Preparation of β-aminoketone by 2,3-dichloro-5,6-dicyanobenzoquinone catalysed three-component Mannich reaction

Article abstract of DOI:10.3184/030823409X12612309457849

2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) was used as an effi cient catalysts for a one-pot, three-component Mannich reaction of cyclohexanone or acetophenone with aromatic aldehydes and aromatic amines under solvent free condition. This protocol has the advantage of high yield, mild reaction conditions, lower catalyst loading and simple work up procedure.

Full text of DOI:10.3184/030823409X12612309457849

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 15
JANUARY, 15–18
Preparation of β-aminoketone by 2,3-dichloro-5,6-dicyanobenzoquinone
catalysed three-component Mannich reaction
Feng Xu*, Peng-Bo Li, You-Ping Tian, Hui-Li Li and Qi Li
Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Materials Science, Shaanxi Normal University, Xi’an,
Shaanxi 710062, P. R. China
2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) was used as an efficient catalysts for a one-pot, three-component
Mannich reaction of cyclohexanone or acetophenone with aromatic aldehydes and aromatic amines under solvent
free condition. This protocol has the advantage of high yield, mild reaction conditions, lower catalyst loading and
simple work up procedure.
Keywords: DDQ, β-amino ketone, Mannich reaction, catalysis
smoothly produced a β-aminoketone in good yield. Encour-
aged by this result, we conducted the reaction in different
solvents, different amount of DDQ and ratio of starting material
in order to optimise the reaction condition. These results shown
in Table 1 imply that the reaction solvent (whether polar or
non-polar), and the amount DDQ cannot dramatically improve
the yields (Table 1 entries 1–5). In the light of the advantage
of solvent free reactions, we carried out this reaction under
solvent free conditions by increasing the amount of cyclo-
hexanone. Fortunately, the yields improved and the reaction
time decreased (Table 1 entries 6–10). Even when the amount
of DDQ was decreased to 2 mmol%, the reaction still goes
well and the yield of product increased a little compared
with the case of 5 mmol% DDQ. This may be caused by the
lower solubility of DDQ in cyclohexanone. Furthermore,
the reaction temperature was also investigated. However,
when the temperature was increased to 40 or 60 °C, a lower
yield was obtained. The optimum reaction condition are
DDQ 2 mmol%, 1.5/1.0/1.0 of cyclohexanone/phenylamine/
benzaldehyde, room temperature.
The development of protocol leading to β-amino/β-acetamido
carbonyl compounds has been important in the synthesis of
natural products and pharmaceuticals. The Mannich reaction
represents one of the most important methods for the prepara-
tion of natural products and biologically active nitrogen-
containing compounds, including β-amino acids, aldehydes
and ketones.1–4 Three-component Mannich reactions are
important in organic synthesis and are used for making inter-
mediates, since several components can be introduced in a
single step into a molecule.
The Mannich reaction relies on two- as well as three-
component systems, but the preferred route is the use of a one-
pot three-component rather than a two-step process. Numerous
versions of the Mannich reaction have been developed in the
past. Bronsted acids,5,6 Lewis acids,7–9 Lewis bases,10 rare metal
salts,11,12 and other compounds13–16 have been investigated as
catalysts for Mannich-type reaction in the past. However, tradi-
tional protocols require somewhat harsh conditions, using
toxic organic solvents, long reaction times,7 the need of a large
amount of catalyst,16 expensive catalyst,9,11 and sometimes give
low yields of the products. The conventional synthetic proce-
dures invariably use organic solvents as media to provide a
homogeneous phase. However, the organic solvents used are
harmful and do not drive the reactions to total completion. The
search for new readily available, green catalysts is still being
actively pursued.
Other substituted arylamines and benzaldehyde were then
subjected to the Mannch reaction using DDQ as catalyst. The
results are shown in Table 2.
Table 2 shows that all the reactions gave good to high yields
and were finished within 10 minutes. In the case of aromatic
aldehydes or amines, a strong electron-withdrawing group is
DDQ is a well-known oxidant in organic chemistry.17
For many years, it has been used for the oxidation of allylic
alcohol18 and allylic ethers19 to α, β-unsaturated carbonyl
compounds. Recently, DDQ has emerged as an important
mediator for the construction of carbon–carbon via a cross-
dehydrogenative-coupling (CDC) reaction.20,21
In continuation of our studies on developing cheap and
environmentally benign methodologies for organic reactions
we sought new efficient catalysts for the three-component
Mannich reaction. DDQ was an attractive candidate reagent
since it is an inexpensive, stable crystalline solid that is easy to
handle. We now report the three-component Mannich reaction
in the presence of DDQ as catalysts under solvent-free
conditions to produce β-amino carbonyl compounds.
Scheme 1 DDQ catalysed reaction of cyclohexanone,
aromatic amine and aromatic aldehyde for preparation
of β-aminoketones.
Table 1 Model reaction for effect of catalyst quantity and
solvent
Entry
DDQ/mol%
Solvent/mL
Time
Yield/%a
Result and discussion
1
2
10
10
10
10
15
10b
5b
Toluene/10
CH Cl2/10
CH32CN/10
EtOH/10
EtOH/10
—
8h
8h
40
53
65
73
72
82
85
90
84
85
The Mannich reaction between the substituted aromatic
aldehydes, aromatic amines and cyclohexanone to produce
β-amino carbonyl compounds catalysed by DDQ is shown in
Scheme 1.
The initial model reaction of cyclohexanone (1 mmol),
phenylamine (1 mmol) and benzaldehyde (1 mmol) in the
presence DDQ (0.1 mmol) at room temperature in ethanol
3
8h
4
8h
5
8h
6
45min
32min
35min
50min
60min
7
—
8
2b
—
9
2c
—
10
1b
—
a Isolated yield. b1.5 mmol cyclohexanone. c3 mmol cyclohexa-
none.
* Correspondent. E-mail: fengxu@snnu.edu.cn

16 JOURNAL OF CHEMICAL RESEARCH 2010
Table 2 DDQ catalysed reaction of cyclohexanone, aromatic amine and aromatic aldehyde for preparation β-aminoketones
Entry
1
R1
R2
Producta
Reaction time/min
Anti/synb
Yield/%c
Phenyl
Phenyl
35
59:41
90
2
3
4
5
6
7
Phenyl
Phenyl
4-Chlorophenyl
4-Bromophenyl
4-Methylphenyl
Phenyl
45
60
60
45
60
40
53:47
64:36
78:21
65:35
74:26
50:50
85
75
82
70
80
92
Phenyl
4-Methoxyphenyl
4-Methylphenyl
4-Methylphenyl
Phenyl
4-Chlorophenyl
8
3,4,5-Trimethoxyphenyl
3,5-Dimethoxyphenyl
3-Bromophenyl
Phenyl
Phenyl
Phenyl
Phenyl
70
65
66:34
64:36
50:50
0
82
88
80
0
9
10
11
80
4-Nitrophenyl
300
aAll products were characterised by m.p., IR, and 1H NMR, product 8 and 9 also by 13C NMR and elemental analysis.
bThe ratio of anti/syn isomer were measured by 1H NMR spectroscopic analysis of the crude reaction mixture.
c Isolated yields.

JOURNAL OF CHEMICAL RESEARCH 2010 17
Scheme 2 DDQ catalysed reaction of acetophenone,
aromatic amine and aromatic aldehyde for preparation
of β-aminoketones.
Fig. 1 The structures of syn- and anti- isomer of product 6.
detrimental to the reaction even unworkable (Table 2 entry 11).
Acetophenone can be used instead of cyclohexanone in the
above reaction as shown in Scheme 2. This resulted in a slight
decrease in yield and an increase in reaction time (Table 3)
compared with the case of cyclohexanone.
1
product was confirmed by the melting point, IR and H NMR. The
data of the products were consistent with that of the expected structure
or identical with those described in the literature
2-(Phenyl(phenylamino)methyl)cyclohexanone (1): White solid,
m.p. 118–120 °C [lit.22:115–116 °C]. IR (KBr): υ 3381 (NH), 1698
The β-aminoketones prepared by the reaction of cyclo-
hexanone, aromatic amine and aromatic aldehyde catalysed
by DDQ as shown in Scheme 1, are mixtures of syn- and
anti- isomer. The ratios of syn- and anti- isomer was measured
(C=O), 1600 (C=C) cm−1. H NMR (300MHz, CDCl3): δ 1.58–2.00
1
(m, 6H), 2.29–2.43 (m, 2H), 2.75–2.77 (m, 1H), 4.61 (d, anti, J = 7.0
Hz, 0.59H), 4.80 (d, syn, J = 4.0 Hz, 0.41H), 6.52–6.62 (m, 3H, ArH),
7.05–7.38 (m, 7H, ArH)
1
by H NMR spectroscopic analysis of the product, and are
2-((4-Chlorophenylamino)(phenyl)methyl)cyclohexanone (2): Whi
te solid, m.p. 114–115 °C. [lit.23]. IR(KBr): υ 3411, 3386 (NH), 1700
indicated in Table 1. The representive structures of syn- and
anti- isomer of product 6 were shown in Fig. 1.
(C=O), 1600 (C=C) cm−1. H NMR (300MHz, CDCl ): δ 1.58–2.03
1
(m, 6H), 2.29–2.44 (m, 2H), 2.75–2.77 (m, 1H), 34.53 (d, anti,
J = 6.9Hz, 0.5H), 4.73 (d, syn, J = 3.8Hz, 0.5H), 6.45 (d, J = 8.3Hz,
2H), 6.97–7.01 (m, 2H, ArH), 7.21–7.32 (m, 5H, ArH).
In conclusion, we have demonstrated an efficient and simple
alternative for the preparation of β-amino carbonyl compounds
via the DDQ catalysed three-component Mannich reaction in
solvent-free conditions. Prominent among the advantages of
this new method are high yield, mild reaction conditions, lower
catalyst loading and a simple work-up procedure.
2-((4-Bromophenylamino)(phenyl)methyl)cyclohexanone (3): Whit
e solid, m.p. 122–124 °C. [lit.24]. IR(KBr): υ 3397 (NH), 1697 (C=O),
1592 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ 1.57–2.00 (m, 6H),
2.32–2.44 (m, 2H), 2.75–2.76 (m, 1H), 4.53 (d, anti, J = 6.51Hz,
0.64H), 4.72 (d, syn, J = 3.8Hz, 0.36H), 6.41 (d, J = 8.1Hz, 2H, ArH),
7.11–7.32 (m, 7H, ArH).
Experimental
2-(Phenyl(p-tolylamino)methyl)cyclohexanone (4): White solid, m.
Starting materials were obtained from commercial suppliers used
without further purification. Melting point was determined with X-5
apparatus in open glass capillaries and was uncorrected. IR spectra
were recorded on Equinx 55 FT-IR spectrometer using KBr pellets.
NMR spectral data were collected on an Avance 300 MHz with TMS
as an internal standard.
p. 102–103 °C. [lit.25:105–108 °C]. IR(KBr): υ 3382 (NH), 1696
(C=O), 1616 (C=C) cm−1. H NMR (300MHz, CDCl3): δ 1.42–2.03
1
(m, 6H), 2.15 (s, 3H, –CH3), 2.29–2.45 (m, 2H), 2.72–2.74 (m, 1H),
4.59 (d, anti, J = 7.41Hz, 0.78H), 4.76 (d, syn, J = 3.93Hz, 0.21H),
6.46 (d, J = 7.47Hz, 2H, ArH), 6.86 (d, J = 7.74Hz, 2H, ArH), 7.17–
7.37 (m, 5H, ArH).
2-((4-Methoxyphenyl)(phenylamino)methyl)cyclohexanone
(5):
General experimental procedure
White solid, m.p.104–106 °C, [lit.26]. IR(KBr): υ 3410 (NH), 1693
DDQ (0.04 mmol, 0.0091 g) was added to the aromatic aldehyde
(2 mmol), aromatic amine (2 mmol) and ketone (3 mmol) in a 50 mL
round flask and the contents were stirred at room temperature for the
fixed period. After completion of the reaction (monitored by TLC, the
time indicated in Table 2). The reaction mixture was added aqueous
saturated sodium bicarbonate 20 mL and extracted with ethyl acetate
(2×20 mL). The organic phase was separated, dried, and purified by
chromatography on silica gel for analysis.
1
(C=O), 1605 (C=C) cm−1. H NMR (300MHz, CDCl3): δ 1.61–2.04
(m, 6H), 2.24–2.46 (m, 2H), 2.70–2.77 (m, 1H), 3.76 (s, 3H, –OCH3),
4.58 (d, anti, J = 6.39Hz, 0.65H), 4.71 (d, syn, J = 3.42Hz, 0.35H),
6.52–6.65 (m, 3H, ArH), 6.82–6.84 (m, 2H, ArH), 7.03–7.08 (m, 2H,
ArH), 7.25–7.30 (m, 2H, ArH).
2-((Phenylamino)(p-tolyl)methyl)cyclohexanone (6): White solid,
m.p. 113–115 °C. [lit.27]. IR(KBr): υ 3387 (NH), 1700 (C=O), 1601
1
(C=C) cm−1. H NMR (300MHz, CDCl3): δ 1.55–2.05 (m, 6H), 2.29
The new products (8) and (9) were characterised by the melting
point, IR, 1H/13C NMR and elemental analysis. The structure of known
(s, 3H, –CH3), 2.32–2.46 (m, 2H), 4.58 (d, anti, J = 7.2Hz, 0.74H),
Table 3 DDQ catalysed reaction of acetophenone, aromatic amine and aromatic aldehyde for preparation β-aminoketones
Entry
R1
R2
Product a
Reaction time /h
Yield /% b
1
Phenyl
4-Methylphenyl
8
80
2
3
Phenyl
Phenyl
4-Chlorophenyl
4-Methylphenyl
8
8
75
70
aAll products were characterised by m.p., IR and 1H NMR.
b Isolated yields.

18 JOURNAL OF CHEMICAL RESEARCH 2010
4.75 (d, syn, J = 4.1Hz, 0.26H), 6.54–6.66 (m, 2H, ArH), 7.03–7.11
(m, 4H, ArH), 7.21–7.25 (m, 3H, ArH).
(d, J = 7.8Hz, 2H, ArH); 6.89 (d, 7.8Hz, 2H, ArH); 7.21–7.57 (m, 8H,
ArH); 7.90 (d, J = 7.8Hz, 2H, ArH).
2-((4-Chlorophenylamino)(p-tolyl)methyl)cyclohexanone (7): Whit
e solid, m.p. 102–103 °C. [lit.28:105–106 °C]. IR (KBr): υ 3409 (NH),
1698 (C=O), 1599 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ 1.58–
2.03 (m, 6H), 2.29 (s, 3H, –CH3), 2.33–2.41 (m, 2H), 2.70–2.73
(m, 1H), 4.50 (d, anti, J = 7.02Hz, 0.5H), 4.69 (d, syn, J = 3.75Hz,
0.5H), 6.43–6.47 (m, 2H, ArH), 6.97–7.01 (m, 2H, ArH), 7.08–7.11
(m, 2H, ArH), 7.18–7.25 (m, 2H, ArH).
2-((Phenylamino)(3,4,5-trimethoxyphenyl)methyl)cyclohexanone
(8): White solid, m.p. 151–153 °C. IR(KBr): υ 3334 (NH), 2931,
2833, 1702 (C=O), 1596 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ
1.63–1.91 (m, 6H), 2.34–2.41 (m, 2H), 2.71–2.73 (m, 1H), 3.80–3.83
(s, 9H, –OCH3), 4.51 (d, anti, J = 6.91, 0.66H), 4.70 (d, syn, J = 3.48,
0.34H), 6.55–6.68 (m, 5H, ArH), 7.06–7.11 (m, 2H, ArH). 13C NMR
(75 MHz, CDCl3) δ: 23.7, 24.9, 27.0, 27.8, 28.7, 31.4, 41.9, 42.4,
56.2, 56.6, 57.5, 57.8, 58.7, 60.8, 104.4, 104.5, 113.9, 114.2, 117.8,
129.0, 129.1, 134.4, 147.2, 147.6, 153.2, 153.3, 211.3, 212.8. Anal.
Calcd for C22H27NO4 (369.45) C, 71.52; H, 7.37; N, 3.79. Found:
C, 71.64; H, 7.42; N, 3.72%.
This work was financially supported by the National Natural
Science Foundation of China (20872085) and the Natural
Science Foundation of Shaanxi Province (No. SJ08B22).
Received 12 October 2009; accepted 11 December 2009
Paper 090824 doi: 10.3184/030823409X12612309457849
Published online: 20 January 2010
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2-((3-Bromophenyl)(phenylamino)methyl)cyclohexanone ( 10):
White solid, m.p. 118–120 °C. [lit.29 ]. IR(KBr): υ 3379 (NH), 1702
1
(C=O), 1600 (C=C) cm−1. H NMR (300MHz, CDCl3): δ 1.54–2.03
(m, 6H), 2.30–2.44 (m, 2H), 2.71–2.75 (m, 1H), 4.55 (d, anti,
J = 6.3Hz, 0.5H), 4.73 (d, syn, J = 3.99Hz, 0.5H), 6.51–6.67 (m, 3H,
ArH), 7.06–7.35 (m, 5H, ArH), 7.49 (s, 1H, ArH).
1-Phenyl-3-(phenylamino)-3-p-tolylpropan-1-one ( 12): White
solid, m.p. 136–138 °C. [lit.27: 139–140 °C]. IR(KBr): υ 3387 (NH),
1668(C=O), 1603 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ 2.30 (s,
3H, –CH3); 3.36–3.54 (m, 2H, –CH2–); 4.97 (t, J = 6.3Hz, 1H, –CH–);
6.56–6.68 (m, 3H, ArH); 7.06–7.58 (m, 9H, ArH); 7.91 (d, J = 7.8Hz,
2H, ArH).
3-(4-Chlorophenylamino)-1,3-diphenylpropan-1-one (13): White
solid, m.p.168–170 °C. [lit.30:170–171 °C]. IR(KBr): υ 3371 (NH),
1665 (C=O), 1598 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ 3.42–
3.48 (m, 2H, –CH2–); 4.92–4.97 (m, 1H, –CH–); 6.49 (d, J = 2.7Hz,
2H, ArH); 7.02 (d, 8.7Hz, 2H, ArH); 7.29–7.59 (m, 8H, ArH); 7.89
(d, J = 7.5Hz, 2H, ArH).
1,3-Diphenyl-3-(p-tolylamino)propan-1-one (14): Solid, m.p. 169–
171 °C. [lit.30: 167–168 °C]. IR (KBr): υ 3401 (NH), 1679 (C=O),
1620 (C=C) cm−1. 1H NMR (300MHz, CDCl3): δ 2.17 (s, 3H, –CH3);
3.39–3.54 (m, 2H, –CH2–); 4.97 (t, J = 6.1Hz, 1H, –CH); 6.49

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