Ligand-free iron/copper cocatalyzed N-arylations of aryl halides with amines under microwave irradiation

Article abstract of DOI:10.1039/b917010c

Ligand-free iron/copper cocatalyzed cross-coupling reactions of aryl halides with amines were carried out to provide the corresponding coupling products in good yields. It is worth noting that the method displays a broad substrate scope, and is convenient, rapid, low-cost and environmentally friendly.

Full text of DOI:10.1039/b917010c

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www.rsc.org/greenchem | Green Chemistry
Ligand-free iron/copper cocatalyzed N-arylations of aryl halides with
amines under microwave irradiation†
Diliang Guo,a,b He Huang, Yu Zhou, Jinyi Xu, Hualiang Jiang, Kaixian Chen and Hong Liu*a,b
b
b
a
b
a,b
Received 18th August 2009, Accepted 19th October 2009
First published as an Advance Article on the web 11th November 2009
DOI: 10.1039/b917010c
Ligand-free iron/copper cocatalyzed cross-coupling reactions of aryl halides with amines were
carried out to provide the corresponding coupling products in good yields. It is worth noting that
the method displays a broad substrate scope, and is convenient, rapid, low-cost and
environmentally friendly.
Introduction
microwave (MW) irradiation. This method is attractive for
several reasons: (i) it employs an economically competitive and
environmentally-friendly catalytic system that is a combination
of readily available iron and copper salts, without ligands or
other additives; (ii) it offers experimental simplicity, and does
not require an inert atmosphere and anhydrous solvents; (iii)
it is applicable to a broad scope of substrates, both aliphatic
and aromatic amines and various substituted aryl halides; (iv)
it proceeds quickly and affords moderate to good yields within
Transition metal-catalyzed carbon–nitrogen bond formation
with aryl halides and aliphatic or aromatic amines is considered
to be an important strategy that finds wide applications in
the synthesis of many substances such as natural products,
agrochemicals, materials, dyes, and pharmaceuticals. In par-
ticular, the majority of the existing protocols for performing the
1
N-arylation of amines with aryl halides have been mediated
2
3
by palladium, copper and, more recently, environmentally
12
minutes under microwave irradiation, which proved to be a
4
benign iron catalysts. Although significant progress has been
green and rapid route in organic synthesis. At the same time,
water is abundant, cheap and an environmentally benign solvent.
In recent years the combination of these two prominent green
chemistry principles, “microwaves” and “water”, has become
made in this field, there are still some drawbacks of these
methods that include the need for (1) specially designed ligands
or stoichiometric amounts of catalysts/reagents, (2) anhydrous
solvents and an inert atmosphere, and (3) long reaction time.
Recently, Norrby, Bolm and their co-workers reported copper-
catalyzed cross-couplings with parts-per-million catalyst load-
ings; they lowered the catalyst loading to 0.01 mol%. And they
found that it was crucial that the ligand-to-metal ratio was
12c
very popular and has received substantial interest.
Results and discussion
Initially, we screened typical reaction parameters including
catalysts, solvents, base and temperature, using iodobenzene
5
high (with 20 mol% of DMEDA). Therefore, it is a highly
challenging and desired endeavor to find a readily available,
(1.5 equiv) and morpholine (1.0 equiv) as model substrates,
6,7
inexpensive and ligand-free catalytic system for cross-coupling
reactions. Taillefer and co-workers reported the first ligand-free
iron/copper cooperative catalysis for N-arylation of nitrogen
and the results are summarized in Table 1. The preliminary
investigation was carried out in water under microwave ir-
◦
radiation at 135 C for 30 min using caesium carbonate as
8
heterocycles. Although these results are encouraging, there is
base. The coupling reaction provided promising products in the
much room for improvement. For example, the methods require
long reaction times and are limited in terms of the substrates
for which they can be used. So room for exploration of an
efficient ligand-free catalytic system, especially proceeding in
short reaction times, still remains.
In continuation of our endeavors devoted to the development
of copper and iron catalyzed cross coupling reactions, herein
we wish to report the first ligand-free iron/copper cocatalyzed
C–N cross coupling reaction in the presence of water under
presence of catalytic amounts of both Fe
2
O
3
(having a purity of
(23% yield; Table 1,
9
9.9995+%, from Alfa Aesar) and Cu(acac)
2
entry 1; acac = acetylacetonate). To our pleasure, switching pure
O to H
O:DMSO = 1:1 promoted the yield to 75% (Table 1,
entry 2), while it was not able to increase the yield in DMSO
Table 1, entry 3). Comparing the microwave-assisted reaction
H
2
2
(
9
conditions with conventional thermal conditions, the former
manifested a significant boost in terms of shorter reaction time
and higher yields (Table 1, entries 2 and 6). When we raised
10
11
◦
the temperature to 150 C, the yields were improved (Table 1,
a
entries 7-9). In the absence of an iron source, catalytic amounts
Department of Medicinal Chemistry, China Pharmaceutical University,
2
4 TongjiaXiang, Nanjing, 210009, P. R. China
of Cu(acac) afforded a moderate yield of the coupling product
2
b
The Center for Drug Discovery and Design, State Key Laboratory of
Drug Research, Shanghai Institute of Materia Medica, Shanghai
Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, 201203, P. R. China. E-mail: hliu@mail.shcnc.ac.cn
(Table 1, entries 5 and 11), and it indicated that the iron
source also had a pronounced impact on the efficient cocatalysis
(compare entries 2 and 9 with 5 and 11, Table 1). However,
1
13
a catalytic amount of Fe O alone was unable to promote the
†
Electronic supplementary information (ESI) available: H and
C
2
3
NMR spectra.
reaction (Table 1, entries 4 and 10), indicating that the copper
2
76 | Green Chem., 2010, 12, 276–281
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Table 1 Optimization of the catalysis conditions
◦
Entry
Iron (0.2 eq)
Copper (0.1 eq)
T/ C
Base (2.0 eq)
Solvent
Yield (%)
1
2
3
4
5
Fe
Fe
Fe
Fe
—
Fe
Fe
Fe
Fe
Fe
—
—
Fe
Fe
Fe
2
2
2
2
O
O
O
O
3
3
3
3
Cu(acac)
Cu(acac)
Cu(acac)
—
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
—
2
2
2
135
135
135
135
135
135
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
H
2
O
23
75
10<
trace
47
56
46
31
83
trace
62
0
70
76
67
71
61
75
DMSO:H
DMSO
DMSO:H
DMSO:H
DMSO:H
H
DMSO
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
DMSO:H
2
O = 1:1
2
2
2
O = 1:1
O = 1:1
O = 1:1
2
2
2
2
2
a
6
2
2
2
2
2
O
O
O
O
O
3
3
3
3
3
7
8
9
2
O
2
2
2
2
2
2
2
2
2
2
2
2
2
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
O = 1:1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Cu(acac)
—
CuI
2
2
2
2
O
O
O
3
3
3
Cu(OAc)
Cu
2
2
O
FeCl
FeCl
Fe(acac)
3
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
Cu(acac)
2
2
2
2
2
2
2
2
2
3
Fe
Fe
Fe
Fe
Fe
2
2
2
2
2
O
O
O
O
O
3
3
3
3
3
NaOtBu
16
29
trace
60
63
K
K
2
CO
PO
3
3
4
Cs
Cs
2
CO
CO
3
3
DMF:H
NMP:H
2
O = 1:1
2
2
O = 1:1
a
b
Performed under conventional thermal conditions, 24h. Yield of isolated product.
source is essential for this process (Table 1, entries 2, 4, 5
were observed for nitrogen heterocycles, such as pyrazole and
indole, but elevating the reaction temperature could lead to an
improvement in reaction yields (Table 2, entries 10 and 11).
As shown, anilines containing an electron-withdrawing group
typically gave lower yields than anilines and those containing an
electron-donating group (Table 2, entries 12-14).
The scope of the process with respect to aryl halides was then
investigated (Table 3). The coupling reactions of morpholine
as the model amine with aryl halides containing various sub-
stituents were carried out under the optimal reaction conditions.
As expected, the desired products were obtained in moderate to
good yields. The results indicated that aryl iodides were more
reactive than aryl bromides and aryl chlorides (Table 3, entries
1, 5 and 8). This protocol was tolerant to electron-donating
functional groups (Table 3, entries 2 and 5); a good yield was
obtained even in the presence of a strongly electron-donating
functional group (Table 3, entry 2). Although a satisfactory
result was obtained for 4-chloroiodobenzene (Table 3, entry
12), the protocol didn’t exhibit good tolerance with aryl halides
bearing the strongly electron-withdrawing functional groups,
and 9-12). Combined with Fe
such as CuI, Cu(OAc) and Cu
entries 13-15). When we screened the iron sources, preliminary
results showed that the yield afforded by Fe was better than
that afforded by FeCl (having a purity of 98+%, from Alfa
Aesar), FeCl (having a purity of 99.5+%, from Alfa Aesar) and
Fe(acac) (having a purity of 99.9+%, from Aldrich) (Table 1,
entries 16-18). Furthermore, we found that the nature of bases
was crucial for the reaction. NaOtBu, K CO and K PO were
all ineffective (Table 1, entries 19-21). Among the solvents used,
2
O
3
as cocatalyst, copper salts
2
2
O were also effective (Table 1,
2
O
3
3
2
3
2
3
3
4
H
2
O:DMSO = 1:1 was superior to other solvents (Table 1,
entries 22 and 23). In summary, the optimum results were
obtained when amine (1.0 equiv) and aryl halide (1.5 equiv) were
allowed to react with Fe
Cs CO (2.0 equiv) stirred in H
0 min.
With the optimized conditions in hand, we investigated
2
O
3
(0.2 equiv), Cu(acac)
2
(0.1 equiv),
◦
2
3
2
O:DMSO = 1:1 at 150 C for
3
the scope of this methodology among a variety of nitrogen-
containing compounds, including aliphatic primary amines,
aliphatic secondary amines, benzylamine, phenethylamine, ani-
lines and nitrogen heterocycles. In general, the corresponding
N-arylation products were obtained in moderate to good yields
such as CF
3
or NO (Table 3, entries 8 and 11). The steric effect
2
was significant, the reactions of para- or meta-substituted aryl
halides afforded higher yields than steric ortho-substituted aryl
halides. The results indicated the reactivity order of substituted
aryl halides: para- > meta- > ortho- (Table 3, entries 2-7, 9
and 10).
(
Table 2). All the aliphatic primary amines and benzylamine,
phenethylamine were effective in the formation of C–N bonds
Table 2, entries 1-5, 8 and 9). Although the steric hindrance of
(
secondary amines often makes them more sluggish than primary
amines to couple with aryl halides, it was a delight to find that
the coupling of aliphatic secondary amines with iodobenzene
was also quite successful (Table 2, entries 6 and 7). Low yields
In an endeavor to expand the scope of the methodology,
we attempted to apply the iron/copper cocatalytic system to
some important compounds that occur in many natural and
13
14
synthetic products, such as indoline, N-alkylanthranilic acid
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Table 2 Iron/copper cocatalyzed N-arylation of aryl iodide with
various nitrogen derivatives
Table 3 Iron/copper cocatalyzed N-arylation of morpholine with
different substituted aryl halides
Entry
1
Amines
Product
Yield (%)
76
Entry Aryl halides
1
Product
Yield (%)
1a
1b
1c
1g
85 (X = I)
2
0
2 (X = Br)
(X = Cl)
2
3
90
93
2
3
2a
2b
80
54
4
5
1d
1e
76
75
4
5
2c
2d
36
83 (X = I)
2
0
0 (X = Br)
(X = Cl)
6
7
8
9
1f
73
83
77
66
6
7
8
2e
2f
45
1g
1h
trace
2g
25 (X = I)
1
1 (X = Br)
9
2h
2i
62
1i
1j
1
1
0
1
35
10
trace
a
5
7
1
1
1
2
2j
39
78
1k
1l
22
51
2k
1
2
a
Yield of isolated product.
1
5
1
1
3
4
1m
1n
35
and quinazolinone. The synthesis of their derivatives has
attracted much attention because of their importance as drug
molecules and key core blocks. Generally, it was encouraging
to reveal that the desired products were obtained in moderate
yields (Scheme 1). Further work is underway in our laboratory.
trace
a
◦
b
Conclusion
MW 165 C, 30 min. Yield of isolated product.
In summary, we have developed a convenient, rapid, economical,
and environmentally friendly protocol for the N-arylation of
2
78 | Green Chem., 2010, 12, 276–281
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3
.07 (m, 2H), 1.61-1.54 (m, 2H), 1.46-1.38 (m, 2H), 0.98-0.93
1
3
(
1
m, 3H). C NMR (100 MHz, CDCl ): d 148.4, 129.1, 117.0,
+
3
12.6, 43.6, 31.6, 20.2, 13.8. MS (EI, m/z): 149 [M] ; HRMS
+
(
EI): Calcd. for C10
H
15N [M] : 149.1204; Found: 149.1208.
1
N-(2-methoxyethyl)benzenamine (1b). H NMR (300 MHz,
CDCl ): d 7.20-7.15 (m, 2H), 6.74-6.69 (m, 1H), 6.64-6.61
3
(
2
7
m,2H), 3.58 (t, J = 5.1 Hz, 2H), 3.37 (s, 3H), 3.27 (t, J = 5.1 Hz,
1
3
H). C NMR (100 MHz, CDCl
3
): d 148.1, 129.1, 117.5, 113.0,
+
0.9, 58.6, 43.3. MS (EI, m/z): 151 [M] ; HRMS (EI): Calcd.
+
for C
9
H13NO [M] : 151.0997; Found: 151.0990.
1
N-(3-methoxypropyl)benzenamine
(1c).
H
NMR
(
1
3
300 MHz, CDCl ): d 7.19-7.14 (m, 2H), 6.71-6.66 (m,
H), 6.62-6.59 (m,2H), 3.50 (t, J = 6.0 Hz, 2H), 3.35 (s,
H), 3.21 (t, J = 6.0 Hz, 2H), 1.91-1.83 (m, 2H). C NMR
): d 148.4, 129.1, 117.0, 112.6, 71.1, 58.6,
3
1
3
(100 MHz, CDCl
3
Scheme 1 Iron/copper cocatalyzed synthesis of indoline, 2-(cyclo-
hexylamino)benzoic acid and 2-methylquinazolin-4(3H)-one.
+
4
C
1.6, 29.2. MS (EI, m/z): 165 [M] ; HRMS (EI): Calcd. for
+
10
H
15NO [M] : 165.1154; Found: 165.1149.
various amines with differently substituted aryl halides pro-
moted by a ligand-free iron/copper cocatalyst under microwave
irradiation. In addition, the short reaction times and simple
reaction conditions coupled with a broad substrate scope make
this method viable for use both in the efficient preparation of
biologically and medicinally interesting molecules, and library
synthesis in drug discovery.
1
N-(cyclopropylmethyl)benzenamine (1d).
H
NMR
(
1
1
300 MHz, CDCl ): d 7.19-7.14 (m, 2H), 6.71-6.66 (m,
H), 6.61-6.58 (m,2H), 2.94 (d, J = 6.3 Hz, 2H), 1.11-1,06 (m,
H), 0.57-0.51 (m,2H), 0.25-0.20 (m,2H). C NMR (100 MHz,
): d 148.4, 129.2, 117.2, 112.7, 49.0, 10.8, 3.4. MS
EI, m/z): 147 [M] ; HRMS (EI): Calcd. for C10
3
1
3
CDCl
3
+
+
(
1
H
13N [M] :
47.1048; Found: 147.1044.
1
N-cyclohexylbenzenamine (1e).
H NMR (300 MHz,
Experimental
CDCl
3
): d 7.18-7.12 (m, 2H), 6.68-6.63 (m, 1H), 6.59-6.56 (m,
H), 3.29-3.21 (m, 1H), 2.08-2.03 (m, 2H), 1.79-1.72 (m, 2H),
.68-1.62 (m, 1H), 1.44-1.08 (m, 5H). C NMR (100 MHz,
General experimental procedures
2
1
1
3
The reagents were purchased from a commercial chemical
reagent company, and used without further purification unless
otherwise stated. All of the microwave-assisted reactions were
CDCl
EI, m/z): 175 [M] ; HRMS (EI): Calcd. for C12
175.1361; Found: 175.1362.
3
): d 147.3, 129.2, 116.8, 113.1, 51.6, 33.4, 25.9, 25.0. MS
+
+
(
H
17N [M] :
TM
performed in an Initiator EXP microwave system (Biotage,
Inc.) at the specified temperature using the standard mode
of operation. Analytical thin-layer chromatography (TLC) was
1
N-phenylpiperidine (1f). H NMR (300 MHz, CDCl
3
):
d 7.26-7.21 (m, 2H), 6.94-6.92 (m, 2H), 6.83-6.78 (m, 1H), 3.14
1
HSGF 254. Proton and carbon magnetic resonance spectra ( H
13
(
t, J = 5.7 Hz, 4H), 1.74-1.66 (m, 4H), 1.59-1.54 (m, 2H).
C
1
3
NMR and C NMR) were recorded using tetramethylsilane
NMR (100 MHz, CDCl ): d 152.2, 128.9, 119.2, 116.5, 50.6,
3
1
(
TMS) in CDCl
3
or DMSO-d
6
as the internal standard ( H
at 7.24 ppm, DMSO at
at 77.0 ppm, DMSO at 40.0 ppm).
+
2
C
5.8, 24.2. MS (EI, m/z): 161 [M] ; HRMS (EI): Calcd. for
NMR: TMS at 0.00 ppm, CDCl
2
3
+
11
H
15N [M] : 161.1204; Found: 161.1201.
1
3
.50 ppm; C NMR: CDCl
3
1
4
-phenylmorpholine (1g). H NMR (300 MHz, CDCl
3
):
General procedure for the coupling reaction
A mixture of Fe (32 mg, 0.2 mmol), Cu(acac)
d 7.30-7.25 (m, 2H), 6.92-6.85 (m, 3H), 3.85 (t, J = 4.8 Hz, 4H),
1
3
3
.14 (t, J = 4.8 Hz, 4H). C NMR (100 MHz, CDCl
3
): d 151.2,
+
2
O
3
2
(26 mg,
1
29.1, 120.0, 115.6, 66.9, 49.3. MS (EI, m/z): 163 [M] ; HRMS
0
.1 mmol), and Cs CO (650 mg, 2.0 mmol) was dissolved in
DMSO (3 mL). Subsequently, iodobenzene (160 mL, 1.5 mmol),
morpholine (88 mL, 1.0 mmol) and H O (3 mL) were added
2
3
+
(
EI): Calcd. for C10
H
13NO [M] : 163.0997; Found: 163.0995.
1
N-benzylbenzenamine (1h). H NMR (300 MHz, CDCl
3
):
2
to this mixture. The vial was sealed and the mixture was then
d 7.34-7.24 (m, 5H), 7.18-7.12 (m, 2H), 6.73-6.68 (m, 1H), 6.61-
◦
13
irradiated for 30 min at 150 C. The mixture was then cooled to
6.58 (m, 2H), 4.27 (s, 2H). C NMR (100 MHz, CDCl ): d
3
room temperature, and diluted with dichloromethane, washed
148.0, 139.3, 129.2, 128.6, 127.4, 127.1, 117.5, 112.8, 48.2. MS
+
+
with brine, dried using anhydrous Na
2
SO
4
, and concentrated in
(EI, m/z): 183 [M] ; HRMS (EI): Calcd. for C13
H
13N [M] :
vacuum. The residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate = 10:1) to yield the expected
product.
183.1048; Found: 183.1090.
1
N-phenethylbenzenamine (1i). H NMR (300 MHz, CDCl
3
):
d 7.35-7.30 (m, 2H), 7.26-7.15 (m, 5H), 6.75-6.69 (m, 1H), 6.61-
.59 (m, 2H), 3.40 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).
C NMR (100 MHz, CDCl ): d 147.9, 139.2, 129.2, 128.7, 128.5,
126.4, 117.4, 112.9, 45.0, 35.4. MS (EI, m/z): 197 [M] ; HRMS
6
Spectroscopic and analytical data
1
3
3
1
+
N-butylbenzenamine (1a). H NMR (300 MHz, CDCl
3
): d
+
7
.19-7.14 (m, 2H), 6.70-6.66 (m, 1H), 6.61-6.58 (m, 2H), 3.12-
(EI): Calcd. for C14
H
15N [M] : 197.1204; Found: 197.1218.
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1
1
-phenyl-1H-pyrazole (1j). H NMR (300 MHz, CDCl
3
): d
6.6 Hz, 2H), 3.87 (t, J = 3.6 Hz, 4H), 3.24 (t, J = 3.6 Hz, 4H).
1
3
7
7
1
[
1
.92-7.91 (m, 1H), 7.74-7.69 (m, 3H), 7.48-7.42 (m, 2H), 7.31-
.26 (m, 1H), 6.47-6.45 (m, 1H). C NMR (100 MHz, CDCl
41.0, 140.0, 129.3, 126.6, 126.3, 119.0, 107.4. MS (EI, m/z): 144
M] ; HRMS (EI): Calcd. for C
44.0691.
-phenyl-1H-indole (1k). H NMR (300 MHz, CDCl
.70-7.67 (m, 1H), 7.57-7.54 (m, 1H), 7.49-7.46 (m, 4H), 7.34-
.30 (m, 2H), 7.24-7.14 (m, 2H), 6.67-6.66 (m, 1H). C NMR
): d 139.8, 135.8, 129.5, 129.3, 127.9, 126.4,
C NMR (100 MHz, CDCl ): d 153.3, 126.5, 126.4, 114.3,
3
1
3
+
3
): d
66.6, 48.1. MS (EI, m/z): 231 [M] ; HRMS (EI): Calcd. for
+
C
11
H
12
F
3
NO [M] : 231.0871; Found: 231.0871.
-(3-(trifluoromethyl)phenyl)morpholine (2h).
300 MHz, CDCl ): d 7.39-7.33 (m, 1H), 7.17-7.11 (m, 2H),
7.08-7.05 (m, 1H), 3.91-3.88 (m, 4H), 3.22-3.20 (m, 4H). C
+
+
9
H
8
N [M] : 144.0687; Found:
2
1
4
H
NMR
(
3
1
13
1
3
): d
7
7
(
NMR (100 MHz, CDCl ): d 151.4, 129.6, 118.4, 116.3, 116.2,
3
1
3
+
111.9, 111.8, 66.7, 48.8. MS (EI, m/z): 231 [M] ; HRMS (EI):
+
100 MHz, CDCl
3
Calcd. for C H F NO [M] : 231.0871; Found: 231.0873.
1
1
12
3
1
24.3, 122.3, 121.1, 120.3, 110.4, 103.5. MS (EI, m/z): 193
1
4
-(4-chlorophenyl)morpholine (2j). H NMR (300 MHz,
+
+
[M] ; HRMS (EI): Calcd. for C14
H
11N [M] : 193.0891; Found:
CDCl ): d 8.16-8.12 (m, 2H), 6.93-6.90 (m, 1H), 6.84-6.81 (m,
3
193.0886.
1
3
1
H), 3.87 (t, J = 5.1 Hz, 4H), 2.93 (t, J = 5.1 Hz, 4H).
C
1
4
-methoxy-N-phenylaniline (1l).
CDCl
H), 5.49 (s, br, 1H), 3.70 (s, 3H). C NMR (100 MHz, CDCl
H
NMR (300 MHz,
NMR (100 MHz, CDCl ): d 155.0, 138.9, 126.2, 125.9, 115.6,
3
+
3
): d 7.23-7.19 (m, 2H), 7.08-7.06 (m, 2H), 6.91-6.81 (m,
112.6, 66.3, 47.1. MS (EI, m/z): 208 [M] ; HRMS (EI): Calcd.
for C H N O [M] : 208.0848; Found: 208.0855.
1
3
+
5
3
):
1
0
12
2
3
d 155.2, 145.1, 135.7, 129.3, 122.1, 119.5, 115.6, 114.6, 55.5. MS
1
+
+
4-(4-chlorophenyl)morpholine (2k). H NMR (300 MHz,
CDCl ): d 7.23-7.20 (m, 2H), 6.84-6.81 (m 2H), 3.86-3.83 (m,
(
EI, m/z): 199 [M] ; HRMS (EI): Calcd. for C13
H
13NO [M] :
3
1
99.0997; Found: 199.0999.
1
3
4
H), 3.13-3.09 (m, 4H). C NMR (100 MHz, CDCl ): d 149.8,
+
3
1
Diphenylamine (1m). H NMR (300 MHz, CDCl
3
): d 7.29-
1
29.0, 124.8, 116.8, 66.7, 49.3. MS (EI, m/z): 197 [M] ; HRMS
1
3
7
.25 (m, 4H), 7.08-7.06 (m, 4H), 6.96-6.91 (m, 2H). C NMR
+
(
EI): Calcd. for C10
H
12ClNO [M] : 197.0607; Found: 197.0610.
(
1
100 MHz, CDCl
69 [M] ; HRMS (EI): Calcd. for C12
3
): d 143.0, 129.3, 121.0, 117.8. MS (EI, m/z):
1
+
+
Indoline (3a). H NMR (300 MHz, CDCl ): d 7.13-7.10 (m,
H), 7.04-6.98 (m, 1H), 6.73-6.70 (m 1H), 6.68-6.62 (m, 1H),
3
H
11N [M] : 169.0891;
1
3
2
1
Found: 169.0886.
.64 (s, br, 1H), 3.52 (t, J = 8.1 Hz, 2H), 3.01 (t, J = 8.1 Hz,
1
4
-(4-methoxyphenyl)morpholine (2a). H NMR (300 MHz,
13
H). C NMR (100 MHz, CDCl
3
): d 151.4, 129.3, 127.1, 124.5,
CDCl
3
): d 6.91-6.83 (m, 4H), 3.87-3.84 (m, 4H), 3.77 (s, 3H),
+
18.6, 109.4, 47.2, 29.7. MS (EI, m/z): 119 [M] ; HRMS (EI):
1
3
3
.07-3.04 (m, 4H). C NMR (100 MHz, CDCl
3
): d 153.9, 145.5,
+
Calcd. for C
8
H
9
N [M] : 119.0735; Found: 119.0730.
+
1
17.8, 114.5, 67.0, 55.5, 50.8. MS (EI, m/z): 193 [M] ; HRMS
1
+
2-(cyclohexylamino)benzoic acid (3b). H NMR (300 MHz,
): d 7.99-7.96 (m, 1H), 7.38-7.33 (m, 1H), 6.73-6.70 (m
H), 6.58-6.53 (m, 1H), 3.43-3.42 (d, br, 1H), 2.07-2.02 (m, 3H),
.80-1.77 (m, 2H), 1.43 (s, 1H), 1.40-1.28 (m, 5H). C NMR
): d 174.8, 151.0, 135.4, 132.8, 114.0, 111.8,
08.3, 50.6, 32.8, 25.8, 24.7. MS (EI, m/z): 219 [M] ; HRMS
(
EI): Calcd. for C11
H
15NO
2
[M] : 193.1103; Found: 193.1108.
CDCl
3
1
4
-(3-methoxyphenyl)morpholine (2b). H NMR (300 MHz,
1
1
CDCl
3
): d 7.23-7.17 (m, 1H), 6.56-6.52 (m, 1H), 6.47-6.44 (m,
H), 3.85 (t, J = 4.8 Hz, 4H), 3.80 (s, 3H), 3.15 (t, J = 4.8 Hz,
H). C NMR (100 MHz, CDCl ): d 160.5, 152.6, 129.8, 108.3,
04.6, 102.1, 66.7, 55.0, 49.1. MS (EI, m/z): 193 [M] ; HRMS
13
2
4
1
(
1
(
100 MHz, CDCl
3
1
3
3
+
+
+
EI): Calcd. for C13
H
17NO
2
[M] : 219.1259; Found: 219.1264.
+
(
EI): Calcd. for C11
H
15NO
2
[M] : 193.1103; Found: 193.1105.
1
2
-methylquinazolin-4(3H)-one (3c). H NMR (300 MHz,
1
4
-(2-methoxyphenyl)morpholine (2c). H NMR (300 MHz,
DMSO-d
t, 1H, J = 7.2 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.44 (t, 1H,
J = 7.2 Hz), 2.35 (s, 3H). C NMR (100 MHz, DMSO-d ): d
61.7, 154.3, 149.0, 134.2, 126.6, 125.8, 125.7, 120.6, 21.4. MS
6
): d 12.2 (s, br, 1H), 8.07(d, 1H, J = 7.8 Hz), 7.76
CDCl
3
): d 7.03-6.99 (m, 1H), 6.94-6.92 (m, 2H), 6.89-6.86 (m,
H), 3.89 (t, J = 4.8 Hz, 4H), 3.86 (s, 3H), 3.07 (t, J = 4.8 Hz,
H). C NMR (100 MHz, CDCl ): d 152.1, 141.0, 123.1, 120.9,
17.9, 111.1, 67.1, 55.2, 51.1. MS (EI, m/z): 193 [M] ; HRMS
(
1
4
1
13
6
1
3
3
1
(
+
+
+
EI, m/z): 160 [M] ; HRMS (EI): Calcd. for C
60.0637; Found: 160.0641.
9
H
8
N O [M] :
2
+
(
EI): Calcd. for C11
H
15NO
2
[M] : 193.1103; Found: 193.1110.
1
1
4
-p-tolylmorpholine (2d). H NMR (300 MHz, CDCl
3
): d
7
2
.21-7.19 (m, 2H), 7.05-7.02 (m, 2H), 3.87 (t, J = 4.5 Hz, 4H),
.93 (t, J = 4.5 Hz, 4H), 2.33 (s, 3H). C NMR (100 MHz,
): d 153.4, 148.8, 130.0, 129.6, 116.3, 115.1, 66.8, 50.1,
1
3
Acknowledgements
CDCl
0.4. MS (EI, m/z): 177 [M] ; HRMS (EI): Calcd. for C11H15NO
3
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (Grant 20721003
and 20872153), International Collaboration Projects (Grant
2007DFB30370 and 20720102040) and the 863 Hi-Tech Pro-
gram of China (Grants 2006AA020602).
+
2
+
[M] : 177.1154; Found: 177.1158.
1
4
-m-tolylmorpholine (2e). H NMR (300 MHz, CDCl
3
): d
7
3
1
1
.20-7.17 (m, 1H), 6.77-6.73 (m, 3H), 3.89-3.86 (m, 4H), 3.19-
1
3
.16 (m, 4H), 2.35 (s, 3H). C NMR (100 MHz, CDCl ): d 151.2,
3
38.8, 128.9, 120.9, 116.5, 112.8, 66.8, 49.4, 21.7. MS (EI, m/z):
77 [M] ; HRMS (EI): Calcd. for C11
+
+
References
H
15NO [M] : 177.1154;
Found: 177.1151.
-(4-(trifluoromethyl)phenyl)morpholine (2g).
300 MHz, CDCl
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): d 7.50 (d, J = 6.6 Hz, 2H), 6.92 (d, J =
2
80 | Green Chem., 2010, 12, 276–281
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9
This journal is © The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 276–281 | 281