Copper-catalyzed C-N bond cross-coupling of aryl halides and amines in water in the presence of ligand derived from oxalyl dihydrazide: Scope and limitation

Article abstract of DOI:10.1016/j.tet.2015.07.071

An efficient and convenient method has been developed for the copper-catalyzed C-N bond cross-coupling of aryl bromides with electron-donor substituents and aliphatic amines in water. The new ligand system N-phenyloxalyl bishydrazide/hexane-2,5-dione has been shown to be considerably more efficient in the copper-catalyzed C-N bond cross-coupling reaction as compared to the ligands described in the literature and allowed decreasing of the catalyst amount (up to 2 mol %) to achieve acceptable yields of isolated products (46-84%). Acceptor substituted aryl bromides, aryl bromides with substituents in the ortho-position, and some aryl dichlorides can undergo the C-N cross-coupling under the developed conditions, but their reactivity is lower.

Full text of DOI:10.1016/j.tet.2015.07.071

Accepted Manuscript
Copper-catalyzed C–N bond cross-coupling of aryl halides and amines in water in the
presence of ligand derived from oxalyl dihydrazide: scope and limitation
D.V. Kurandina, E.V. Eliseenkov, T.S. Khaibulova, A.A. Petrov, V.P. Boyarskiy
PII:
S0040-4020(15)01148-5
10.1016/j.tet.2015.07.071
TET 27016
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 February 2015
Revised Date: 13 July 2015
Accepted Date: 27 July 2015
Please cite this article as: Kurandina DV, Eliseenkov EV, Khaibulova TS, Petrov AA, Boyarskiy VP,
Copper-catalyzed C–N bond cross-coupling of aryl halides and amines in water in the presence
of ligand derived from oxalyl dihydrazide: scope and limitation, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.07.071.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Leave this area blank for abstract info.
Copper-catalyzed C–N cross-coupling of aryl
halides and amines in water in the presence of
ligand derived from oxalyl dihydrazide: scope and limitation
D. V. Kurandinaa, E. V. Eliseenkovb, T. S. Khaibulovab, A. A. Petrovb, V. P. Boyarskiyb
aDept. of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, US
bDept. of Chemistry, Saint-Petersburg State University, Saint-Petersburg 198504, Russia

ACCEPTED MANUSCRIPT
Copper-catalyzed C–N bond cross-coupling of aryl halides and amines in water in the
presence of ligand derived from oxalyl dihydrazide: scope and limitation
D. V. Kurandinaa*, E. V. Eliseenkovb, T. S. Khaibulovab, A. A. Petrovb, V. P. Boyarskiyb
aDepartment of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago,
Illinois 60607–7061, United States
bDepartment of Chemistry, Saint Petersburg State University, Saint Petersburg 198504,
Universitetskiy pr. 26, Russia
*Corresponding author. Tel.: +1–872–235–88–58; E-mail address: dkuran2@uic.edu (Daria V.
Kurandina)
Keywords: C−N bond cross-coupling, Copper catalysis, Aryl bromides, Catalysis in aqueous
media
Abstract
An efficient and convenient method has been developed for the copper-catalyzed C–N
bond cross-coupling of aryl bromides with electron-donor substituents and aliphatic amines in
water. The new ligand system N-phenyloxalyl bishydrazideL/hexane-2,5-dione has been shown
to be considerably more efficient in the copper-catalyzed C–N bond cross-coupling reaction as
compared to the ligands described in the literature and allowed decreasing of the catalyst amount
(up to 2 mol%) to achieve the acceptable yields of isolated products (46–84%). Acceptor
substituted aryl bromides, aryl bromides with substituents in the ortho-position, and some aryl
dichlorides can undergo the C‒N cross-coupling under the developed conditions, but their
reactivity is lower.
1. Introduction
C–N bond cross-couplings catalyzed by transition metal complexes represent an
irreplaceable tool for C–N bond formation in contemporary organic synthesis.1 The copper-
mediated processes, such as Ullmann and Goldberg reactions, were discovered in the beginning
of the last century but became broadly applicable only recently when scientists managed to
considerably improve classical reactions conditions. Thus, numerous copper-containing catalytic
systems have been designed which allow the synthesis of important pharmaceutical
4
intermediates2,3 and natural products via C–N bond cross-coupling. The use of an appropriate
ligand was found to be as essential for the success in a of protocol as the use of an appropriate
base, solvent and other components of the reaction mixtures.5 As a result, researchers have
gained the opportunity to modify the reaction conditions of copper-catalyzed C–N bond cross-
coupling reactions by many ways that has led to the creation of various protocols. Most of these
processes are carried out in common organic solvents like 2-propanol,6 DMF,7 DMSO,8 toluene,9
and NMP,10 but recently copper-catalyzed C–N bond cross-coupling was found to proceed in
aqueous media.11 Water as a solvent requires the use of special ligands for the implementation of
the couplings of aryl halides and amines. Oxalyl dihydrazide derivatives and their nearest
equivalents allow C–N bond cross-coupling in aqueous media in the presence of a phase transfer
1

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catalyst. Thus, the system of CuO (25 mol%)/bis(cyclohexanone)oxalyldihydrazone (L1) (50
mol%) was first to be successfully used for the coupling of aryl halides and amines in an aqueous
solution.12 Then, the protocols for microwave-assisted coupling reactions of aryl halides with
anilines and aliphatic amines in water were elaborated using CuO (5 mol%) with
(CONHNR'R'')2 (L2)(25 mol%)13 or (CONHNH2)2 (L3) (50 mol%)/ketone (100 mol%).14 Also,
pyrrole-2-carbohydrazides (25 mol%) were found to be effective ligands for copper-catalyzed C–
N bond coupling reactions in water with CuI (5 mol%).15
O
O
H
H
H2N
N
N
N
N
NH2
N
N
H
H
O
O
L3 (Wan et al. Eur. J.
Org. Chem. 2010, 3219)
L1 (Wan et al. Synthesis 2006, 3955)
R'
N
O
R = c-C6H11, c-C5H9, Ad, Ph, Me, i-
H
Pr, i-Bu, CH3(CH2)3CH(CH3), Bn,
PhCH(CH3), 4-MeOC6H4CH(CH3),
4-NO2C6H4CH(CH3); R' = H, Me
N
R
R
N
N
H
O
R'
L2 (Wan et al. Appl. Organometal. Chem. 2011, 25, 341;
Wan et al. Eur. J. Org. Chem. 2009, 635)
O
H
H
O
N
N
N
H
NH2
+
O
A
O
L4
(Boyarskiy et al. Russ. Chem. Bull. 2012, 61, 1009
and this work)
Recently, we described the system of Cu(II)/PhNHNHCOCONHNH2(L4)/ hexane-2,5-
dione (A) which successfully catalyzes the arylation of aniline and substituted anilines with
several aryl bromides.16 Unlike the aforementioned methods for the coupling in water, only 2
mol% of the copper source and 8 mol% of L4 and 8 mol% of additive A were used in our
method.
Herein, we report the application of this catalytic system for the cross-coupling of a wide
range of aryl halides with 5- and 6-membered saturated N-heterocyclic compounds and aliphatic
amines in aqueous media. Only 2 mol% of the copper source and 8 mol% of N'-phenyloxalyl
bishydrazide (L4) and 8 mol% of additive hexane-2,5-dione (A) should be used to achieve good
isolated yields. Furthermore, scope and limitation of the reaction are discussed.
2. Results and Discussion
Copper-catalyzed arylation of aliphatic amines and, especially saturated N-heterocyclic
compounds is considerably more interesting than the arylation of anilines. In the published
data,12–15 the yield of the product is always lower in the case of arylation of morpholine than
aniline (even at a ratio of amine: aryl bromide is of 4). It can be concluded that the optimum
conditions for the arylation of aniline and saturated N-heterocyclic compounds are different.
2

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We carried out the Cu(OAc)2·H2O/L4/A-catalyzed reaction of 4-bromotoluene with
morpholine in water for 1 h under the conditions described for the arylation of anilines: 4-
bromotoluene (1 mmol), morpholine (130 mol%), Cu(OAc)2·H2O (2 mol%), ligand L4 (8
mol%), TBAB (20 mol%), KOH (200 mol%), water (500 mg/1 mmol ArBr), 100 °C, 1 h. The
yield of N-(4-methylphenyl)morpholine (8) was only a 5% (Table 1, entry 1) vs. 66% for the
prototype reaction of bromobenzene with aniline. Consequently, there is a need to adapt the
reaction conditions taking into account aliphatic amines features. The reaction of 4-
bromotoluene with morpholine was chosen as a model process to optimize the reaction
conditions.
Morpholine is a stronger nucleophile than aniline but its concentration in organic phase
(where the cross-coupling reaction proceeds) is low as compared with aniline under the reaction
conditions. This inherent fact could result in the decrease of the rate of reaction. To minimize the
extraction of morpholine from the organic phase we reduced the amount of water in the reaction
mixture from 500 mg to 100 mg on 1 mmol ArBr. Indeed, the yield of the target product
increased from 5% up to 36% (Table 1, entry 2).
Inorganic bases in C–N bond-formingation reactions are employed to facilitate the
deprotonation /coordination of the nucleophile. However, they suffer from demerits deficiencies,
such as low solubility and/or low reactivity in organic phase. For the coupling reaction in two-
phase system containing water, phase transfer catalysts (PTC) are used to facilitate the hydroxyl
ion transfer from the aqueous to the organic phase. It is well known that tetra-n-butylammonium
bromide (TBAB) can transfer only a trace amount of hydroxyl ions to the organic phase (as tetra-
n-butylammonium hydroxide (TBAH)) from water in a two-phase system (containing KOH and
organic solvent (toluene, CH2Cl2).17 To overcome these drawbacks, organic ionic bases have
been introduced as new and promising promoters for coupling reactions.18 These are quaternary
ammonium or phosphonium salts with basic anions which are relatively well soluble in organic
solvents and, more importantly, their resulting solutions have a relatively high electrical
conductivity, therefore there is an appreciable quantity of free ions along with the ion pairs. For
example, tetrabutylammonium adipate was advantageously used as a base for copper-catalyzed
C–N bond cross-coupling of aryl iodides with benzylamine at room temperature in DMF with 20
mol% of L-proline as a ligand.18
We applied the same approach for to our reactions in two-phase systems containing
water. The use of ionic organic bases in stoichiometric amounts was rejected for economic
reasons, as their synthesis is carried out by neutralizing expensive TBAH with a carboxylic acid.
The addition of adipic acid (30 mol%) to the reaction mixture led to the formation of potassium
adipate in situ which resulted in an increase of the yield of the desired product up to 72% for 1 h
(Table 1, entries 3, 4). Cetyltrimethylammonium bromide (CTAB) in a combination with
potassium adipate was found to be a more active base than TBAB/potassium adipate and
triethylbenzylammonium chloride (TEBA)/potassium adipate (Table 1, entries 5, 6, 7). These
data are can be well explained by that quaternary ammonium cations of a large volume form
salts having possess higher conductivity in an organic solvent.18 The combination of potassium
adipate with surfactants such as potassium stearate and sodium dodecyl sulfate (SDS) (Table 1,
entries 8, 9) was less successful. The addition of sodium acetate led to a further increase in the
3

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yield (87%), which was probably due to the cooperative action of cetyltrimethylammonium
adipate and cetyltrimethylammonium acetate as bases (Table 1, entry 10).
What was interesting that CuO applied for the coupling of aryl bromides with anilines in
the works12–15 did not catalyze the reaction with morpholine (Table 1, entry 11). The use of 3
mol% of Cu(OAc)2·H2O did not lead to an increase of the yield of the target product (Table 1,
entry 12). A 85% yield was obtained for 2 hours when 1 mol% of Cu(OAc)2·H2O, 4 mol% of L4,
and 4 mol% of A were used (Table 1, entry 13). The use of 0.5 mol% of Cu(OAc)2·H2O for the
coupling reaction resulted in a 63% yield (Table 1, entry 14). According to this data, TON of
copper acetate Cu(OAc)2 reached 126, TOF 0.018 s-1, which indicated a significant improvement
of the catalytic activity of the investigated system, as compared with the previously studied
analogues.12–15 As a result, the optimal conditions for copper-catalyzed arylation of morpholine
were obtained: Cu(OAc)2·H2O (2 mol%), ligand (L4) (8 mol%), CTAB (10 mol%), KOH (200
mol%), water (100 mg/1 mmol ArBr), morpholine (130 mol%), adipic acid (30 mol%), NaOAc
(60 mol%), 100 °C, 1 h. Thus, on the example the chosen model reaction it was shown that the
change of the quantity of water and the modification of the base with the PTC allow an increase
of the yield from 5 to 87%. The fact that aliphatic and saturated heterocyclic amines are weaker
NH-acids than anilines explains that they require stronger bases.
Table 1
Copper-catalyzed C–N bond cross-coupling of 4-bromotoluene with morpholine – the
optimization of reaction conditionsa
KOH
(mol%)
Additive
(mol%)
Entry
PTC (mol%)
Yield,b%
1c
2
3
4
5
6
7
200
200
260
260
260
260
260
TBAB (20)
TBAB (20)
TBAB (20)
TBAB (20)
TBAB (10)
CTAB (10)
TEBA (10)
–
5
–
36
72
64
63
79
12
Adipic acid (30)
Adipic acid (15)
Adipic acid (30)
Adipic acid (30)
Adipic acid (30)
4

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Potassium
8
9
260
Adipic acid (30)
42
78
stearate (10)
SDS (20)
260
200
260
200
Adipic acid (30)
Adipic acid
(30), NaOAc
(60)
10
11d
12e
CТАВ (10)
CТАВ (10)
CТАВ (10)
87
0
Adipic acid (30)
Adipic acid
(30), NaOAc
(60)
86
Adipic acid
(30), NaOAc
(60)
13f
14g
200
200
CТАВ (10)
CTAВ (10)
85
63
Adipic acid
(30), NaOAc
(60)
aReaction conditions: 4-bromotoluene (1 mmol), morpholine (1.3
mmol), Cu(OAc)2·H2O (0.02 mmol), L4 (0.08 mmol), A (0.08 mmol),
PTC, additives, KOH, H2O (100 mg), 100 °C (100 mg), 1 h.
c
bDetermined by GC analysis (internal standard – biphenyl). 500 mg
of H2O. d2 mol% CuO instead of Cu(OAc)2·H2O. e3 mol%
f
Cu(OAc)2·H2O. 1 mol% Cu(OAc)2·Н2О, 4 mol% L4, 4 mol% A, 2 h.
g0.5 mol% Cu(OAc)2·Н2О, 4 mol% L4, 4 mol% A, 2 h.
We applied a the new protocol for the cross-coupling of aryl bromides and N-heterocyclic
compounds and aliphatic amines to establish its scope (Table 2). As shown, morpholine,
pyrrolidine,
piperidine,
cyclohexanamine,
4-methylpiperidine,
(tetrahydrofuran-2-
yl)methanamine, and 2-phenylethanamine reacted with aryl bromides giving the products 1–9 in
good to moderate yields.
Table 2
Cu(OAc)2·H2O/L4/A-catalyzed cross-coupling of aryl bromides and heterocyclic and aliphatic
amines on a 5 mmol scalea
5

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Entry
1
ArBr
Amine
Product
Time, h Yield,b%
(1)
1.5
75
2
3
4
5
(2)
(3)
(4)
(5)
1.5
2
71
70
51
84
3
3
6
7
8
(6)
(7)
(8)
3
3
3
80
72
72
9
(9)
3
72
10
10
11
12
(10)
(10)
(14)
(1)
3
3
3
3
46c
28
68
ca. 0.2c
(ortho-
13
3
22c
1)
aReaction conditions: aryl bromide (5 mmol), amine (6.5 mmol),
Cu(OAc)2·H2O (0.1 mmol), L4 (0.4 mmol), A (0.4 mmol), CTAB (0.5
mmol), adipic acid (1.5 mmol), NaOAc (3 mmol), KOH (10 mmol), H2O
b
c
(0.5 mL), 100 °C, 1 h. Yields of isolated products. GC data, the product
was identified by GC-MS
6

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Aryl bromides with donor substituents readily reacted with amines to give the products
with good yields as shown in Table 2 (Entries 1−9). Our results are the best for copper-catalyzed
C–N bond cross-coupling of donor-substituted bromobenzenes with aliphatic amines up to data
so far. The reaction of 4-bromotoluene with diethylamine gave only a 28% yield of the
corresponding C–N coupling product 10. The rate of the desired reaction may be slowed due to
high volatility of the amine (boiling point 55 °C), so that a significant part of the reagent was in
the gas phase. In addition, products of the side reactions as C−O cross-coupling (11, 12) and
hydrodehalogenation of aryl bromide (13) were detected in that reaction mixture (Scheme 1).
Scheme 1
A similar pattern was observed for the reaction of piperazine with 2 equivalents of 4-
bromotoluene (Scheme 2). Althogh the appreciable amount of the by-products 11–13 was
detected by GC desired product 14 was isolated from the reaction mixture with a good yield.
Scheme 2
The reaction of aryl bromides with acceptor substituents (4-Cl) surprisingly led to lower
yields of the amination products at the same reaction conditions (Entry 10). The reason is that the
reaction selectivity decreases drastically for these substrates that This fact can be demonstrated
on by the example of the reaction of 4-chlorobromobenzene with pyrrolidine (Scheme 13), The
reaction produced which gave only a 46% of product 10 15 for after 3 hours. Chlorobenzene 11
7

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16 found in a large amount in the case of this process was formed probably via reductive
hydrodehalogenation of 4-chlorobromobenzene.
Scheme 1 3
The absence of the chlorine atom substitution product in the reaction mixture shows small
reactivity of aryl chlorides in this reaction. We confirmed this also on an example of 4-
chlorotoluene, which yields only a trace amount of the amination product (Entry 12). Also it is
evidently from the Table 2 that ortho-bromotoluene is less reactive than the para-isomer in
under the applied conditions (Entry 13). In order to study the ortho-effect of substituents in more
detail, we measured the regioselectivity of the amination for substituted dichlorobenzenes, which
usually are more reactive in couplings than monochlorobenzenes.19,20 This approach to ortho-
effect studying was developed by us early previously for cobalt-catalyzed methoxycarbonylation
of aryl halides19,20 and for palladium-catalyzed cross-couplings.21 The essence is to make a
difference between the chlorine atoms due to an additional substituent into the dichlorobenzene
molecule. This method has the advantage in compareison with the inter-substrate selectivity
measurement, since it minimizes the influence of extraneous factors.
The amination of substituted dichlorobenzenes 1217 and 1722 with morpholine was
carried out under the standard conditions up to a low conversion (40%–50%). Analysis of the
1
reactions mixtures by GC-MS and H NMR showed that the reaction occurred in both cases
although the amination products yields are low with low yields of the amination products
(Scheme 24)(the yields are calculated based on GC data). The resulting substituted N-
phenylmorpholines were isolated and their structures were determined by NMR analysis. For
both compounds 1217 and 1722 the substituent directs the amination into position 4 previously
regardless its own nature (see Scheme 24). Thus, the regioselectivity study indicates thus the
universal inhibitory effect of ortho-substituents (both the donor and acceptor).
Scheme 2 4
8

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As well as for aryl bromides, the yield of the amination products in the case of the
substrate with a donor substituent (1217) substantially exceeds that of the acceptor-substituted
substrate (1722). We believe the reason is that the amination and the reduction were catalyzed by
different catalytic species. Perhaps, substrates with donor substituents are not capable to be
activated by the catalytic species that catalyze hydrodehalogenation of aryl halides, therefore
only the amination reaction proceeds with these substrates.
3. Conclusion
To summarize, we have developed an efficient and convenient method for the copper-
catalyzed C–N bond cross-coupling of aryl bromides and aliphatic amines in water. The new
ligand system L/hexane-2,5-dione has been proved found considerably more efficient in the
copper-catalyzed C–N cross-coupling reaction as compared to the ligands described in the
literature that allowed decreasing of the catalyst amount to achieve the acceptable yields of the
isolated products. The found developed catalytic system is more suitable for amination of aryl
bromides with electron-donor substituents, although acceptor substituted aryl bromides also
react. Aryl bromides with substituents in the ortho-position, along with and some aryl
dichlorides undergo cross-coupling under the same conditions mentioned above but their
reactivity is lower.
4. Experimental section
4.1. General chemical procedures
All reagents (except for ligand L4) were obtained commercially and used without further
purification. Commercial KOH was used (Reakhim, reagent grade, 85%). Ligand L4 was
synthesized according to the methods described in our previous work.21 Solvents were purified
9

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according to the standard procedures.22 1H and 13C NMR spectra were recorded on a Bruker
Avance II+ 400 MHz (UltraShield Magnet) spectrometer at room temperature. Chemical shifts
are reported in δ (ppm downfield from tetramethylsilane). Spectra in CDCl3 are referenced to the
residual solvent peaks at δ 7.27 (1H ) and 77.00 (13C). Spectra in DMSO-d6 и DMSO-d6+CCl4
(1:2) are referenced to the residual solvent peaks at δ 2.50 (1H) and 39.52 (13C). 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. GC-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. Melting points were
determined on a capillary melting point apparatus and not corrected.
4.2. C–N bond coupling reaction of 4-bromotoluene with morpholine on a 1 mmol
scale
A 8 mL screw cap test tube was charged with the required amounts of Cu(OAc)2·H2O (4
mg, 0.02 mmol, 2 mol%), ligand L4 (15.6 mg, 0.08 mmol, 8 mol%), additive A - hexane-2,5-
dione (9.2 mg, 0.08 mmol, 8 mol%), adipic acid (73 mg, 0.3 mmol, 30 mol%), NaOAc (49 mg,
0.6 mmol, 60 mol%), KOH (169 mg, 2.6 mmol, 260 mol%) , PTC – TBAB (64.5 mg, 0.2 mmol,
20 mol%) or CTAB (36.4 mg, 0.1 mmol, 10 mol%), H2O (100 mg), morpholine (115 mg, 1.3
mmol, 130 mol%) and 4-bromotoluene (170 mg, 1 mmol). Argon (flow rate 5−7 mL/min) was
bubbled through the resulting mixture for 5 min and it was stirred at 100 °C for the required
time. Then the reaction mixture was cooled to room temperature and extracted with EtOAc (5
mL). The samples of organic phase (0.1–0.2 mL) were separated, dried with anhydrous Na2SO4,
filtered and analyzed by GC.
4.3. General procedure for C–N bond coupling reaction of aryl bromides with 5-
and 6-membered saturated N-heterocyclic compounds and aliphatic amines on a 5 mmol
scale
A 15 mL screw cap test tube was charged with Cu(OAc)2·H2O (20 mg, 0.1 mmol, 2
mol%), L4 (78 mg, 0.4 mmol, 8 mol%), hexane-2,5-dione (46 mg, 0.4 mmol, 8 mol%), KOH
(650 mg, 10 mmol, 200 mol%), adipic acid (219 mg, 1.5 mmol, 30 mol%), NaOAc (246 mg, 3
mmol, 60 mol%), CTAB (182 mg, 0.5 mmol, 10 mol%), H2O (0.5 mL), aryl bromide (5 mmol)
and amine (6.5 mmol, 130 mol%). Argon (flow rate 5−7 mL/min) was bubbled through the
resulting mixture for 5 min. The reaction mixture was stirred in a closed test tube at 100 °C for
3–4 h until complete consumption of starting material as monitored by TLC (eluent–hexane),
then cooled to room temperature and diluted with EtOAc (30 mL). The EtOAc solution was
purified by flash-chromatography, washed with water (3×10 mL), and dried with anhydrous
Na2SO4. Then EtOAc was evaporated under reduced pressure and the residue was recrystallized
from hexane (substances 1–4) or aq. EtOH (substances 5–9). In a case of the substances 5, 7–9
the residue was dissolved in diethyl ether. Aq. НCl (37%) was added dropwise to the resulting
solution until pH 3−4. The formed precipitate was filtered, washed with diethyl ether (10 mL)
and dried at 50 °C.
10

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N-(4-Methylphenyl)morpholine (1).23 Pale brown solid (666 mg, 75%), mp 44–45 °C (from
hexane) (lit. 47.3–48 °C) 1Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ 7.00 (d, J=8.4 Hz,
13
2H), 6.76 (d, J=8.4 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.05 (t, J=4.8 Hz, 4H), 2.26 (s, 3H). C
NMR (DMSO-d6+CCl4 (1:2), 101 MHz, ppm): δ 148.6, 128.9, 127.8, 115.2, 65.9, 49.0, 19.9.
HR-MS (ESI+): calcd for C11H16NO [M+H]+: 178.1226; found 178.1226.
N-Phenylmorpholine (2).23 Pale brown solid (579 mg, 71%), mp 55–56 °C (from hexane)(lit.
52.5-53.4 °C). 1Н NMR (CDCl3, 400 MHz, ppm): δ 7.34–7.28 (m, 2H), 6.97–6.91 (m, 3H), 3.90
13
(t, J=4.8 Hz, 4H), 3.19 (t, J=4.8 Hz, 4H). C NMR (CDCl3, 101 MHz, ppm): δ 151.3, 129.2,
120.1, 115.6, 66.9, 49.4. HR-MS (ESI+): calcd for C10H14NO [M+H]+: 164.1070; found
164.1072.
N-(4-Methoxyphenyl)morpholine (3).24 Pale brown solid (680 mg, 70%), mp 70–72 °C (from
1
hexane)(lit. 71-72 °C). Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ 6.82 (d, J=9.1 Hz,
13
2H), 6.76 (d, J=9.1 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.73 (s, 3H), 2.99 (t, J=4.8 Hz, 4H). C
NMR (DMSO-d6+CCl4 (1:2), 101 MHz, ppm): δ 153.1, 145.0, 116.9, 113.7, 66.0, 54.6, 50.0.
HR-MS (ESI+): calcd for C11H16NO2 [M+H]+: 194.1176; found 194.1186.
N-(4-methylphenyl)pyrrolidine (4).25 Brown solid (415 mg, 51%), mp 40–42 °C (from
1
hexane)(lit. 40-42 °C). Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ 6.92 (d, J=8.0 Hz,
13
2H), 6.40 (d, J=8.0 Hz, 2H), 3.24 (t, J=6.4 Hz, 4H), 2.24 (s, 3H), 2.02 (t, J=6.4 Hz, 4H). C
NMR (DMSO-d6+CCl4 (1:2), 101 MHz, ppm): δ 145.3, 128.9, 123.1, 111.2, 47.1, 24.8, 19.8.
HR-MS (ESI+): calcd for C11H16N [M+H]+: 162.1277; found 162.1280.
N-(4-Methoxyphenyl)piperidine hydrochloride (5).26 Brown solid (958 mg, 84%), mp 185–
1
187 °C (from 85% EtOH) (lit. 186-187 °C). H NMR (400 MHz, CDCl3): δ 13.73 (br. s, 1H),
7.84 (d, J=8.9 Hz, 2H), 6.97 (d, J=8.9 Hz, 2H), 3.83 (s, 3H), 3.62 (d, J=11.4 Hz, 2H), 3.23 (dd,
J=22.3 Hz, 10.5 Hz, 2H), 2.72 (q, J=13.4 Hz, 2H), 2.02 (d, J=13.4 Hz, 1H), 1.92 (d, J=14.4 Hz,
13
2H), 1.57–1.47 (m, 1H). C NMR (CDCl3, 101 MHz, ppm): δ 160.2, 135.6, 122.7, 115.2, 57.6,
55.7, 23.0, 21.7. HR-MS (ESI+): calcd for C12H18NO [M+H]+: 192.1383; found 192.1386.
N-Cyclohexyl-4-methylaniline (6).27 Brown solid (749 mg, 79%), mp 43–44 °C (from 85%
1
EtOH) (lit. 40-41 °C). Н NMR (CDCl3, 400 MHz, ppm): δ 6.99 (d, J=8.3 Hz, 1H), 6.56 (d,
J=8.3 Hz, 1H), 3.56 (br.s, 1H), 3.28–3.21 (m, 1H), 2.26 (s, 3H), 2.10–2.06 (m, 2H), 1.80–1.75
(m, 2H), 1.69–1.64 (m, 1H), 1.44–1.33 (m, 2H), 1.29–1.11 (m, 3H). 13C NMR (CDCl3, 101
MHz, ppm): δ 145.1, 129.8, 126.2, 113.5, 52.1, 33.6, 26.0, 25.1, 20.4. HR-MS (ESI+): calcd for
C13H20N [M+H]+: 190.1590; found 190.1592.
4-Methyl-(N-phenyl)piperidine hydrochloride (7). Pale brown solid (762mg, 72%), mp 155–
157 °C (from 85% EtOH). 1Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ 13.75 (br. s, 1H),
8.04 (m, 2H), 7.52–7.43 (m, 3H), 3.64 (m, 2H), 3.46–3.44 (m, 2H), 2.18 (m, 2H), 1.91–1.87 (m,
3H), 1.09 (d, J= 6.0 Hz, 3Н). 13C NMR (DMSO-d6, 101 MHz, ppm):δ 143.1, 129.2, 121.5, 95.5,
55.2, 30.4, 27.4, 20.8. HR-MS (ESI+): calcd for C12H18N [M+H]+: 176.1434; found 176.1437.
4-Ethoxy-N-((tetrahydrofuran-2-yl)methyl)aniline hydrochloride (8). Brown solid (929 mg,
1
72%), mp 98–100 °C (from 85% EtOH). Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ
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11.48 (br.s, 2Н), 7.51 (d, J=8.8 Hz, 2Н), 6.93 (d, J=8.8 Hz, 2Н), 4.27 (m, 1H), 4.03 (q, J=6.9
Hz, 2H), 3.90 (dd, J=14.3, 7.4 Hz, 1H), 3.77 (dd, J=14.3, 7.3 Hz, 1H), 3.25 (dd, J=12.7, 3.4 Hz,
1H), 3.16 (dd, J=12.7, 8.8 Hz, 1H), 2.10–2.02 (m, 1H), 2.00–1.85 (m, 2H), 1.70–1.61 (m, 1H),
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1.40 (t, J=6.9 Hz, 3H). C NMR (CDCl3, 101 MHz, ppm): δ 159.2, 127.9, 124.9, 115.3, 72.9,
68.3, 63.8, 56.1, 29.4, 25.4, 14.7. HR-MS (ESI+): calcd for C13H20NO2 [M+H]+: 222.1489;
found 222.1495.
4-Methoxy-N-phenethylaniline hydrochloride (9).28 Pale pink solid (941 mg, 71%), mp 127–
129 °C (from 85% EtOH) (lit. 127-129 °C). 1Н NMR (DMSO-d6+CCl4 (1:2), 400 MHz, ppm): δ
11.68 (br. s, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.28–7.18 (m, 5H), 6.98 (d, J= 8.9 Hz, 2H), 3.81 (s,
13
3H), 3.39 (dd, J=10.4, 6.5 Hz, 2H), 3.12 (dd, J=10.4, 6.5 Hz, 2H). C NMR (DMSO-d6+CCl4
(1:2), 101 MHz, ppm): δ 159.1, 136.7, 128.7, 128.4, 128.0, 126.2, 124.2, 114.6, 55.0, 52.5, 31.3.
HR-MS (ESI+): calcd for C15H18NO [M+H]+: 228.1383; found 228.1383.
1
N-(4-methylphenyl)diethylamine (10).29 Yellow oil (228 mg, 28%). Н NMR (CDCl3, 400
MHz, ppm): δ 7.08 (d, J=8.2 Hz, 2H), 6.69 (d, J= 8.0 Hz, 2H), 3.37 (q, J= 6.9 Hz, 4Н), 2.30 (s,
3Н), 1.2 (t, J= 6.8 Hz, 6H). 13C NMR (CDCl3, 101 MHz, ppm): δ 145.9 (С), 129.8 (2СH), 124.8
(2СH), 112.6 (С), 44.6 (2С, CH2), 20.2 (СH3), 12.6 (2С, СН3). HR-MS (ESI+): calcd for
C11H17N [M+H]+: 164.1434; found 164.1442.
1,4-bis(4-methylphenyl)piperazine (14).30 Prepared according to General procedure 4.3 from
2.5 mmol piperazine (molar ratio of 4-bromotoluene and piperazine 2:1). Light brown solid (450
1
mg, 68%), mp 191−192 °C (lit. 189−191 °C). Н NMR (CDCl3, 400 MHz, ppm): δ 7.14 (d,
J=8.4 Hz, 4H), 6.94 (d, J= 8.4 Hz, 4H), 3.32 (s, 8Н), 2.32 (s, 6Н), 13C NMR (CDCl3, 101 MHz,
ppm): δ 149.2 (C), 129.7, 129.6, 116.7, 50.1, 20.5 (C, CH3). HR-MS (ESI+): calcd for C18H23N2
[M+H]+: 267.1856; found 267.1856.
4.4. General procedure for C–N bond coupling reaction of aryl chlorides with
morpholine
A 8 mL screw cap test tube was charged with Cu(OAc)2·H2O (12 mg, 0.06 mmol, 2
mol%), L (25 mg, 0.12 mmol, 4 mol%), hexane-2,5-dione (18 mg, 0.12 mmol, 4 mol%), KOH
(85%) (225 mg, 3.3 mmol, 110 mol%), adipic acid (70 mg, 0.45 mmol, 15 mol%), NaOAc (78
mg, 0.9 mmol, 30 mol%), CTAB (60 mg, 0.15 mmol, 5 mol%), H2O (0.3 mL), corresponding
aryl chloride (3 mmol) and morpholine (350 mg, 3.9 mmol, 130 mol%). Argon (flow rate 5−7
mL/min) was bubbled through the resulting mixture for 5 min. The reaction mixture was stirred
in a closed test tube at 110 °C for 3 h, then cooled to room temperature and diluted with EtOAc
(30 mL). The EtOAc solution was washed with water (2 × 30 mL), dried with anhydrous
Na2SO4, filtered and analyzed by GC and GC-MS. Then EtOAc was evaporated under reduced
pressure and the residue was chromatographed with using a SiO2 column (EtOAc/hexane 1:5 or
petroleum ether (40–70 °С)/EtOAc 9:1).
4-(3-Chloro-4-methylphenyl)morpholine (1318):
1
Dark yellow oil (90 mg, 14%). Н NMR (CDCl3, 400 MHz, ppm): δ 7.13 (d, J=8.4 Hz, 1Н, Н-
5), 6.92 (d, J=2.6 Hz, 1Н, Н-2), 6.75 (dd, J=8.4 Hz, J=2.6 Hz, 1Н, Н-6), 3.87 (t, J=4.8 Hz, 4Н),
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3.13 (t, J=4.8 Hz, 4Н), 2.31 (s, 3Н).13C NMR (CDCl3, 101 MHz, ppm): δ 150.49 (С), 134.87
(С), 131.19 (СH), 127.10 (С), 116.30 (СH), 114.30 (СH), 66.80 (СH2O), 49.40 (СH2N), 18.99
(С, СН3). MS, m/z (%): 211 (М+, 68%), 153 (100%). HR-MS (ESI+): calcd for C11H15ClNO:
212.0837 [M+H]+; found 212.0836.
4-(5-Chloro-2-methylphenyl)morpholine (1419):
1
Brown oil (20 mg, 3%). Purity (1Н NMR data): ca. 90%. Н NMR (CDCl3, 400 MHz, ppm): δ
7.12 (d, J=8.7 Hz, 1Н, Н-3), 6.99 (m, 2Н, Н-4 and Н-6), 3.87 (t, J=4.6 Hz, 4Н), 2.91 (t, J=4.6
Hz, 4Н), 2.29 (s, 3Н, CH3). 13C NMR (CDCl3, 101 MHz, ppm): δ 152.32 (C), 132.06 (CH),
131.85 (C), 130.84 (C), 123.26 (CH), 119.48 (CH), 67.28 (СH2O), 52.02 (СH2N), 17.48 (С,
СН3). MS, m/z (%): 211 (М+, 100%), 153 (99%). HR-MS (ESI+): calcd for C11H15ClNO:
212.0837 [M+H]+; found 212.0824.
4-(3-Chloro-4-trifluoromethylphenyl)morpholine (1823):
Brown oil (41 mg, 5%). 1Н NMR (CDCl3, 400 MHz, ppm): δ 7.54 (d, J=8.9 Hz, 1Н, H-5), 6.95
(d, J=2.4 Hz, 1Н, H-2), 6.77 (dd, J=8.9 Hz, J=2.4 Hz, 1Н, H-6), 3.87 (t, J=4.9 Hz, 4Н), 3.26 (t,
J=4.9 Hz, 4Н). 13C NMR (CDCl3, 101 MHz, ppm): δ 153.80 (C), 133.32 (br.s, С-Сl), 128.35 (q,
J=5.2 Hz, CH), 123.41 (q, J=271.4 Hz, C-F), 118.20 (q, J=31.8 Hz, С), 116.46 (СН), 111.70
(СН), 66.44 (2СH2O), 47.62 (2СH2N). MS, m/z (%): 265 (М+, 79%), 207 (100%). HR-MS
(ESI+): calcd for C11H12ClF3NO: 266.0554 [M+H]+; found 266.0555.
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.
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References and notes
1. Bariwal, J.; Van der Eycken, E. Chem. Soc. Rev. 2013, 42, 9283.
2. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
3. Ziegler, D. T.; Choi, J.; Muñoz-Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J.
Am. Chem. Soc. 2013, 135, 13107.
4. Evano, G.; Theunissen, C.; Pradal, A. Nat. Prod. Rep., 2013, 30, 1467.
5. Beletskaya, I. P.; Cheprakov, A. V. Organometallics 2012, 31, 7753.
6. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
7. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
8. Feng, Y.-S.; Man, Q.-S.; Pan, P.; Pan Z.-Q.; Xu H.-J. Tetrahedron Lett. 2009, 50, 2585.
9. Liu, Y.-H.; Chen, C.; Yang, L.-M. Tetrahedron Lett. 2006, 47, 9275.
10. Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. Org. Lett. 2005, 7,
5241.
11. Marinelli, F. Current Organic Synthesis, 2012, 9, 2.
12. Zhu, X.; Ma, Y.; Su, L.; Song, H.; Chen, G. Liang, D.; Wan, Y. Synthesis 2006, 3955.
13. Meng, F.; Wang, C.; Xie, J.; Zhu, X.; Wan, Y. Appl. Organometal. Chem. 2011, 25, 341.
14. Zhu, X.; Su, L.; Huang, L.; Chen, G.; Wang, J.; Song, H.; Wan, Y. Eur. J. Org. Chem.
2009, 635.
15. Xie, J.; Zhu, X.; Huang, M.; Meng, F.; Chen W.; Wan, Y. Eur. J. Org. Chem. 2010,
3219.
16. Kurandina, D. V.; Eliseenkov, E. V.; Petrov, A. A.; Boyarskiy, V. P. Russ. Chem. Bull.
2012, 61, 1009.
17. Dehmlow E. V.; Dehmlow S. S. Phase Transfer Catalysis; Verlag Chemie: Weinheim,
Deerfield Beach, Florida – Basel, 2nd rev. ed., 1983, 386 pp.
18. Yang, C.-T., Fu Y.; Huang, Y.-B.; Yi, J.; Guo Q.-X.; Liu, L. Angew.Chem., Int. Ed. 2009,
48, 7398.
19. Boyarskiy, V. P.; Fonari, M. S.; Khaybulova, T. S.; Gdanies, M.; Simonov. Y. A. J.
Fluorine Chem. 2010, 131, 81.
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20. Khaybulova, T. S.; Boyarskaya, I. A.; Larionov, E.; Boyarskiy, V. P. Molecules 2014, 19,
5876.
21. Kurandina, D. V.; Eliseenkov, E. V.; Ilyin, P. V.; Boyarskiy, V. P. Tetrahedron 2014, 70,
4043.
22. Armarego W. L. F.; Chai C. L. L. Purification of Laboratory Chemicals, 5th ed., Elsevier
Science (USA), 2003, 609 pp.
23. Lu, B.; Li, P.; Fu, C.; Xue, L.; Lin, Z.; Ma, S. Adv. Synth. Catal. 2011, 353, 100.
24. Cheung, C. W.; Buchwald, S. L. Org. Lett. 2013, 15, 3998.
25. Komaromi, A.; Novak, Z. Adv. Synth. Catal. 2010, 352, 1523.
26. Grigor’eva, N. E.; Oganes’yan, A. B.; Mysh, I. A. Zhurnal Obshchei Khimii 1957, 27,
1565.
27. Wu, Z.; Zhou, L.; Jiang, Z.; Wu, D.; Li, Z.; Zhou, X. Eur. J. Org. Chem. 2010, 4971.
28. Julia, M.; Igolen, J.; Igolen, H. Bull. Soc. Chim. Fr. 1962, 1060.
29. Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Cat. A: Chem. 2002, 182−183, 515.
30. Gulbins, E.; Hamann, K. Chem. Ber. 1966, 99, 55.
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Supplementary Material
Copper-catalyzed C–N cross-coupling of aryl bromides and amines in water in the presence of ligand
derived from oxalyl dihydrazide: scope and limitation
Daria V. Kurandina, Eugene V. Eliseenkov, Tatyana S. Khaibulova, Alexander A. Petrov, Vadim P. Boyarskiy
General chemical procedures
1H and 13C NMR spectra were recorded on a Bruker Avance II+ 400 MHz (UltraShield Magnet) spectrometer at room temperature. Chemical shifts are
reported in δ (ppm downfield from tetramethylsilane). Spectra in CDCl
3
are referenced to the residual solvent peaks at δ 7.27 (1H ) and 77.00 (13C).
Spectra in DMSO-d
6
are referenced to the residual solvent peaks at δ 2.50 (1H) and 39.52 (13C). 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 mm) 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
mm) capillary column. Mass spectra were recorded on a Bruker micrOTOF spectrometer equipped with an electrospray ionization (ESI) source.

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1H NMR of N-(4-methylphenyl)morpholine (1) (400.13 MHz, DMSO-d6+CCl4)

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13C NMR of N-(4-methylphenyl)morpholine (1) (100.61 MHz, DMSO-d6+CCl4)
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1H NMR of N-phenylmorpholine (2) (400.13 MHz, CDCl3)
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13C NMR of N-phenylmorpholine (2) (100.61 MHz, CDCl3)
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1H NMR of N-(4-methoxyphenyl)morpholine (3) (400.13 MHz, DMSO-d6+CCl4)
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13C NMR of N-(4-methoxyphenyl)morpholine (3) (100.61 MHz, DMSO-d6+CCl4)

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1H NMR of N-(4-methylphenyl)pyrrolidine (4) (400.13 MHz, DMSO-d6+CCl4)

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13C NMR of N-(4-methylphenyl)pyrrolidine (4) (100.61 MHz, DMSO-d6+CCl4)
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1H NMR of N-(4-methoxyphenyl)piperidine hydrochloride (5) (400.13 MHz, CDCl3)
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13C NMR of N-(4-methoxyphenyl)piperidine hydrochloride (5) (100.61 MHz, CDCl3)
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1H NMR of N-cyclohexyl-4-methylaniline (6) (400.13 MHz, CDCl3)
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