Facile and convenient synthesis of aryl hydrazines via copper-catalyzed C-N cross-coupling of aryl halides and hydrazine hydrate

Article abstract of DOI:10.1016/j.tet.2014.04.048

An efficient and convenient method for the synthesis of aryl hydrazines has been developed via copper-catalyzed cross-coupling of aryl bromides and hydrazine with a readily accessible ligand and water as a solvent. The multigram scale procedure is applicable to aryl bromides bearing both moderately electron-donating and electron-withdrawing substituents in the aromatic nucleus. No column chromatography is required to obtain aryl hydrazine hydrochlorides in good yields.

Full text of DOI:10.1016/j.tet.2014.04.048

Accepted Manuscript
Facile and convenient synthesis of aryl hydrazines via copper-catalyzed C–N cross-
coupling of aryl halides and hydrazine hydrate
Daria V. Kurandina, Eugene V. Eliseenkov, Petr V. Ilyin, Vadim P. Boyarskiy
PII:
S0040-4020(14)00569-9
10.1016/j.tet.2014.04.048
TET 25498
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 January 2014
Revised Date: 31 March 2014
Accepted Date: 14 April 2014
Please cite this article as: Kurandina DV, Eliseenkov EV, Ilyin PV, Boyarskiy VP, Facile and convenient
synthesis of aryl hydrazines via copper-catalyzed C–N cross-coupling of aryl halides and hydrazine
hydrate, Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.048.
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Graphical Abstract
Leave this area blank for abstract info.
Facile and convenient synthesis of aryl hydrazines via
copper-catalyzed C–N cross-coupling of aryl halides
and hydrazine hydrate
Daria V. Kurandina, Eugene V. Eliseenkov, Petr V. Ilyin, Vadim P. Boyarskiy
Department of Chemistry, Saint-Petersburg State University, Saint-Petersburg 198504, Russia
1

ACCEPTED MANUSCRIPT
Facile and convenient synthesis of aryl hydrazines via copper-catalyzed
C–N cross-coupling of aryl halides and hydrazine hydrate
Daria V. Kurandina*, Eugene V. Eliseenkov, Petr V. Ilyin, Vadim P. Boyarskiy
Department of Chemistry, Saint Petersburg State University, Saint-Petersburg 198504, Russia
*Corresponding author. Tel.: +7 981 724-71-46; fax: +7 981 724-71-46. E-mail address:
dashakura@gmail.com (Daria V. Kurandina)
Keywords: C−N cross-coupling reaction, Copper catalysis, Hydrazine hydrate, Aryl bromides,
Preparation of aryl hydrazines
ABSTRACT
An efficient and convenient method for the synthesis of aryl hydrazines has been developed via
copper-catalyzed cross-coupling of aryl bromides and hydrazine with a readily accessible ligand
and water as a solvent. The multigram scale procedure is applicable to aryl bromides bearing
both moderately electron-donating and electron-withdrawing substituents in the aromatic
nucleus. No column chromatography is required to obtain aryl hydrazine hydrochlorides in good
yields.
1. Introduction
Aryl hydrazines are widely used as intermediates in the synthesis of various nitrogen-containing
heterocyclic systems such as indoles,1 indazoles,2 arylpyrazoles,3 and aryltriazoles.4 These
heterocyclic compounds are of biological and medicinal interest.5 Preparation of aryl hydrazines
is typically carried out via the reduction of the corresponding diazonium salts with tin(II)
compounds6 or alkali metal bisulfites,7 but these methods have substantial drawbacks. Firstly,
they involve the generation of unstable diazonium intermediates which makes this method
dangerous at multigram use. Secondly, they produce large volumes of toxic aqueous wastes.
Furthermore, yields of aryl hydrazines can be decreased because their deamination is often facile
under the reaction conditions, especially for aryl hydrazines with donor substituents.8 The
alternative classical method for the synthesis of aryl hydrazines is based on nucleophilic
aromatic substitution of aryl halides with hydrazine. However, such uncatalyzed processes can
be applied only for strongly electron-deficient substrates.9
Over the last years palladium and copper-catalyzed cross-coupling reactions of aryl halides and
amines – Buchwald-Hartwig reactions10 and modified Ullmann reactions,11 respectively – have
represented the most effective instruments for the construction of new C−N bonds in aromatic
systems. Perhaps, because hydrazine is a strong reducing agent capable of destroying a metal-
containing system, its derivatives such as benzophenone hydrazone12 and BOC-hydrazines13
have been used in palladium-catalyzed cross-coupling in several studies. Stradiotto et al. have
recently reported the first palladium-catalyzed method for synthesis of aryl hydrazines from
hydrazine.14 While this protocol has obvious advantages, as compared to the classical methods
for the synthesis of aryl hydrazines, a number of drawbacks restricts its applicability. To
illustrate, the reactions were conducted in a nitrogen-filled glovebox with the high loading of an
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expensive catalyst (1.5−10 mol% of [{Pd(cinnamyl)Cl}2] and 4.5−6 mol% of the ligand Mor-
DalPhos).
Copper-catalyzed C–N couplings of aryl halides with amines (Ullmann reaction), which can be
performed with cheap catalysts and often do not require inert atmosphere, have recently become
as popular as Buchwald−Hartwig reactions.15 Although tremendous progress has been achieved
in the field of Ullmann reactions over the past decades, only one paper describing the cross-
coupling of unprotected hydrazine with aryl halides catalyzed by copper has been published.16
The authors performed the coupling reactions of hydrazine and aryl iodides with 10 mol% CuI as
a catalyst, PEG−400 as a solvent and 200 mol% K3PO4 as a base in a sealed tube at 120 °C for 6
h. The apparent disadvantages of this method are a large amount of PEG−400 (2 mL/1 mmol
ArI) and excess hydrazine (1 mL of 85% aqueous hydrazine/1 mmol ArI) obstructing the
isolation of product from the reaction mixtures. Furthermore, all of aryl hydrazines (except for
phenylhydrazine) had to be transformed into their N-tosyl derivatives in order to be isolated. All
of these factors appear to restrict the synthetic utility of the method described.
The objective of our work was to design a new and more efficient method of aryl hydrazines
synthesis using copper-catalyzed C–N cross-coupling reaction of hydrazine with aryl halides. It
has been recently found that copper catalysts containing oxalyl dihydrazide derivatives
(CONHNR'R'')2 as ligands allow C–N cross-coupling processes in water in the presence of phase
transfer
catalysts
(PTCs).17-20
For
example,
the
catalytic
systems
of
Cu(0,I,II)/(CONHNH2)2(L1)/hexane-2,5-dione(A1)17 and Cu(0,II)/PhNHNHCOCONHNH2(L2)/
hexane-2,5-dione(A1)19 were successfully applied for arylation of anilines. Inspired by these
results, we used the ligand systems based on the derivatives of oxalyl dihydrazide for copper-
catalyzed arylation of hydrazine. As an extension of their applicability for catalysis in water, we
are the first to report a new method for the synthesis of aryl hydrazines hydrochlorides via
copper-catalyzed cross-coupling of aryl bromides with hydrazine in an aqueous solution.
2. Results and discussion
The reaction of bromobenzene with hydrazine hydrate was chosen as a model process for the
study. We carried out the CuBr/L1/A1-catalyzed reaction of bromobenzene with hydrazine
hydrate for 1 h and detected that the conversion of bromobenzene was 96% and the yield of
phenylhydrazine was 73%.21 In addition, aniline (3%), which was the by-product formed by
deamination of phenylhydrazine, was found in the reaction mixture (Table 1, entry 1). As we
suppose based on the data of Pd-catalyzed C–N cross-coupling of aryl halides with hydrazine,14
the rest of the starting material was turned into benzene, whose yield we did not determine in the
optimization experiments.
We optimized the reaction conditions by screening the ligand systems of RNHNHCOCONHNH2
(ligand L)/ketone (additive A) (Table 1). Initially, it is worth to note that the reaction did not
proceed without addition of the ligand system (Table 1, entry 2). At the same time, the ligand
system did not catalyze this process without a copper source (Table 1, entry 3). The ligand L1
and the additive A1 did not work properly without each other (Table 1, entry 4, 5). The ligand
system of L1/A1 proved to be slightly more active than the ligand system of L2/A1 (Table 1,
entries 1, 6). However, the drawback of the ligand system of L2/A1 was that L2 reacted with
hydrazine to give an additional amount of phenylhydrazine. This was proven by the reaction of
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1-bromo-4-methoxybenzene with hydrazine hydrate where phenylhydrazine was found in the
reaction mixture. Therefore, our further investigation was concentrated on the ligand systems
composed of L1 and different mono- and dicarbonyl compounds as additives. The additives such
as cyclohexanone (A2) (entry 7), pentane-2,4-dione (A3) (entry 8), and 1,4-diphenylbutane-1,4-
dione (A4) (entry 9) proved to be less efficient than hexane-2,5-dione (A1).
Table 1
Cross-coupling of bromobenzene and hydrazine hydrate using different ketones as components of the ligand systema
Yield of
Yield of
Conversion,b
%
Entry
L+A
PhNHNH2,b PhNH2,b
%
%
3
1
2
3c
4
5
6
7
8
9
L1+A1
–
96
3
73
0
0
0
0
0
0
4
0
0
0
L1+A1
L1
0
38
6
9
A1
0
L2+A1
L1+A2
L1+A3
L1+A4
90
13
24
4
69
9
9
3
a Reaction conditions: bromobenzene (1 mmol), N2H4ꢀH2O (2 mmol), CuBr (0.05 mmol), L (0.1 mmol), A (0.1 mmol), СТАВ (0.1 mmol), K3PO4
(1 mmol), H2O (50 mg), 110 oC, 1 h.
b Determined by GC analysis (internal standard – 4-chloro-1-methoxybenzene, that is stable under the reaction condition). Conversion is based on
consumption of bromobenzene.
c without any copper source.
To optimize the reaction conditions we varied the hydrazine hydrate amount, base, and PTC
(Table 2). The optimal amount of hydrazine hydrate was found to be 200 mol% (Table 2, entries
1–3). The bases which were used (Table 2, entries 2, 4–8) led to high conversions of
bromobenzene, but the yield of the target product was maximal with K3PO4 and decreased
markedly when KOH, K2CO3, K2HPO4 or Na3PO4 were applied. This decrease was probably a
result of hydrolysis of bromobenzene22 (in addition to the previously mentioned reduction).
Selectivity was maximal in the case of K3PO4 possibly due to its strong basity (pKa = 12.3 for
the conjugate acid) and low nucleophilicity.23 Cetyltrimethylammonium bromide (CTAB) or
tetrabutylammonium bromide (TBAB) was applied as a PTC with near equal efficiency for the
model reaction (Table 2, entries 2, 9). The reaction proceeded without a PTC (Table 2, entry 10),
4

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however, the conversion of the substrate and selectivity of the process were less than in the
presence of a PTC. Further, the reaction showed similar level of efficiency at the lower PTC
loadings (5 mol% and 2 mol%) (Table 2, entries 11, 12).
Table 2
CuBr/(CONHNH2)2/hexane-2,5-dione-catalyzed cross-coupling of bromobenzene and hydrazine hydrate:
optimization of the reaction conditionsa
Amount of
N2H4ꢀH2O
(mol%)
Conversion,b
%
Yield of
PhNHNH2,b
Yield of
PhNH2 , %
Entry
X
PTC (mol%)
Base
b
%
1
2
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
400
200
110
200
200
200
200
200
200
200
200
200
200
200
CTAB (10)
СТАВ (10)
CTAB (10)
СТАВ (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
ТВАВ (10)
-
K3PO4
K3PO4
92
96
65
73
24
46
46
25
54
44
72
55
73
70
68
0
4
3
3
4c
K3PO4
100
98
14
11
3
K3PO4
5
KOH
97
6
K2CO3
K2HPO4ꢀ3H2O
Na3PO4
K3PO4
79
2
7
95
8
8
95
3
9
100
83
3
10
11
12
13
14d
K3PO4
2
CTAB (5)
CTAB (2)
CTAB (10)
CTAB (10)
K3PO4
100
100
95
3
K3PO4
3
K3PO4
1
Cl
K3PO4
0
0
a Reaction conditions: bromobenzene (1 mmol), N2H4ꢀH2O (2 mmol), CuBr (0.05 mmol), (CONHNH2)2 (0.1 mmol), A1 (0.2 mmol), PTC (0.1
mmol), base (1 mmol), H2O (50 mg), 110 °C, 1 h.
b Determined by GC analysis (internal standard–4-chloro-1-methoxybenzene). Conversion is based on consumption of aryl bromide.
c 50 mol% K3PO4.
d 8 h, 120 °C.
The reactivity of chlorobenzene and iodobenzene was compared with that of bromobenzene
(Table 3, entries 2, 13, 14). The reaction of iodobenzene produced approximately the same yield
of the product and the conversion of the substrate as the reaction of bromobenzene. In contrast,
chlorobenzene was inert in this process even under more drastic reaction conditions (8 h, 120
°C).
It is known that hexane-2,5-dione can react with oxalyl dihydrazide to give N,N'-bis(2,5-
dimethylpyrrol-1-yl)oxalamide (L3) via a Paal-Knorr reaction.24 We synthesized L3 from L1 and
A1 and compared the catalytic activity of CuBr/L3 with that of CuBr/L1/A1 in the reaction of
hydrazine hydrate with bromobenzene. The yield of phenylhydrazine increased from 73% up to
86% in the reaction when CuBr/L3 was used (Table 3, entry 1). The optimization experiments
with this catalytic system (Table 3) showed its enhanced activity as compared with CuBr/L1/A1.
The amount of CuBr and L3 could be diminished down to 2.5 mol% and 4 mol%, respectively,
5

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without a loss of phenylhydrazine yield (Table 3, entry 2). A moderate yield of the target product
(66%) was obtained in the reaction with 0.6 mol% of CuBr and 1.2 mol% of L3 (Table 3, entry
4). In addition, arylation of hydrazine could proceed at room temperature but with a relatively
low yield of the target phenylhydrazine (21%) at a moderate conversion of bromobenzene (59%)
(Table 3, entry 6). Presumably, reductive hydrodehalogenation of bromobenzene is the main
process at room temperature. The same problem occurred for the reaction of chlorobenzene
with hydrazine hydrate where the yield of phenylhydrazine was 19% while the conversion of
chlorobenzene was 70% after 7 h at 130 °C (Table 3, entry 7). The amount of CTAB could be
reduced from 10 mol% to 3 mol% without lowering the yield of phenylhydrazine (Table 3, entry
8). Besides, CTAB, as a phase transfer catalyst, was superior to TBAB and tetrabutylammonium
hydroxide (TBAH) (Table 3, entries 8–10). Cu(0), Cu(I) and Cu(II) were active as catalysts for
the cross-coupling with hydrazine (Table 3, entries 8, 11–12). As a result, the optimal conditions
for copper-catalyzed arylation of hydrazine were obtained: CuBr (2.5 mol%), ligand (L3) (4
mol%), CTAB (3 mol%), K3PO4 (100 mol%), water (50 mg/1 mmol ArBr), hydrazine hydrate
(200 mol%), 110 °C, and 1 h.
Table 3
СuBr/L3-catalyzed cross-coupling of bromobenzene and hydrazine hydrate: optimization of the reaction conditionsa
Amount
of PTC
(mol%)
Yield of
Yield of
Copper/L3
(mol%)
T,
°C
Conversion,b
%
Entry Copper source
PTC
PhNHNH2,b PhNH2,b
%
%
3
1
2
CuBr
CuBr
5/10
2.5/4
1.2/2.5
0.6/1.2
0.3/0.6
5/10
СТАВ
СТАВ
СТАВ
СТАВ
СТАВ
СТАВ
CТАВ
СТАВ
ТВАВ
ТВАН
CTAB
CTAB
10
10
10
10
10
10
10
3
110
110
110
110
110
25
100
99
97
80
49
59
70
99
97
98
98
95
86
85
73
66
38
21
19
84
77
65
87
80
4
2
2
1
0
0
3
3
4
5
5
3
CuBr
4
CuBr
5
CuBr
6c
7d
8
CuBr
CuBr
5/10
130
110
110
110
110
110
CuBr
2.5/4
2.5/4
2.5/4
2.5/4
2.5/4
9
CuBr
3
10
11
12
CuBr
3
Cu(OAc)2·H2O
Cu
3
3
aReaction conditions: bromobenzene (1 mmol), N2H4ꢀH2O (2 mmol), CuBr, L3, PTC, K3PO4 (1 mmol), H2O (50 mg), 1 h.
b Determined by GC analysis (internal standard–4-chloro-1-methoxybenzene). Conversion is based on consumption of aryl bromide.
c The reaction was run for 72 h.
d Reaction conditions: chlorobenzene (1 mmol), N2H4ꢀH2O (2 mmol), CuBr (0.05 mmol), L3 (0.1 mmol), CTAB (0.1 mmol), K3PO4 (1.5 mmol),
H2O (50 mg), 7 h.
To establish the scope of this protocol, a number of aryl bromides were coupled with hydrazine
under the optimal conditions and the corresponding aryl hydrazines were transformed into
hydrochloride salts to be isolated. Aryl bromides with moderately electron-donating meta- or
para- substituents, as well as with electron-withdrawing
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meta- or para-substituents, reacted with hydrazine to give good isolated yields of the products
(Table 4, entries 1–7). The strong electron-donating substituents in a substrate like 4-MeO and 4-
EtO led to large amounts of the corresponding anilines in the isolated aryl hydrazine
hydrochlorides. The method of column chromatography was found to be inapplicable for aryl
hydrazines with donor substituents because they were quickly oxidized by oxygen in the air.25
Aryl hydrazine hydrochlorides can be separated from the corresponding aniline hydrochlorides
by recrystallization but with considerable losses in isolated yield.
Table 4
СuBr/L3 –catalyzed cross-coupling of aryl bromides and hydrazine hydrate on a 10 mmol scalea
Yield of
Entry
1
ArBr
Product
Time, h
1
T, °C
110
ArNHNH2·HCI,b %
71
2c
1
2
110
80
73
70
80
3
4
1.5
110
1
1
110
110
75
70
5
6
7
2
2
80
80
52
55
a Reaction conditions: aryl bromide (10 mmol), N2H4ꢀH2O (20 mmol), CuBr (0.25 mmol), L3 (0.4 mmol), СТАВ (0.3 mmol), K3PO4 (12 mmol),
H2O (500 mg), 80–110 oC, 1–2 h.
b Yields of isolated products.
c The reaction at 110 oC was run on a 300 mmol scale.
Also, we have investigated C–N cross-coupling of ortho-substituted aryl bromides with
hydrazine on the example of the reaction with o-bromotoluene (Scheme 1). This reaction,
performed by Method 4.5 from Experimental section, produced the corresponding aryl
hydrazine with only 32% yield after 7 h and with a high loading of the catalyst. Toluene was
found to be the main product in the reaction of o-bromotoluene and hydrazine hydrate (yield of
58%).
Scheme 1
7

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In order to determine the nature of the side reactions in C–N cross-coupling of aryl bromides
with hydrazine, the coupling of N2H4·H2O and 1-bromo-4-methoxybenzene (Scheme 2) was
carried out by Method 4.5 from Experimental section and then analyzed by GC and GC-MS. 4-
Methoxyphenylhydrazine, 4-methoxyaniline, and anisole were detected in the reaction mixture,
as well as trace amounts of 1,2-bis(4-methoxyphenyl)diazene and N,N'-bis(4-
methoxyphenyl)hydrazine. 4-Methoxyaniline (16%) and anisole (12%) formed through known
side reactions14 – metal-mediated N−N bond cleavage in 4-methoxyphenylhydrazine and
reductive hydrodehalogenation of 1-bromo-4-methoxybenzene, respectively. A low yield of
N,N'-bis(4-methoxyphenyl)hydrazine (2% at 100% conversion of aryl bromide) indicates the
high monoarylation/diaryaltion selectivity in this process. The possible explanation of this fact is
lower nucleophilicity of aryl hydrazine as compared with hydrazine. The trace amount of 1,2-
bis(4-methoxyphenyl)diazene (1%) was presumably formed by oxidation of N,N'-bis(4-
methoxyphenyl)hydrazine by oxygen in the air.
Scheme 2
3. Conclusion
To summarize, we have developed an efficient method for the synthesis of aryl hydrazines with
electron-withdrawing and moderately electron-donating substituents via C–N cross-coupling of
aryl bromides and hydrazine in water with 2.5 mol% of CuBr and 4 mol% of the ligand. This
method is attractive due to a few reasons. Firstly, it can be applied for both aryl iodides and
bromides. Secondly, the catalytic system employed is easily accessible and inexpensive. Finally,
the isolation of products can be readily performed without column chromatography, which is
essential
for
large
scale
syntheses.
4. Experimental section
4.1. General chemical procedures
All reagents (except for ligands of L2, L3 and additive A4) and solvents were obtained
commercially and used without further purification. Ligands L2, L3 and additive A4 were
synthesized according to the methods described below. Hydrazine hydrate (100%), and K3PO4 (>
98 wt% pure) were from Acros Organics and Sigma, respectively.1H and 13C NMR spectra were
recorded on a Bruker Avance II+ 400 MHz (UltraShield Magnet) spectrometer at room
temperature. GC analysis was performed on a Chromatec Crystal 5000.2 chromatograph
equipped with a flame ionization detector and a VRH-1 (10 m×0.53 mm×2.65 µm) capillary
column. GS-MS analysis was conducted on a Shimadzu GCMS QP-2010 SE spectrometer
equipped with an electron impact ionization source and Rtx-5MS (30 m×0.32 mm×0.25 µm)
8

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capillary column. Mass spectra were recorded on a Bruker micrOTOF spectrometer equipped
with an electrospray ionization (ESI) source. For this analysis species were dissolved in
methanol. Infrared spectra (4000−400 cm-1) were recorded on a Shimadzu FTIR-8400S
instrument as KBr pellets. The IR data is reported within 4000–1400 cm-1. Melting points were
determined on a capillary melting point apparatus and not corrected.
4.2. Synthesis of 1,4-diphenyl-butane-1,4-dione (A4)26
Additive A4 was prepared according to the previously described protocol26 by the reaction of
acetophenone with α-chloroacetophenone. White solid (62%), mp 144−145 °C (ethyl acetate)
1
(lit.26: 144–145 °C); IR (KBr) ν (cm-1): 2966, 2905, 1686–1676, 1593, 1574, 1447. H NMR
(DMSO-d6, 400 MHz, ppm) δ 8.03 (d, J = 7.2 Hz, 4H), 7.60 (t, J = 7.3 Hz, 2H), 7.53–7.49 (m,
4H), 3.41 (s, 4H). 13C NMR (DMSO-d6+CCl4, 101 MHz, ppm) δ 199.2, 137.0, 133.7, 129.2,
128.4, 32.8. HRMS (ESI+): calcd for C16H15O2 [M+H]+: 239.1072; found 239.1069.
4.3. Synthesis of N′-phenyl oxalyl dihydrazide (L2)27
Diethyl oxalate (200 mL, 1.47 mol) and phenylhydrazine (80 mL, 0.814 mol) were dissolved in
ethanol (300 mL) in a 1 L flask with a reflux condenser. The reaction mixture was stirred at
reflux for 30 min, and then the solution cooled to 50–60 °C and quickly filtered from a
precipitate of (PhNHNHCO)2. After cooling the filtrate to room temperature, a precipitate of
PhNHNHCOCOOEt was filtered off, washed with water and dried at room temperature (79.6 g,
47%). Then PhNHNHCOCOOEt (20.8 g, 0.1 mol) of and N2H4ꢀH2O (98%) (6.4 g, 0.13 mol)
were dissolved in ethanol (100 mL) in a 500 mL flask with a reflux condenser. The reaction
mixture was stirred at reflux for 1 h, and then cooled to room temperature. A precipitate of L2
was filtered off, washed with ethanol and dried at 100 °C in the air. Pale yellow solid (18.4 g,
95%), mp 209−210 °C (ethanol) (lit.27: 205–206 °C); IR (KBr) ν (cm-1): 3619−2879, 2812,
1932, 1845, 1772, 1703−1585, 1519, 1472.1H NMR (DMSO-d6+CCl4, 400 MHz, ppm): δ 10.33
(d, J = 2.6 Hz, 1H), 9.95 (s, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.13–7.10 (m, 2H), 6.75–6.69 (m,
13
3H), 4.41 (s, 2H). C NMR (DMSO-d6, 101 MHz, ppm): δ 160.2, 158.2, 148.9, 129.2, 119.3,
112.8. HRMS (ESI+): calcd for C8H10N4NaO2 [M+Na]+: 217.0702; found 217.0698.
4.4. Synthesis of N, N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide (L3)24
Hexane-2,5-dione (13.7 g, 0.12 mol) was added to a suspension of oxalyl dihydrazide (11.8 g,
0.1 mol) in acetic acid (100 mL) in a 500 mL flask equipped with a reflux condenser. The
reaction mixture was refluxed for 2 h, cooled to room temperature, and the formed precipitate
was filtered off, washed with water and dried at 100 °C. Pale yellow solid (14.8 g, 54%), mp
275−276 °C (ethanol); IR (KBr) ν (cm-1): 3428, 3282−3168, 3109, 2987, 2917, 2856,
1724−1676, 1636, 1526, 1482.1H NMR (CDCl3, 400 MHz, ppm): δ 9.38 (s, 2H), 5.89 (s, 4H),
13
2.16 (s, 12H). C NMR (CDCl3, 101 MHz, ppm): δ 157.4, 127.6, 105.0, 11.1. HRMS (ESI+):
calcd for C14H18N4NaO2 [M+Na]+: 297.1328; found 297.1323.
4.5. General procedure for C–N coupling reaction of aryl halides and hydrazine hydrate on
a 1 mmol scale (see Tables 1, 2, 3, Schemes 1, 2)
Required amounts of CuBr, ligand, PTC and water were mixed in a 8 mL screw cap test tube.
After aryl halide (1 mmol) and 10 mol% of the required amount of base were added, the
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resulting mixture was stirred at the required temperature (bath temperature) for 10 min. The
remaining quantity of base and the required amount of N2H4ꢀH2O were added. The reaction
mixture was stirred in a closed test tube at required temperature for 1 h, then cooled to room
temperature and extracted with EtOAc (5 mL). Samples of the organic phase (0.1–0.2 mL) were
separated, dried with anhydrous Na2SO4, and analyzed by GC.
4.6. General procedure for C–N coupling reaction of aryl bromides and hydrazine hydrate
on a 10 mmol scale
CuBr (36 mg, 0.25 mmol, 2.5 mol%), L3 (110 mg, 0.4 mmol, 4 mol%), H2O (0.5 mL), and
K3PO4 (254 mg, 1.2 mmol) were mixed in a 15 mL screw cap test tube. After СТАВ (110 mg,
0.3 mmol, 3 mol%) and aryl bromide (10 mmol) were added, the resulting mixture was stirred at
80−110 °C (bath temperature) for 10 min. Then K3PO4 (2.29 g, 10.8 mmol) and N2H4ꢀH2O (1 g,
20 mmol) were added and argon (flow rate 5−7 mL/min) was bubbled through the reaction
mixture for 5 min.28 The reaction mixture was stirred in a closed test tube at 80−110 °C (bath
temperature) for 1−2 h until complete consumption of starting material was observed as
monitored by TLC (eluent–hexane), then cooled to room temperature and diluted with СH2Cl2
(50 mL). The resulting solution was filtered and washed with brine (2×25 mL). Aq. НСl (37%)
was added to the CH2Cl2 solution dropwise until pH 3−4. The formed precipitate was filtered,
washed with СH2Cl2 (15 mL) and dried at room temperature. NMR spectra of certain
synthesized aryl hydrazine hydrochlorides showed that they contained 1–5 mol% of the
corresponding aniline hydrochlorides as impurities (see Supplementary Material). Analytical
samples of aryl hydrazine hydrochlorides were purified via precipitation from methanol solution
by adding two–three volumes of diethyl ether.
4-Chlorophenylhydrazine hydrochloride29
Pale pink solid (1.42 g, 80%), mp 222–224 °C (lit.29: 218 °C); IR (KBr) ν (cm-1): 3207,
3156−2763, 2682, 1996, 1876, 1583. 1H NMR (DMSO-d6, 400 MHz, ppm): δ 10.41 (s, 3H), 8.49
(s, 1H, br), 7.31 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H). 13C NMR (DMSO-d6, 101 MHz,
ppm): δ 145.0, 129.1, 125.5, 116.6. HRMS (ESI+): calcd for C6H8ClN2 [M–Сl]+: 143.0376;
found 143.0378.
4-Fluorophenylhydrazine hydrochloride29
Pale pink solid (1.22 g, 75%), mp 243−245 °C (lit.29: 252–253 °C); IR (KBr) ν (cm-1): 3211,
1
3162−2784, 2720−2473, 2131, 2034, 1955, 1876, 1589, 1516, 1494. H NMR (DMSO-d6, 400
MHz, ppm): δ 10.36 (s, 3H), 7.13–7.05 (m, 4H). 13C NMR (DMSO-d6, 101 MHz, ppm): δ 157.9
1
4
3
2
(d, JCF = 237.4 Hz), 142.4 (d, JCF = 2.0 Hz), 117.06 (d, JCF = 7.8 Hz), 115.9 (d, JCF = 22.6
Hz). HRMS (ESI+): calcd for C6H8FN2 [M–Сl]+: 127.0672; found 127.0669.
3-(Trifluoromethyl)phenylhydrazine hydrochloride30
Pale yellow solid, (1.48 g, 70%) mp 230−232 °C (lit.30: 224–225 °C); IR (KBr) ν (cm-1): 3205,
3158–2755, 2668, 2061, 1999, 1955, 1881, 1591, 1494. 1H NMR (DMSO-d6, 400 MHz, ppm): δ
13
10.52 (s, 3H), 8.77 (s, 1H, br), 7.52–7.48 (m, 1H), 7.34 (s, 1H), 7.28–7.24 (m, 2H). C NMR
2
1
(DMSO-d6, 101 MHz, ppm): δ 146.8, 130.5, 130.2 (q, JCF = 31.6 Hz), 124.6 (q, JCF = 272.4
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Hz), 118.6 , 117.9 (q, 3JCF = 3.7 Hz), 110.9 (q, 3JCF = 3.9 Hz). HRMS (ESI+): calcd for C7H8F3N2
[M–Сl]+: 177.0640; found 177.0638.
Phenylhydrazine hydrochloride31
Pale yellow solid (1.02 g, 71%), mp 256–258 °C (lit.31: 250– 252 °C); IR (KBr) ν (cm-1): 3210,
1
3153−2774, 2682, 2000, 1920, 1848, 1765, 1609, 1587, 1523, 1494. H NMR (DMSO-d6, 400
MHz, ppm): δ 10.37 (s, 3H), 8.34 (s, 1H, br), 7.27–7.23 (m, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.92
(t, J = 7.3 Hz, 1H). 13C NMR (DMSO-d6, 101 MHz, ppm): δ 146.0, 129.4, 121.9, 115.0. HRMS
(ESI+): calcd for C6H9N2 [M–Сl]+: 109.0766; found 109.0761.
4-Methylphenylhydrazine hydrochloride8
Pale yellow solid (1.11 g, 70%), mp 220–222 °C (lit.8:222–235 °C ; IR (KBr) ν (cm-1): 3221,
)
3162−2761, 2690, 2008, 1880, 1587, 1519, 1494. 1H NMR (DMSO-d6+CCl4, 400 MHz, ppm): δ
10.28 (s, 3H), 7.02 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 2.27 (s, 3H). 13C NMR (DMSO-
d6, 101 MHz, ppm): δ 143.6, 130.9, 129.7, 115.4, 20.7. HRMS (ESI+): calcd for C7H11N2 [M–
Сl]+: 123.0922; found 123.0919.
3,4-Dimethylphenylhydrazine hydrochloride32
Pale brown solid (894 mg, 52%), mp 205−206 °C (lit.32:197 °C); IR (KBr) ν (cm-1): 3153−2217,
1
2016, 1915, 1851, 1749, 1597, 1509, 1448. H NMR (DMSO-d6, 400 MHz, ppm): δ 10.22 (s,
3H), 7.00 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.76 (dd, J = 8.1, 1.7 Hz, 1H), 2.15 (s, 3H), 2.12 (s,
3H). 13C NMR (DMSO-d6, 101 MHz, ppm): δ 143.9, 137.1, 130.2, 129.7, 116.7, 112.7, 20.1,
19.0. HRMS (ESI+): calcd for C8H13N2 [M–Сl]+: 137.1079; found 137.1076.
4-Ethylphenylhydrazine hydrochloride33
o
Pale brown solid (947 mg, 55%), mp 208−210 °C (lit.33: 200 C); IR (KBr) ν (cm-1): 3232,
3162−2747, 2686, 1947, 1889, 1591, 1568, 1535, 1513. 1H NMR (DMSO-d6, 400 MHz, ppm): δ
10.30 (s, 3H), 7.08 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 2.50 (q, J = 7.6 Hz, 2H), 1.11 (t,
J = 7.6 Hz, 3H). 13C NMR (DMSO-d6, 101 MHz, ppm): δ 143.8, 137.4, 128.6, 115.4, 27.9, 16.4.
HRMS (ESI+): calcd for C8H13N2 [M–Сl]+: 137.1079; found 137.1075.
4.7. Typical procedure for C–N coupling reaction of 4-bromotoluene and hydrazine on a
300 mmol scale. Preparative synthesis of 4-tolylhydrazine hydrochloride
CuBr (1.1 g, 7.5 mmol, 2.5 mol%), L3 (3.3 g, 12 mmol, 4 mol%), H2O (15 mL) and
K3PO4·7Н2О (12.2 g, 36 mmol) were mixed in a 250 mL flask. After СТАВ (3.3 g, 9 mmol) and
4-bromotoluene (51.3 g, 300 mmol) were added, the resulting mixture was stirred at 110 °C for
10 min. Then K3PO4·7Н2О (109.5 g, 324 mmol) and N2H4ꢀH2O (98%) (30 g, 600 mmol) were
added. The reaction mixture was stirred at 110 °C for 1 h until complete consumption of starting
material as monitored by TLC (eluent–hexane), then cooled to room temperature and diluted
with СH2Cl2 (300 mL). The resulting solution was filtered and washed with brine (2×100 mL).
НСl (37%) were added to the CH2Cl2 solution dropwise until pH 3−4. The formed precipitate
was filtered off, washed with СH2Cl2 and dried at room temperature (34.6 g, 73%).
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Supplementary data
Acknowledgments
The authors thank the Russian Foundation for Basic Research (Grant 14-03-00297a) and Saint
Petersburg State University (Grant 12.38.195.2014 for financial support of this work. Studies
)
were performed at Center for Magnetic Resonance and Center for Chemical Analysis and
Material Research of Saint Petersburg State University.
References and notes
1. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
2. Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 2008, 4073–4095.
3. Gosselin, F.; O'Shea, P. D.; Webster, R. A.; Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J.
Synlett 2006, 3267–3270.
4. Polya, J.P. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon, 1997;
Vol. 5, pp 734–790.
5. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. B. J. Org. Chem. 2011, 7, 442–495.
6. Coleman, G. H. Org. Synth. 1941, 1, 442–445.
7. Vogel, A. I. In Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Furniss, B. S., Ed.;
Longman: England, 1989; pp 959–960.
8. Hunsberger, I. M.; Shaw, E. R.; Fugger, J.; Ketchum, R.; Lednicer, D. J. Org. Chem. 1956,
21, 394–399.
9. Holland, D. G.; Moore, G. J.; Tamborski, C. J. Org. Chem. 1964, 29, 1562–1565.
10. Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley: Weinheim, 2000; pp
195–262.
11. Thomas, A. W.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
12. Mauger, C. C.; Mignani, G. A. Org. Process Res. Dev. 2004, 8, 1065–1071.
13. Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543–3546.
14. Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 8686–8690.
15. Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971.
16. Chen, J.; Zhang, Y.; Hao, W.; Zhang, R.; Yi, F. Tetrahedron 2013, 69, 613–617.
17. Zhu, X.; Su, L.; Huang, L.; Chen, G.; Wang, J.; Song, H.; Wan, Y. Eur. J. Org. Chem. 2009,
635–642.
18. Zhu, X.; Ma, Y.; Su, L.; Song, H.; Chen, G. Liang, D.; Wan, Y. Synthesis 2006, 3955–3962.
19. Kurandina, D. V.; Eliseenkov, E. V.; Petrov, A. A.; Boyarskiy, V. P. Russ. Chem. Bull. 2012,
61, 1009–1013.
20. Meng, F.; Wang, C.; Xie, J.; Zhu, X.; Wan, Y. Appl. Organomet. Chem. 2011, 25, 341–347.
21. The system of CuBr and (CONHNR'R'')2 could successfully catalyze arylation of hydrazine
due to the special preparation of the reaction mixtures, as described in the experimental section.
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22. Phenols are well-known by-products in copper-catalyzed C−N cross-coupling reactions of
amines with aryl bromides in the presence of KOH.17 We have demonstrated that copper-
catalyzed reaction of aryl bromides and hydrazine with K3PO4 as a base gives no detectable (GC
analysis) amounts of the corresponding phenols.
23. Beitia, J. L. L. Synlett 2011, 139–140.
24. Buelow, C. Chem. Ber. 1905, 38, 3914–3917.
25. Stroh, H.–H.; Ebert, L. Chem. Ber. 1964, 97, 2335–2341.
26. Nevar, N. M.; Kel’in, A. V.; Kulinkovich, O. G. Synthesis 2000, 1259–1262.
27. Buelow, C. Chem. Ber 1904, 37, 2424–2428.
28. Inert reaction atmosphere is not necessary for C–N cross-coupling of aryl bromides with
hydrazine. However, it is desirable to remove the air from a reaction vessel by bubbling argon
before the reaction in order to avoid oxidation of aryl hydrazines.
29. Zhang, F.; Zhao, Y.; Sun, L.; Ding, L.; Gong, P.; Gu, Y. Eur. J. Med. Chem. 2011, 46, 3149–
3157.
30. Forbes, E. J.; Stacey, M.; Tatlow, J. C.; Wragg, R. T. Tetrahedron 1960, 8, 67–72.
31. Gaber, A. E.-A. M.; Atalla, A. A.; El-Dean, A. M. K. Phosphorus, Sulfur, Silicon Relat.
Elem. 1996, 112, 131–136.
32. Padoa, M.; Graziani, F. Atti Accad. Naz. Lincei Cl. Sci. Fis. Mat. Natur. Rend. Lincei 1910,
19, 489−495.
33. Willgerodt, C.; Harter, H. J. Prakt. Chem. (Leipzig) 1905, 71, 409–416.
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Supplementary Material
Facile and convenient copper-catalyzed synthesis of aryl hydrazines via C–N cross-coupling of aryl halides and
hydrazine hydrate
Daria V. Kurandina, Eugene V. Eliseenkov, Petr V. Ilyin, Vadim P. Boyarskiy
General chemical procedures
All reagents (except for ligands of L2, L3 and additive A4) and solvents were obtained commercially and used without further purification. Ligands L2, L3 and
additive A4 were synthesized according to the methods described below. Hydrazine hydrate (100%), and K3PO4 (> 98 wt% pure) were from Acros Organics
and Sigma, respectively.1H and 13C NMR spectra were recorded on a Bruker Avance II+ 400 MHz (UltraShield Magnet) spectrometer at room temperature. GC
analysis was performed on a Chromatec Crystal 5000.2 chromatograph equipped with a flame ionization detector and a VRH-1 (10 m×0.53 mm×2.65 µm)
capillary column. GS-MS analysis was conducted on a Shimadzu GCMS QP-2010 SE spectrometer equipped with an electron impact ionization source and
Rtx-5MS (30 m×0.32 mm×0.25 µm) capillary column. Mass spectra were recorded on a Bruker micrOTOF spectrometer equipped with an electrospray
ionization (ESI) source. For this analysis species were dissolved in methanol. Infrared spectra (4000−400 cm-1) were recorded on a Shimadzu FTIR-8400S
instrument as KBr pellets. Melting points were determined on a capillary melting point apparatus and not corrected.
General procedure for C–N coupling reaction of aryl bromides and hydrazine hydrate on a 10 mmol scale
3
CuBr1 (36 mg, 0.25 mmol, 2.5 mol%), L3 (110 mg, 0.4 mmol, 4 mol%), H2O2 (0.5 mL), and K3PO4 (254 mg, 1.2 mmol) were mixed in a 15 ml screw cap test
tube. After СТАВ (110 mg, 0.3 mmol, 3 mol%) and aryl bromide (10 mmol) were added, the resulting mixture was stirred at 80−110 °C (bath temperature) for
10 min. Then K3PO4 (2.29 g, 10.8 mmol) and N2H4ꢀH2O (1 g, 20 mmol) were added and argon (flow rate 5−7 mL/min) was bubbled through the reaction
mixture for 5 min.4 The reaction mixture was stirred in a closed test tube at 80−110 °C (bath temperature) for 1−2 h until complete consumption of starting
material as monitored by TLC (hexane as an eluent), then cooled to room temperature and diluted with СH2Cl2 (50 mL). The resulting solution was filtered and
washed with brine (2×25 mL). Aq. НСl (37%) was added to the CH2Cl2 solution dropwise until pH 3−4. The formed precipitate was filtered, washed with
СH2Cl2 (15 mL) and dried at room temperature.
1Although CuBr, Cu(OAc)2·H2O and Cu have showed nearly the same activity as catalysts, we have chosen CuBr for preparative syntheses for the following
reasons. CuBr led to more reproductive results than Cu and a less amount of aniline than Cu(OAc)2·H2O.
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2It is important to add H2O initially to the reaction mixture in order to compose the catalytic system of ligand and copper in basic aqueous medium before
N2H4ꢀH2O addition.
3 We used 120 mol% K3PO4 for preparative syntheses of aryl hydrazines because KH2PO4 formed during the reaction led to worse results than K3PO4.
4Inert reaction atmosphere is desirable to prevent oxidation of aryl hydrazine by oxygen in the air.
In order to prevent the destruction of the catalytic system, hydrazine hydrate should be the last to be added to the reaction mixture. The reproducible results
were obtained only if the catalytic system was initially prepared before performing the reaction.
1H NMR and 13C NMR spectra
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1H NMR of 1,4-diphenylbutane-1,4-dione (400.13 MHz, Solvent – DMSO-d6 + CCl4, T = 297 K)
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1H NMR of N′-phenyl oxalyl dihydrazide (400.13 MHz, Solvent – DMSO-d6+CCl4, T = 298 K)
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1H NMR of N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide (400.13 MHz, Solvent – CDCl3, T = 298 K)
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1H NMR of 4-methylphenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6 + CCl4, T = 298 K)
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1H NMR of phenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6, T = 296 K)
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1H NMR of 4-ethylphenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6, T = 296 K)
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1H NMR of 4-chlorophenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6, T = 298 K)
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1H NMR of 3,4-dimethylphenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6, T = 297 K)
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1H NMR of 4-fluorophenylhydrazine hydrochloride (400.13 MHz, Solvent – DMSO-d6, T = 297 K)
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1H NMR of 3-(trifluoromethyl)phenylhydrazine hydrochloride (100.61 MHz, Solvent – DMSO-d6, T = 297 K)
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13C NMR of 1,4-diphenyl-1,4-butanedione (100.61 MHz, Solvent – DMSO-d6, T = 298 K)
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13С NMR of N′-phenyl oxalyl dihydrazide (100.61 MHz, Solvent – DMSO-d6, T = 299 K)
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13C NMR of N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide (100.61 MHz, Solvent – CDCl3, T = 299 K)
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13C NMR of 3,4-dimethylphenylhydrazine hydrochloride (100.61 MHz, Solvent – DMSO-d6, T = 297 K)
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