, 965, 828, 771,
696; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.92−7.79 (m, 4H, ArH),
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7.69−7.54 (m, 6H, ArH), 7.54−7.44 (m, 6H, ArH), 7.33 (d, J = 8.2
Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) (δ, ppm) 132.6, 132.1,
129.6, 129.1, 128.8, 128.7, 128.6, 128.4, 127.2, 126.5,64.3; HRMS
(APCI) m/z calcd for C30H19Br2I2N6 876.8103 [M + H]+, found
876.8123.
(APCI) m/z calcd for C20H16Cl2N6 411.0886 [M + H]+, found
411.0848.
(E)-1,2-Bis(1-methyl-1H-pyrazol-5-yl)diazene (3h): yellow solid
(eluent, petroleum ether/ethyl acetate 30:1 v/v), 0.035 g; yield 37%;
mp 77−78 °C; IR (KBr, ν, cm−1)1730, 1571, 1447, 1335, 1287, 1124,
1075, 968, 873, 833, 744; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.71
(dd, J = 9.0, 4.0 Hz, 1H, CH), 7.61 (s, 2H, CH), 7.53 (dd, J = 5.4, 3.0
Hz, 1H, CH), 4.27 (s, 6H, CH3); 13C NMR (100 MHz, CDCl3) (δ,
ppm) 144.9, 130.9, 128.8, 42.2; HRMS (APCI) m/z calcd for C8H11N6
191.1045 [M + H]+, found 191.1040.
Example for the Synthesis of 3a. (E)-1,2-Bis(3-methyl-1-phenyl-
1H-pyrazol-5-yl)diazene. 3-Methyl-1-phenyl-1H-pyrazol-5-amine (1a,
1 mmol, 173 mg) was introduced in a 25 mL reaction flask. CuI (0.05
mmol, 9.5 mg), 1,10-phenanthroline (0.15 mmol, 27 mg), and CH2Cl2
(2.0 mL) as well as aq TBHP (TBHP 70% solution in water, 0.15 mL,
1.5 mmol) were then successively added and the mixture stirred at
room temperature for 2 h. After the completion of the reaction
(monitored by TLC), the solvent was removed under vacuum. The
residue was separated by column chromatography on silica gel (eluent,
petroleum ether/ethyl acetate 10:1 v/v) to afford the pure product 3a:
oil, (eluent, petroleum ether/ethyl acetate 10:1 v/v), 0.096 g; yield
56%; IR (KBr, ν, cm−1)1597, 1517, 1422, 1343, 1141, 1021, 831, 764,
(E)-1,2-Bis(1-ethyl-1H-pyrazol-5-yl)diazene (3i): yellow solid (elu-
ent, petroleum ether/ethyl acetate 30:1 v/v), 0.031 g; yield 28%; mp
91−92 °C; IR (KBr, ν, cm−1)1520, 1464, 1363, 1190, 1082, 968, 855,
1
819, 722; H NMR (400 MHz, CDCl3) (δ, ppm) 7.51 (s, 2H, CH),
7.06 (s, 2H, CH), 4.66 (q, J = 7.2 Hz, 4H, CH2), 1.50 (t, J = 7.2 Hz,
6H, CH3); 13C NMR (100 MHz, CDCl3) (δ, ppm) 137.8, 128.8,
106.7, 48.6, 15.2; HRMS (APCI) m/z calcd for C10H15N6 219.1358
[M + H]+, found 219.1388.
1
693; H NMR (400 MHz, CDCl3) (δ, ppm) 7.49 (d, J = 5.6 Hz, 6H,
ArH), 7.41−7.35 (m, 4H, ArH), 6.99 (s, 2H, CH), 2.38 (s, 6H, CH3);
13C NMR (100 MHz, CDCl3) (δ, ppm) 148.9, 138.7, 129.34, 129.1,
128.8, 125.7, 125.0, 124.8, 106.6, 13.8; HRMS (APCI) m/z calcd for
C20H19N6 343.1666 [M + H]+, found 343.1701.
(E)-1,2-Bis(1-(4-bromophenyl)-3-phenyl-1H-pyrazol-5-yl)diazene
(3j): yellow solid (eluent, petroleum ether/ethyl acetate 30:1 v/v),
0.131 g; yield 42%; mp 161−163 °C; IR (KBr, ν, cm−1)1588, 1526,
1
1505, 1422, 1345, 1069, 1006, 834, 765, 685; H NMR (400 MHz,
(E)-1,2-Bis(1,3-dimethyl-1H-pyrazol-5-yl)diazene (3b): yellow
solid (eluent, petroleum ether/ethyl acetate 10:1 v/v), 0.056 g; yield
51%; mp 140−144 °C; IR (KBr, ν, cm−1) 1598, 1521, 1444, 1341,
CDCl3) (δ, ppm) 7.84 (d, J = 7.7 Hz, 4H, ArH), 7.67 (d, J = 8.6 Hz,
4H, ArH), 7.53−7.37 (m, 10H, ArH), 7.35 (s, 2H, CH); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 151.5, 137.8, 132.4, 130.7, 129.4, 129.0,
127.5, 125.8, 123.7, 119.6, 104.2; HRMS (APCI) m/z calcd for
C30H21Br2N6 625.0170 [M + H]+, found 625.0174.
1
1028, 993, 837, 742; H NMR (400 MHz, CDCl3) (δ, ppm) 6.33 (s,
2H, CH), 4.11 (s, 6H, CH3), 2.32 (s, 6H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 130.9, 128.9, 93.1, 35.6, 19.2, 13.9; HRMS (APCI)
m/z calcd for C10H15N6 219.1358 [M + H]+, found 219.1358.
(E)-1,2-bis(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)diazene (3c):
red oil (eluent, petroleum ether/ethyl acetate 10:1 v/v), 0.093 g;
yield 69%; IR (KBr, ν, cm−1)2926, 1653, 1517, 1448, 1289, 1008, 785,
679; 1H NMR (400 MHz, CDCl3) (δ, ppm) 6.72 (s, 2H, CH), 4.16 (s,
6H, CH3), 1.99−1.82 (m, 2H, CH), 1.00−0.93 (m, 4H, CH2), 0.81−
0.70 (m, 4H, CH2); 13C NMR (100 MHz, CDCl3) (δ, ppm) 163.9,
153.5, 102.6, 40.5, 9.0, 8.1; HRMS (APCI) m/z calcd for C14H19N6
271.1671 [M + H]+, found 271.1673.
(E)-1,2-Bis(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)diazene (3d):
brown oil (eluent, petroleum ether/ethyl acetate 20:1 v/v), 0.121 g;
yield 57%; IR (KBr, ν, cm−1) 2955, 1596, 1522, 1419, 1345, 1234, 985,
815, 774, 697; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.51−7.45 (m,
6H, ArH), 7.42−7.38 (m, 4H, ArH), 7.06 (s, 2H, CH), 1.37 (s, 18H,
CH3); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.8, 138.9, 129.2,
129.1, 128.8, 125.8, 103.8, 32.6, 30.3; HRMS (APCI) m/z calcd for
C26H31N6 427.2610 [M + H]+, found 427.2623.
Example for the Synthesis of 5a. (E)-1,2-Bis(3-methyl-1-phenyl-4-
(phenylethynyl)-1H-pyrazol-5-yl)diazene. Under an argon atmos-
phere, (E)-1,2-bis(4-iodo-3-methyl-1-phenyl-1H-pyrazol-5-yl)diazene
(2a) (593 mg, 1 mmol) and CuI (19 mg, 0.1 mmol) as well as
bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol)
were introduced into a 25 mL Schlenk reaction flask, and
ethynylbenzene 3a (208 mg, 2 mmol) and TEA (4 mL) were then
successively added into this reaction mixture. The reaction system was
stirred at 50 °C for 12 h. After completion of the reaction (monitored
by TLC), the TEA was removed under vacuum. The residue was
purified by flash column chromatography (silica gel, mixtures of
petroleum ether/ethyl acetate, 40:1, v/v) to afford the pure product
5a: red solid, 0.190 g; yield 35%; mp 192−193 °C; IR (KBr, ν, cm−1)
1
2287, 1594, 1500, 1464, 1366, 1117, 807, 750, 686. H NMR (400
MHz, CDCl3) (δ, ppm) 7.82 (d, J = 8.0 Hz, 4H, ArH), 7.29−7.28 (m,
2H, ArH), 7.24−7.19 (m, 8H, ArH), 7.12−7.08 (m, 6H, ArH), 2.49 (s,
6H, CH3); 13C NMR (100 MHz, CDCl3) (δ, ppm) 153.1, 152.5,
138.7, 131.5, 128.8, 128.2, 128.1, 127.5, 124.4, 123.2, 95.3, 93.9, 81.9,
12.8; HRMS (ESI) m/z calcd for C36H27N6 543.2297 [M + H]+, found
543.2306.
(E)-1,2-Bis(3-methyl-1-p-tolyl-1H-pyrazol-5-yl)diazene (3e): yel-
low solid (eluent, petroleum ether/ethyl acetate 20:1 v/v), 0.143 g;
yield 77%; mp 82−83 °C; IR (KBr, ν, cm−1) 2924, 1698, 1509, 1434,
(E)-1,2-Bis(3-methyl-1-phenyl-4-(p-tolylethynyl)-1H-pyrazol-5-yl)-
diazene (5b): red solid, 0.291 g, yield 51%; mp 204−205 °C; IR (KBr,
ν, cm−1) 2203, 1594, 1505, 1420, 1364, 1116, 815, 755, 690. 1H NMR
(400 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.0 Hz, 4H, ArH), 7.24−
7.20 (m, 4H, ArH), 7.15−7.12 (m, 2H, ArH), 7.04−6.98 (m, 8H,
ArH), 2.49 (s, 6H, CH3), 2.36 (d, J = 6.4 Hz, 6H, CH3); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 153.0, 152.5, 138.7, 138.3, 131.4, 128.9,
128.8, 127.5, 124.4, 120. 1, 95.5, 94.1, 81.3, 21.6, 12.8; HRMS (ESI)
m/z calcd for C38H31N6 571.2610 [M + H]+, found 571.2638.
(E)-1,2-Bis(4-((4-tert-butylphenyl)ethynyl)-3-methyl-1-phenyl-1H-
pyrazol-5-yl)diazene (5c): red solid, 0.327 g; yield 50%; mp 208−209
°C; IR (KBr, ν, cm−1) 2210, 1594, 1499, 1461, 1363, 1101, 833, 756,
1
1349, 1020, 840, 814, 740; H NMR (400 MHz, CDCl3) (δ, ppm)
7.28 (d, J = 8.6 Hz, 6H, ArH), 7.25 (d, J = 8.8 Hz, 2H, ArH), 6.97 (s,
2H, CH), 2.43 (s, 6H, CH3), 2.37 (s, 6H, CH3); 13C NMR (100 MHz,
DMSO-d6) (δ, ppm) 143.5, 134.3, 131.0, 124.4, 120.2, 101.1, 25.7,
16.0, 8.6; HRMS (APCI) m/z calcd for C22H25N6 373.2141 [M + H]+,
found 373.2153.
(E)-1,2-Bis(1-phenyl-3-p-tolyl-1H-pyrazol-5-yl)diazene (3f): yellow
solid (eluent, petroleum ether/ethyl acetate 15:1 v/v), 0.124 g; yield
50%; mp 157−158 °C; IR (KBr, ν, cm−1) 1595, 1506, 1423, 1332,
1012, 950, 806, 765, 689; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.75
(d, J = 8.0 Hz, 4H, ArH), 7.59−7.50 (m, 7H, ArH), 7.49−7.40 (m, 7H,
ArH), 7.27 (s, 2H, CH), 2.40 (s, 6H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 151.2, 139.3, 138.9, 129.8, 129.6, 129.5, 129.2, 128.2,
125.9, 125.7, 103.7, 21.4; HRMS (APCI) m/z calcd for C32H27N6
495.2297 [M + H]+, found 495.2287.
1
688. H NMR (400 MHz, CDCl3) (δ, ppm) 7.81 (d, J = 8.2 Hz, 4H,
ArH), 7.24−7.22 (m, 4H, ArH), 7.19−7.16 (m, 4H, ArH), 7.08−7.04
(m, 6H, ArH), 2.48 (s, 6H, CH3), 1.32 (s, 18H, CH3); 13C NMR (100
MHz, CDCl3) (δ, ppm) 152.9, 152.5, 151.5, 138.7, 131.2, 128.7, 127.3,
125.1, 124.4, 120.2, 95.6, 94.1, 81.3, 34.8, 31.2, 12.8; HRMS (ESI) m/z
calcd for C44H43N6 655.3549 [M + H]+, found 655.3550.
(E)-1,2-Bis(3-methyl-1-phenyl-4-(m-tolylethynyl)-1H-pyrazol-5-
yl)diazene (5d): red solid, 0.182 g, yield 32%; mp 161−163 °C; IR
(KBr, ν, cm−1) 2273, 1596, 1499, 1409, 1366, 1158, 784, 752, 687. 1H
NMR (400 MHz, CDCl3) (δ, ppm) 7.84 (d, J = 8.2 Hz, 4H, ArH),
7.20−7.18 (m, 4H, ArH), 7.14−7.06 (m, 6H, ArH), 6.97−6.90 (m,
(E)-1,2-Bis(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)diazene
(3g): yellow solid (eluent, petroleum ether/ethyl acetate 15:1 v/v),
0.131 g; yield 64%; mp 132−133 °C; IR (KBr, ν, cm−1) 1600, 1543,
1
1494, 1437, 1333, 1091, 951, 837, 819, 743; H NMR (400 MHz,
CDCl3) (δ, ppm) 7.72 (d, J = 8.4 Hz, 4H, ArH), 7.41 (d, J = 8.4 Hz,
4H, ArH), 7.30 (s, 2H, CH), 4.30 (s, 6H, CH3); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 148.4, 134.9, 129.8, 129.1, 126.8, 102.7, 41.0; HRMS
4023
dx.doi.org/10.1021/jo5004967 | J. Org. Chem. 2014, 79, 4018−4024

The Journal of Organic Chemistry
Article
4H, ArH), 2.50 (s, 6H, CH3), 2.28 (s, 6H, CH3); 13C NMR (100
MHz, CDCl3) (δ, ppm) 153.1, 152.5, 138.7, 137.8, 131.9, 129.1, 128.8,
128.7, 128.1, 127.4, 124.3, 123.0, 95.6, 94.0, 81.5, 21.3, 12.8; HRMS
(ESI) m/z calcd for C38H31N6 571.2610 [M + H]+, found 571.2611.
(E)-1,2-Bis(4-((3-methoxyphenyl)ethynyl)-3-methyl-1-phenyl-1H-
pyrazol-5-yl)diazene (5e): red solid, 0.169 g; yield 28%; mp 174−176
°C; IR (KBr, ν, cm−1) 2246, 1594, 1499, 1420, 1368, 1116, 844, 757,
H. J. Org. Chem. 1995, 60, 1326. (d) Lim, Y.-K.; Lee, K.-S.; Cho, C.-G.
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1965, 30, 1203. (b) Firouzabadi, H.; Mostafavippor, Z. Bull. Chem. Soc.
Jpn. 1983, 56, 914. (c) Birchall, J. M.; Haszeldine, R. N.; Kemp, J. E. G.
Chem. Commun. 1970, 449. (d) Wenkert, K.; Wickberg, B. J. Am.
Chem. Soc. 1962, 84, 4914. (e) Farhadi, S.; Zaringhadam, P.; Sahamieh,
R. Z. Acta Chim. Slov. 2007, 54, 647. (f) Goldstein, S. L.; McNelis, E. J.
Org. Chem. 1973, 38, 183. (g) Huang, H.; Sommerfeld, D.; Dunn, B.
C.; Lloyd, C. R.; Eyring, E. M. J. Chem. Soc., Dalton Trans. 2001, 1301.
(h) Kumar, A.; Bhattacharjee, G. J. Indian Chem. Soc. 1991, 68, 523.
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77.
(9) Dabbagh, H. A.; Teimouri, A.; Chermahini, A. N. Dyes Pigments
2007, 73, 239.
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Tetrahedron Lett. 2007, 48, 8819.
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1983, 48, 3607. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 56.
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2010, 12, 2841. (b) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z.
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K.; Prabhu, K. R. Org. Lett. 2013, 15, 1092.
1
682. H NMR (400 MHz, CDCl3) (δ, ppm) 7.82 (d, J = 8.2 Hz, 4H,
ArH), 7.22−7.07 (m, 8H, ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 6.77−
6.69 (m, 4H, ArH), 3.76 (s, 6H, CH3), 2.49 (s, 6H, CH3); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 159.2, 153.1, 152.6, 138.6, 129.2, 128.8,
127.5, 124.3, 124.2, 116.2, 114.8, 95.3, 93.8, 81.7, 55.3, 12.8; HRMS
(ESI) m/z calcd for C38H31N6O2 603.2508 [M + H]+, found 603.2501.
(E)-1,2-Bis(4-(hex-1-yn-1-yl)-3-methyl-1-phenyl-1H-pyrazol-5-yl)-
diazene (5f): red solid, 0.136 g; yield 27%; mp 238−240 °C, IR (KBr,
ν, cm−1) 2238, 1595, 1504, 1422, 1340, 1186, 824, 768, 688, 760, 688;
1H NMR (400 MHz, CDCl3) (δ, ppm) 7.84−7.79 (m, 4H, ArH),
7.46−7.42 (m, 4H, ArH), 7.33 (m, 2H, ArH), 2.38 (s, 6H, CH3), 2.05
(m, 4H, CH2), 1.33 (m, 8H, CH2), 0.87 (d, J = 7.2 Hz, 6H, CH3); 13
C
NMR (100 MHz, CDCl3) (δ, ppm) 153.0, 152.5, 139.1, 128.7, 127.2,
124.6, 96.9, 94.4, 72.4, 29.7, 22.0, 19.5, 13.6, 12.6; HRMS (ESI) m/z
calcd for C32H34N6 503.2923 [M + H], found 503.2927.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all pure products, and X-ray
crystal data (CIF) for 2a and 5b. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Crystal data for 2a (CCDC-953161).
(14) Frota, C.; Casagrande, G. A.; Pizzuti, L.; Raminelli, C. Curr. Org.
Synth. 2013, 10, 265.
(15) (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
(b) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(c) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, 1998. (d) Miyaura, N. Cross-Coupling
Reaction; Springer: Berlin, 2002. (e) de Meijere, A.; Diederich, F.
Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim,
2004.
(16) For the preparation of 4-iodopyrazoles, see: Kim, M. M.; Ruck,
R. T.; Zhao, D.; Huffman, M. A. Tetrahedron Lett. 2008, 49, 4026.
(17) (a) Hub, W.; Schneider, S.; Doerr, F.; Oxman, J. D.; Lewis, F. D.
J. Am. Chem. Soc. 1984, 106, 701. (b) Scaiano, J. C.; Garca, S.; Garca,
H. Tetrahedron Lett. 1997, 38, 5929. (c) Brede, O.; Maroz, A.;
Hermann, R.; Naumov, S. J. Phys. Chem. A 2005, 109, 8081.
(18) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174.
(19) (a) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett. 2013,
15, 1802. (b) Xia, X.-F.; Zhang, L.-L.; Song, X.-R.; Niu, Y.-N.; Liu, X.-
Y.; Liang, Y.-M. Chem. Commun. 2013, 1410.
AUTHOR INFORMATION
Corresponding Authors
*Fax: 86-516-83500065. E-mail: jiangchem@jsnu.edu.cn.
*Fax: 86-516-83500065. E-mail: laotu@jsnu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (Nos.
21232004, 21272095, and 21102124) and PAPD of Jiangsu
Higher Education Institutions, Jiangsu Science and Technology
Support Program (No. SBE2011045), the Qing-Lan Project
(12QLG006), the Robert A. Welch Foundation (D-1361), and
the NIH (R33DA031860). We thank Dr. Venkatesh Kattamuri
for his generous assistance.
(20) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908.
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