Highly efficient one-pot, three-component synthesis of β-aminoketones catalyzed by Fe(O2CCF3)3

Article abstract of DOI:10.1080/00397911.2011.569866

(Chemical Equation Presented) A highly efficient one-pot, three-component synthesis of β-aminoketones was demonstrated using the cost-effective, noncorrosive, and easily available Fe(O₂CCF₃)₃ as a catalyst for the first time. The method can be employed to synthesize a wide range of target compounds and to introduce different functional groups into the β-aminoketone skeleton. Additionally, the method consistently has the advantages of good yields, short reaction time, and simply experimental workup procedure, which makes it a useful process for the synthesis of functionalized β-aminoketones. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.569866

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Highly Efficient One-Pot, Three-
Component Synthesis of β-Aminoketones
Catalyzed by Fe(O2CCF3)3
Min Zhang a , Biao Xiong a , Wei Yang a , Ling Chen a , Feng Wu a ,
Quan Wang a & Yuqiang Ding a
a School of Chemical and Materials Engineering, Jiangnan University,
Wuxi, Jiangsu Province, China
Accepted author version posted online: 17 Nov 2011.Version of
record first published: 29 May 2012.
To cite this article: Min Zhang , Biao Xiong , Wei Yang , Ling Chen , Feng Wu , Quan Wang & Yuqiang
Ding (2012): Highly Efficient One-Pot, Three-Component Synthesis of β-Aminoketones Catalyzed
by Fe(O2CCF3)3 , Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:19, 2831-2843
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Synthetic Communications1, 42: 2831–2843, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.569866
HIGHLY EFFICIENT ONE-POT, THREE-COMPONENT
SYNTHESIS OF b-AMINOKETONES CATALYZED
BY Fe(O2CCF3)3
Min Zhang, Biao Xiong, Wei Yang, Ling Chen, Feng Wu,
Quan Wang, and Yuqiang Ding
School of Chemical and Materials Engineering, Jiangnan University,
Wuxi, Jiangsu Province, China
GRAPHICAL ABSTRACT
Abstract A highly efficient one-pot, three-component synthesis of b-aminoketones was
demonstrated using the cost-effective, noncorrosive, and easily available Fe(O2CCF3)3 as
a catalyst for the first time. The method can be employed to synthesize a wide range of
target compounds and to introduce different functional groups into the b-aminoketone
skeleton. Additionally, the method consistently has the advantages of good yields, short
reaction time, and simply experimental workup procedure, which makes it a useful process
for the synthesis of functionalized b-aminoketones.
Keywords b-Aminoketones; iron(III) trifluoroacetate; three-component reaction
INTRODUCTION
b-Aminoketones represent an important class of compounds because of their
significant applications in of biological activities[1] and as key intermediates for
manufacturing pharmaceuticals and natural products including b-amino alcohols,
b-amino acids, b-lactams, and aminocyclopropanols.[2,3] Owing to these significant
properties and functions, the development of effective methods to construct this type
of compound has been attracting considerable attention. Generally, b-aminoketones
Received August 29, 2010.
Address correspondence to Min Zhang, School of Chemical and Materials Engineering, Jiangnan
University, Lihu Road 1800, Wuxi, Jiangsu Province 214122, China. E-mail: zm31289@yahoo.com.cn
2831

2832
M. ZHANG ET AL.
can be prepared by Mannich reaction in the presence of a suitable catalyst such as
organobismuth(III) perfluorooctanesulfonate,[4] BiCl3,[5] sulfamic acid,[6] functiona-
lized ionic liquid,[7] ZrOCl2,[8] polymer-supported Yb(OTf)3,[9] and K2CO3,[10] More-
over, the modified Mannich-type reactions from imines and ketones,[11,12] imines and
enolate derivatives,[13] or coupling reactions of amides and vinyl Grinard reagents
provide new access to functionalized b-aminoketones.[14] However, many of these
reported methods suffer from the drawbacks such as unsatisfactory yields, prolonged
reaction time, the use of not readily available starting materials, or expensive or toxic
catalysts. Therefore, the search for an effective catalytic process along with
eco-compatible merit for the availability of b-aminoketones is of great importance.
In recent years, iron, a rising star in catalysis, has attracted much attention. It was
associated with sustainable chemistry and has notable advantages such as high abun-
dance in nature, easy availability, and environmental friendliness.[15,16] Iron(III) tri-
fluoroacetate was found to be a cost-effective, noncorrosive, crystalline Lews acid
with outstanding physical stability.[17,18] We therefore investigate its new catalytic
applications in the formation of carbon–carbon and carbon–heteroatom bonds.
Hereby, we report a highly efficient one-pot, direct, three-component synthesis of
b-aminoketone 4 and 5 via iron(III) trifluoroacetate–catalyzed coupling reaction
of aldehyde 1, amine 2, and ketone 3 under mild reaction conditions [Eq. (1)].
Table 1. Screening suitable catalyst and catalytic loading for the synthesis of 4aa
Entry
Catalyst
Reaction time (h)
Catalyst loading (mol%)
4a yields (%)b
1
2
3
4
5
6
7
FeCl3
Fe2(SO4)3
ZnCl2
20
20
20
2
10
10
10
10
10
5
17
10
47
90
93
90
0
NH2SO3H
Fe(O2CCF3)3
Fe(O2CCF3)3
Fe(O2CCF3)3
1
1
20
0
aReaction conditions: Unless otherwise stated, benzaldehyde 1a (1.1 mmol, 106 mg), aniline 2a (1 mmol,
93 mg), and 3a (1 mL) along with different catalysts were stirred in a Schlenk tube at room temperature for
the appropriate reaction time according to Table 1.
bIsolated yields.

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
2833
Table 2. Fe(O2CCF3)3-catalyzed one-pot, three-component synthesis of 1-methy-b-aminoketonesa
Entry
Aldehyde 1
Amine 2
Time (h)
4 yields (%)b
2a: R1 ¼ Ph
2
=
1a: R Ph
1
2b: R1 ¼ 4-CH3
=
1a: R Ph
2
3
4
1.5
1.5
2
C6H4
2c: R1 ¼ 2-OCH3
=
1a: R Ph
C6H4
2d: R1 ¼ 4-Cl
=
1a: R Ph
C6H4
1b: R ¼ 4-OCH3
5
2a: R1 ¼ Ph
2
C6H4
1b: R ¼ 4-OCH3 2b: R1 ¼ 4-CH3
6
1.5
C6H4
C6H4
(Continued )

2834
M. ZHANG ET AL.
Table 2. Continued
Entry
Aldehyde 1
Amine 2
Time (h)
4 yields (%)b
1b: R ¼ 4-OCH3 2d: R1 ¼ 4-Cl
7
2
C6H4
C6H4
8
1c: R ¼ 4-ClC6H4 2a: R1 ¼ Ph
1.5
1d: R ¼ 3-NO2
2a: R1 ¼ Ph
C6H4
9
10
11
1
1d: R ¼ 3-NO2
2b:
1
C6H4
R1 ¼ 4-CH3C6H4
1d: R ¼ 3-NO2
2d: R1 ¼ 4-Cl
1.5
C6H4
C6H4
1e:
12
2a: R1 ¼ Ph
2
=
R
CH3(CH2)4
(Continued )

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
Table 2. Continued
2835
Entry
Aldehyde 1
Amine 2
Time (h)
4 yields (%)b
=
1a: R Ph
=
2e: R CH3(CH2)7
13
14
2
2
=
1e: R CH3
(CH2)4
=
2e: R CH3(CH2)7
—
aReaction conditions: The mixture of Fe(O2CCF3)3 (0.05 mmol, 19.8 mg), aldehyde 1 (1.1 mmol), amine
2 (1 mmol), and acetone 3a (1 mL) was stirred in a schlenk tube at room temperature for appropriate
reaction time according to Table 2.
bIsolated yields.
cExpected product was not found.
To establish an effective conversion system, the synthesis of 4-phenyl-4-
(phenylamino)butan-2-one 4a from benzaldehyde 1a (1.1 mmol), aniline 2a
(1 mmol), and acetone 3a (1 mL) was chosen as a model reaction to evaluate the cata-
lytic activities of several Lewis acids and sulfamic acid. Initially, we carried out the
reaction at room temperature (rt) for 20 h by using 10 mol% of FeCl3 as the catalyst,
and a 17% isolated yield of 4a was obtained (Table 1, entry 1). Using 10 mol% of
Fe2(SO4)3, ZnCl2, NH2SO3H, and Fe(O2CCF3)3 resulted in 10%, 47%, 90%, and
93% isolated yields, respectively (Table 1, entries 2–5). Clearly, Fe(O2CCF3)3 showed
the best activity for the formation of 4a in the shortest reaction time. Decreasing the
catalyst loading from 10 mol% to 5 mol% did not lead to a significantly decreased
yield (Table 1, entry 6). Thus, 5 mol% of Fe(O2CCF3)3 is sufficient to promote the
reaction. The reaction under catalyst-free conditions failed to afford the expected
product even after prolonged reaction time (20 h) (Table 1, entry 7). Based on these
results, the optimized reaction conditions can be summarized as 5 mol% of
Fe(O2CCF3)3 catalyst, neat reaction conditions, and room temperature.
With the best reaction conditions in hand, we then investigated the generality
of this synthetic protocol. A variety of aldehydes 1, amines 2, and acetone 3a were
employed for the formation of 1-methly-b-aminoketone 4. As shown in Table 2, all
the reactions proceeded smoothly and afforded the expected products in good to excel-
lent isolated yields (Table 1, from 71% to 96%). It was found that electronic effects of
substituents on the benzene ring of arylaldehydes and arylamines were quite effective
on the reactions. The arylaldehyde 1 tolerating an electron-withdrawing group (such
as ꢀCl, ꢀNO2) or arylamine 2 bearing an electron-releasing groups (such as ꢀOCH3,
ꢀCH3) resulted in relatively faster reaction and completed the conversion of starting
materials in 1.5 h (Table 2, entries 2, 3, 6, and 8–11), which could be attributed to easy
formation of imine intermediates according to the Mannich reaction mechanism.[10–12]
It is noteworthy that substrate of 4-methoxybenzaldehyde (Table 2, entries 5–7) gave
greater product yields compared to 3-nitrobenzaldehyde (Table 2, entries 9–11),
and the result can be explained as follows: An arylaldehyde bearing an electron-
withdrawing group (ꢀNO2) could decrease the stability of the final coupling product,

2836
M. ZHANG ET AL.
Table 3. Fe(O2CCF3)3-catalyzed one-pot, three-component synthesis of 1-phenyl-b-aminoketonesa
Entry
Aldehyde 1
Amine 2
Time (h)
4 yields (%)b
2a: R1 ¼ Ph
3
=
1a: R Ph
1
2b: R1 ¼ 4-CH3
=
1a: R Ph
2
3
4
3
3
5
C6H4
2c: R1 ¼ 4-O
=
1a: R Ph
CH3C6H4
2d: R1 ¼ 4-Cl
=
1a: R Ph
C6H4
1b: R ¼ 4-OCH3
5
2a: R1 ¼ Ph
3
C6H4
1b: R ¼ 4-OCH3 2d: R1 ¼ 4-Cl
6
4
C6H4
C6H4
(Continued )

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
Table 3. Continued
2837
Entry
Aldehyde 1
Amine 2
Time (h)
4 yields (%)b
7
1c: R ¼ 4-ClC6H4 2a: R1 ¼ Ph
3
1d: R ¼ 3-NO2
2d: R1 ¼ 4-Cl
8
4
C6H4
C6H4
=
2e: R CH3
(CH2)7
=
1a: R Ph
9
3
3
=
1a: R Ph
=
2f: R C6H11
10
=
1a: R Ph
11
2g:
3
aReaction conditions: The mixture of Fe(O2CCF3)3 (0.05 mmol, 19.8 mg), aldehyde 1 (1.1 mmol), amine
2 (1 mmol), and acetophenone 3b (1 mL) was stirred in a Schlenk tube at room temperature for the
appropriate reaction time according to Table 3.
bIsolated yields.
and Fe(O2CCF3)3 catalyst could promote aniline elimination and lead to the enone
formation.[1] This speculation was further confirmed by gas chromatography–mass
spectrometry (GC-MS) analysis. The three-component reactions for the coupling of
alkylaldehyde 1d with aniline 2a and acetone 3a, or alkylamine 2d with benzaldehyde
1a and 3a, also worked well and provided b-carbon alkylated product 4j and N-
alkylated product 4k respectively in good yields (Table 2, entries 12 and 13). However,
the extension for coupling reaction of 1d, 2d, and ketone failed to give the expected

2838
M. ZHANG ET AL.
product and resulted in a complex reaction system (Table 2, entry 14). The highly
reactive alkylaldehyde and alkylamine along with Fe(O2CCF3)3 catalyst could lead
to some side reactions prior to the formation of b-aminoketones.
The reactions of acetophenone 3b with different arylaldehydes 1 and aryla-
mines 2 were subsequently surveyed to form 1-phenyl-b-aminoketone 5 under the
optimized reaction conditions; the results are outlined in Table 3. The electronic
effects of substituents in the arylaldehydes and arylamines are similar to the results
obtained in Table 3. Compared to the substrate of acetone 3a, applying acetophe-
none 3b for the synthesis of product 5 requires a longer reaction time to complete
the conversion of benchmark substrate of amine (Table 3, entries 1–8), and thus acet-
ophenone was considered to be less reactive than acetone under the same employed
reaction conditions. Notably, alkylamines such as n-octylamine 2d, cyclohexanamine
2e, and piperidine 2f were also proved to be effective substrates for the synthesis of
N-alkylated b-aminoketones (Table 2, entries 9–11).
In conclusion, we have developed a highly efficient, simple, general, and straight-
forward method for the synthesis of b-aminoketones by using the cost-effective, non-
corrosive, and easily available Fe(O2CCF3)3 as a catalyst for the first time.[19] The
represented protocol allows assembly of a wide range of target compounds and intro-
duction of different functional groups into the b-aminoketone skeleton by employing
a variety of readily available aldehydes, amines, and ketones. In addition, the method
consistently has the advantages of good yields, short reaction times, and simple experi-
mental workup procedure, which make it a highly practical process for the synthesis of
functionalized b-aminoketones. Further applications on this type of compound are
ongoing in our laboratory and will be published in due course.
EXPERIMENTAL
1
All the known products were characterized by melting points (mp), H NMR,
and infrared (IR) spectra, and the new compounds 4c, 4g, 4j 4l, and 4m were
additionally characterized by 13C NMR and high-resolution mass spectra (HRMS).
Melting points were measured on an Electrothemal SGW-X4 microscopy digital
melting-point apparatus and are uncorrected, IR spectra were recorded on a
FTLA2000 spectrometer, and 1HNMR spectra were obtained on a Bruker-200
instrument. Chemical shifts are reported in parts per million (ppm, d) downfield
from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m), and broad (br). LRMS and HRMS were
measured on Finnigan MAT 95 spectrometer; TLC was performed using commer-
cially prepared 100 to 400-mesh silica gel plates (GF254), and visualization is
effected at 254 nm. All the reagents were purchased from commercial sources (Alfa,
Acros, Aldrich) and used without further purification.
General Procedure for the Preparation of 4a–4k and 5a–5f
The catalyst Fe(O2CCF3)3 (0.05 mmol, 19.8 mg) was added to the solution of
arylaldehyde (1.1 mmol) and aniline (1 mmol) in acetone or acetophenone (1 mL).
The resulting mixture was stirred at room temperature for an appropriate reaction
time (determined by thin-layer chromatography, TLC), filtered, and washed with

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
2839
diethyl ether. The combined organic solvent was evaporated under vacuum to
afforded the crude product, which was purified on preparative TLC eluting with pet-
roleum ether: Ethyl–acetate (10:1). Desired products 4a–4i were afforded in 80% to
96% yields. Products 5a–5i were obtained via recrystallization of the crude products
in ethanol solution.
All the new compounds were characterized by their spectral (1H NMR,
13C NMR, IR, MS, and HRMS) and physical data. Known compounds were
1
characterized by H NMR and IR. Wherever literature examples were available,
the data were compared and were found to be identical with authentic samples.
Spectral Data
4-Phenyl-4-(phenylamino)butan-2-one (4a)[20]. Yield: 90%; white solid;
1
mp: 85–86 ꢁC; H NMR (400 MHz, CDCl3): d 2.11 (s, 3H), 2.93 (d, J ¼ 6.8 Hz,
2H), 4.46 (br, 1H), 4.85 (t, J ¼ 6.8 Hz, 1H), 6.55 (dd, J ¼ 7.6 Hz, 2H), 6.66–6.70
(m, 1H), 7.08–7.12 (m, 3H), 7.24–7.39 (m, 4H); IR (neat): 3370, 1708, 1602, 1509,
.
1489,1282, 1092, 816 cmꢀ1
4-Phenyl-4-(p-tolylamino)butan-2-one (4b)[12]. Yield: 92%; yellow solid;
1
mp: 92–94 ꢁC; H NMR (400 MHz, CDCl3): d 2.13 (s, 3H), 2.21 (s, 3H), 2.94 (d,
J ¼ 6.4 Hz, 2H), 4.35 (br, 1H), 4.84 (t, J ¼ 6.8 Hz, 1H), 6.50 (dd, J ¼ 8.4 Hz, 2H),
6.94 (d, J ¼ 8.0 Hz, 2H), 7.25–7.27(m, 1H), 7.32–7.40 (m, 4H); IR (neat): 3380,
2917, 1708, 1617, 1519, 1452, 1264, 1163, 808 cmꢀ1
.
4-(2-Methoxyphenylamino)-4-phenylbutan-2-one (4c). Yield: 86%; color-
less oil; 1H NMR (400 MHz, CDCl3): d 2.02 (s, 3H), 2.87 (d, J ¼ 6.8 Hz, 2H), 3.78 (s,
3H), 4.79 (br, 1H), 4.80 (t, J ¼ 6.8 Hz, 1H), 6.33–6.36 (m, 1H), 6.54–6.69 (m, 3H),
7.13–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): d 206.83, 147.00, 142.79, 136.68,
128.83, 127.36, 126.35, 121.16, 117.02, 111.29, 109.48, 55.54, 54.09, 51.78, 30.70;
IR (neat): 3395, 2956, 1710, 1600, 1511, 1464, 1358, 1753 cmꢀ1; MS (EI, m=z): 269
[M]þ; HRMS (EI, m=z) calcd. for C17H19NO2[M þ H]þ: 269.1416; found 269.1406.
4-(4-Chlorophenylamino)-4-phenylbutan-2-one (4d)[12]. Yield: 90%;
1
yellow solid; mp: 76–78 ꢁC; H NMR (400 MHz, CDCl3): d 2.12 (s, 3H), 2.94 (d,
J ¼ 6.4 Hz, 2H), 4.55 (br, 1H), 4.81 (t, J ¼ 6.4 Hz, 1H), 6.48 (dd, J ¼ 8.8 Hz, 2H),
7.03–7.07 (m, 2H), 7.27–7.37 (m, 5H); IR (neat): 3370, 1707, 1602, 1508, 1489,
.
1455, 1281, 1092, 816 cmꢀ1
4-(4-Methoxyphenyl)-4-(phenylamino)butan-2-one (4e)[20]. Yield: 93%;
1
yellow solid; mp: 89–91 ꢁC; H NMR (400 MHz, CDCl3): d 2.12 (s, 3H), 2.93 (d,
J ¼ 6.8 Hz, 2H), 3.80 (s, 3H), 4.36 (br, 1H), 4.82 (t, J ¼ 6.8 Hz, 1H), 6.52–6.59 (m,
2H), 6.65–6.72 (m, 1H), 6.85–6.89 (m, 2H), 7.09–7.32 (m, 4H); IR (neat): 3394,
.
2956, 2836, 1710, 1602, 1511, 1438, 1359, 1247, 1175, 831 cmꢀ1
4-(4-Methoxyphenyl)-4-(p-tolylamino)butan-2-one (4f)[20]. Yield: 96%;
1
yellow solid; mp: 55–57 ꢁC; H NMR (400 MHz, CDCl3): d 2.16 (s, 3H), 2.37 (dd,
J ¼ 9.2 Hz, 3H), 2.86 (d, J ¼ 6.4 Hz, 2H), 3.74 (s, 3H), 4.20 (br, 1H), 4.75 (t,
J ¼ 6.4 Hz, 1H), 6.45 (dd, J ¼ 6.4 Hz, 2H), 6.80-6.90 (m, 4H), 7.11–7.26 (m, 2H); IR

2840
M. ZHANG ET AL.
(neat): 3388, 2956, 2917, 2836, 1710, 1613, 1512, 1422, 1358, 1249, 1173, 1032,
809 cmꢀ1
.
4-(4-Chlorophenylamino)-4-(4-methoxyphenyl)butan-2-one (4g). Yield:
1
96%; yellow solid; mp 123–125 ꢁC; H NMR (400 MHz, CDCl3): d 2.12 (s, 3H),
2.92 (d, J ¼ 6.4 Hz, 2H), 3.81 (s, 3H), 4.50 (br, 1H), 4.75 (t, J ¼ 6.4 Hz, 1H),
6.45–6.50 (m, 2H), 6.86–7.08 (m, 4H), 7.24–7.29 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 207.73, 159.31, 145.82, 134.33, 129.39, 127.74, 122.82, 115.31, 114.64,
78.10, 77.46, 76.83, 55.67, 54.32, 51.50, 31.34; IR (neat): 3395, 2956, 1710, 1600,
1511, 1464, 1358, 11753 cmꢀ1; MS (EI, m=z): 303 [M]þ. HRMS (EI, m=z) calcd.
for C17H19ClNO2[M þ H]þ: 304.1104, found 304.1096.
4-(4-Chlorophenyl)-4-(phenylamino)butan-2-one (4h)[20]. Yield: 86%;
1
yellow solid; mp 123–125 ꢁC; H NMR (400 MHz, CDCl3): d 2.12 (s, 3H), 2.93 (d,
J ¼ 6.4 Hz, 2H), 4.55 (br, 1H), 4.88 (t, J ¼ 6.4 Hz, 1H), 6.45–6.50 (m, 2H),
6.66–6.72 (m, 1H), 7.08–7.12 (m, 2H), 7.48–7.61 (m, 4H); IR (neat): 3382, 2931,
.
1706, 1622, 1381, 1176, 820 cmꢀ1
4-(3-Nitrophenyl)-4-(phenylamino)butan-2-one
(4i)[20]. Yield:
80%;
1
Yellow solid; mp: 97–98 ꢁC; H NMR (400 MHz, CDCl3): d 2.18 (s, 3H), 3.02 (d,
J ¼ 6.4 Hz, 2H), 4.58 (br, 1H), 4.97 (t, J ¼ 6.4 Hz, 1H), 6.54 (dd, J ¼ 8.4 Hz, 2H),
6.69–6.76 (m, 1H), 7.09–7.17 (m, 2H), 7.28–7.80 (m, 2H), 8.10–8.28 (m, 2H); IR (neat):
3398, 2919, 1714, 1672, 1602, 1527, 1440, 1350, 1318, 1265, 1164, 1123, 808 cmꢀ1
.
4-(3-Nitrophenyl)-4-(p-tolylamino)butan-2-one (4j). Yield: 85%; yellow
1
solid; mp: 71–73 ꢁC; H NMR (400 MHz, CDCl3): d 2.18 (s, 3H), 2.19 (s, 3H), 3.02
(d, J ¼ 6.4 Hz, 2H), 4.45 (br, 1H), 4.97 (t, J ¼ 6.4 Hz, 1H), 6.47 (dd, J ¼ 8.0 Hz,
2H), 6.92–6.96 (m, 2H), 7.51–7.79 (m, 2H), 8.10–8.27 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 206.53, 145.79, 144.21, 133.34, 130.20, 128.25, 122.89, 121.81,
114.46, 78.12, 77.45, 76.84, 54.32, 51.23, 31.08, 20.80; IR (neat): 3399, 2919, 2867,
1714, 1618, 1584, 1524, 1406, 1350, 1369, 1263, 1164, 1129, 809 cmꢀ1; MS (EI,
m=z): 298 [M]þ; HRMS (EI, m=z) calcd. for C17H19N2O3[M þ H]þ: 299.1396; found
299.1389.
4-(4-Chlorophenylamino)-4-(3-nitrophenyl)butan-2-one
(4k)[7]. Yield:
1
82%; yellow solid; M.P: 86–89 ꢁC; H NMR (400 MHz, CDCl3): d 2.18 (s, 3H),
3.02 (d, J ¼ 6.4 Hz, 2H), 4.65 (br, 1H), 4.91 (t, J ¼ 6.4 Hz, 1H), 6.46 (m, 2H), 7.05–
7.09 (m, 2H), 7.48–7.76 (m, 2H), 8.11–8.25 (m, 2H); IR (neat): 3400, 2950, 1714,
1600, 1529, 1402, 1350, 1314, 1262, 1164, 818 cmꢀ1
.
4-(Phenylamino)nonan-2-one (4l). Yield: 71%; yellow oil; 1H NMR
(400 MHz, CDCl3): d 0.80–0.94 (m, 3H), 1.18–1.49 (m, 8H), 2.07 s, 3H), 2.51–2.84
(m, 3H), 3.66 (br, 1H), 6.51–7.18 (m, 5H); 13C NMR (100 MHz, CDCl3): d 207.21,
144.64, 134.65, 129.44, 117.46, 47.97, 32.42, 31.95, 25.98, 23.30, 22.90, 14.12; IR
(neat): 3387, 2966, 2862, 1701, 1628, 1544, 1406, 1385, 1362, 1261, 1161, 1129,
811 cmꢀ1; MS (EI, m=z): 233 [M]þ; HRMS (EI, m=z) calcd. for C15H23NO [M þ H]þ:
233.1780; found 233.1776.
1
4-(Octylamino)-4-phenylbutan-2-one (4m). Yield: 73%; yellowish oil; H
NMR (400 MHz, CDCl3): d 0.74–0.82 (m, 3H), 1.17–1.22 (m, 12H), 2.32 (s, 3H),

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
2841
2.74 (m, 3H), 3.16–3.18 (m, 2H), 4.29–4.31 (m, 1H); 7.19–7.47 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 207.12, 143.50, 131.01, 130.59, 127.18, 47.69, 45.32, 30.12,
29.40, 27.58, 14.16; IR (neat): 3382, 2972, 1704, 1632, 1382, 1264, 1163, 1131,
821 cmꢀ1; MS (EI, m=z): 275 [M]þ; HRMS (EI, m=z) calcd. for C18H29NO
[M þ H]þ: 275.2249; found 275.2201.
1,3-Diphenyl-3-(phenylamino)propan-1-one (5a)[7]. Yield: 86%; white
solid; mp: 167–168 ꢁC; 1H NMR (400 MHz, CDCl3): d 3.50 (m, 2H), 4.62 (br,
1H), 5.02 (t, J ¼ 6.8 Hz, 1H), 6.56–6.72 (m, 5H), 7.07–7.39 (m, 4H), 7.43–7.60 (m,
4H), 7.91–7.95 (m, 2H); IR (neat): 3386, 3024, 2875, 2364, 1673, 1603, 1515, 1454,
1371, 1227, 1000, 865 cmꢀ1
.
1,3-Diphenyl-3-(p-tolylamino)propan-1-one (5b)[7]. Yield: 80%; white
1
solid; mp: 167–168 ꢁC; H NMR (400 MHz, CDCl3): d 2.20 (s, 3H), 3.48 (m, 2H),
4.38 (br, 1H), 5.00 (t, J ¼ 7.2 Hz, 1H), 6.51 (dd, J ¼ 8.0 Hz, 2H), 6.92 (dd, J ¼ 8.0,
2H), 7.25–7.38 (m, 4H), 7.45–7.59 (m, 4H), 7.93 (m, 2H); IR (neat): 3403, 3025,
.
2916,,2358, 1681, 1621, 1527, 1449, 1370, 1321, 1292, 1215, 1002, 803 cmꢀ1
3-(4-Methoxyphenylamino)-1,3-diphenylpropan-1-one (5c)[21]. Yield: 85%;
white solid; mp: 163–166 ꢁC; 1H NMR (400 MHz, CDCl3): d 3.52–3.40 (m, 2H), 3.70
(s, 3H), 4.30 (br, 1H), 4.96 (t, J ¼ 6.8 Hz, 1H), 6.52 (d, J ¼ 8.4 Hz, 2H), 6.68
(d, J ¼ 8.2, 2H), 7.25 (s, 1H), 7.32 (t, J ¼ 7.2 Hz, 2H), 7.45 (t, J ¼ 6.8 Hz, 4H), 7.56
(t, J ¼ 7.2 Hz, 1H), 7.92 (d, J ¼ 7.6 Hz, 2H); IR (neat): 3397, 2976,,2358, 1679,
1597, 1381, 1115, 803 cmꢀ1
.
3-(4-Chlorophenylamino)-1,3-diphenylpropan-1-one (5d)[7]. Yield: 95%;
1
white solid; mp: 165–167 ꢁC; H NMR (400 MHz, CDCl3): d 3.48 (m, 2H), 4.67
(br, 1H), 4.96 (t, J ¼ 6.8 Hz, 1H), 6.50 (dd, J ¼ 6.8 Hz, 2H), 7.05 (dd, J ¼ 6.8 Hz,
2H), 7.26–7.60 (m, 8H), 7.90–7.95 (m, 2H); IR (neat): 3373, 3021, 2900, 2364,
.
1666, 1602, 1508, 1489, 1448, 1400, 1371, 1285, 1220, 1175, 1004, 806 cmꢀ1
3-(4-Methoxyphenyl)-1-phenyl-3-(phenylamino)propan-1-one
(5e)[7]
.
1
Yield: 83%; White solid; mp: 148–150 ꢁC; H NMR (400 MHz, CDCl3): d 3.47 (m,
2H), 3.80 (s, 3H), 4.57 (br, 1H), 4.99 (t, J ¼ 6.8 Hz, 1H), 6.57–6.72 (m, 3H), 6.87
(m, 2H), 7.12 (m, 2H), 7.36–7.59 (m, 5H), 7.93 (m, 2H); IR (neat): 3376, 2917,
2849, 1666, 1606, 1510, 1447, 1287, 1248, 1175, 1028, 833 cmꢀ1
.
3-(4-Chlorophenylamino)-3-(4-methoxyphenyl)-1-phenylpropan-1-one
1
(5f)[7]. Yield: 90%; yellow solid; mp: 156–158 ꢁC; H NMR (400 MHz, CDCl3): d
2.96 (d, J ¼ 6.8 Hz, 2H), 3.81 (s, 3H), 4.45 (br, 1H), 4.88 (t, J ¼ 6.8 Hz, 1H), 6.56–
6.74 (m, 4H), 7.10–7.42 (m, 9H); IR (neat): 3384, 2929, 1670, 1604, 1595, 1447,
.
1289, 1251, 1106, 1029, 812 cmꢀ1
3-(4-Chlorophenyl)-1-phenyl-3-(phenylamino)propan-1-one (5g)[22]. Yield:
1
86%; yellow solid; mp: 130–132 ꢁC; H NMR (400 MHz, CDCl3): d 3.41–3.52 (m,
2H), 4.56 (br, 1H), 4.98 (t, J ¼ 6.8 Hz, 1H), 6.32 (t, J ¼ 7.6 Hz, 2H), 6.53 (d,
J ¼ 7.6 Hz, 2H), 6.92 (t, J ¼ 6.8 Hz, 2H), 7.05 (d, J ¼ 8.4 Hz, 2H), 7.42–7.51 (m,
2H), 7.62 (d, J ¼ 7.6 Hz, 2H), 7.92–7.94 (m, 2H); IR (neat): 3378, 2992, 1667,
1442, 1112, cmꢀ1
.

2842
M. ZHANG ET AL.
3-(4-Chlorophenylamino)-3-(3-nitrophenyl)-1-phenylpropan-1-one (5h)[8].
Yield: 70%; yellow oil; 1H NMR (400 MHz, CDCl3): d 2.11 (s, 3H), 2.93 (d, J ¼ 6.8 Hz,
2H), 4.13 (br, 1H), 4.08 (br, 2H), 4.85 (t, J ¼ 6.8 Hz, 1H), 6.55 (dd, J ¼ 7.6 Hz, 2H),
6.68–6.69 (m, 1H), 7.10–7.12 (m, 1H), 7.24–7.39 (m, 4H); IR (neat): 3400, 3070,
2878, 2352, 1709, 1614, 1537, 1446, 1350, 1202, 1121, 1009, 933, 810 cmꢀ1
.
3-(Octylamino)-1,3-diphenylpropan-1-one (5i)[23]. Yield: 79%; colorless
1
oil; H NMR (400 MHz, CDCl3): d 0.84–0.89 (m, 3H), 1.14–1.42 (m, 12H), 1.85
(brs, 1H), 2.36–2.49 (m, 2H), 3.24–3.42 (m, 2H), 4.28 (q, J ¼ 4.8 Hz, 1H), 7.23–
8.12 (m, 10H); IR (neat): 3321, 2916, 1681, 1343, 1245, 1002, 821 cmꢀ1
.
3-(Cyclohexylamino)-1,3-diphenylpropan-1-one (5j)[23]. Yield: 71%;
1
colorless solid; mp: 37–39 ꢁC; H NMR (400 MHz, CDCl3): d 1.07–1.70 (br, 10H),
2.06 (s, 1H), 2.25–2.30 (m, 1H), 3.24–3.28 (m, 2H), 4.50 (q, J ¼ 5.0 Hz, 1H), 7.21–
8.13 (m, 10H); IR (neat): 3403, 2923, 1675, 1378, 1326, 1076, 831 cmꢀ1
;
1,3-Diphenyl-3-(piperidin-1-yl)propan-1-one (5k)[23]. Yield: 67%; white
1
solid; M.P: 90–93 ꢁC; H NMR (400 MHz, CDCl3): d 1.23–1.52 (br, 6H), 2.25–
2.48 (m, 4H), 3.34–3.60 (m, 2H), 4.23 (t, J ¼ 6.8 Hz, 1H), 7.20–8.00 (m, 10H); IR
(neat): 2983, 2879, 1676, 1544, 1481, 1379, 1032, 862 cmꢀ1
.
ACKNOWLEDGMENTS
The authors thank the Fundamental Research Funds for the Central
Universities (JUSRP10905), the Start-up grant of Jiangnan University
(1045210372090460), and New Century Excellent Talents in University (NCET-
06-0483) for financial support.
REFERENCES
1. Simplicio, A. L.; Clancy, J. M.; Gilmer, J. F. b-Aminoketones as prodrugs with
pH-controlled activation. Int. J. Pharm. 2007, 336, 208–214.
2. Kleinman, E. F.; Trost, B.M. (Ed.). In Comprehensive Organic Synthesis; Oxford: Perga-
mon, UK, 1991; pp. 893–951.
3. Weigel, W.; Schiller, S.; Henning, H. G. Stereoselective photocyclization to 2-aminocyclo-
propanols by photolysis of b-aminoketones and oxidative ring opening to enaminones.
Tetrahedron 1997, 53, 7855–7866.
4. Zhang, X. W.; Yin, S. F.; Qiu, R. H. Synthesis and structure of an air-stable hypervalent
organobismuth(III) perfluorooctanesulfonate and its use as high-efficiency catalyst for
Mannich-type reactions in water. J. Organomet. Chem. 2009, 694, 3559–3564.
5. Li, H.; Zeng, H. Y.; Shao, H. W. Bismuth(III) chloride-catalyzed one-pot Mannich
reaction: Three-component synthesis of b-amino carbonyl compounds. Tetrahedron Lett.
2009, 50, 6858–6860.
6. Xia, M.; Lu, Y.D. A novel direct and one-pot Mannich synthesis of fluorinated b-amino-
butanones with sulfamic acid as a green catalyst. J. Fluorine Chem. 2006, 127, 1119–1124
7. Dong, F.; Fei, Z. H.; Liu, Z. L. Functionalized ionic liquid as the recyclable catalyst for
Mannich-type reaction in aqueous media. Catal. Commun. 2009, 10, 1267–1270.
8. Eftekhari-Sis, B.; Abdollahifar, A.; Hashemi, M. M.; Zirak, M. Stereoselective Synthesis
of b-amino ketones via direct Mannich-type reactions, catalyzed with ZrOCl2 ꢂ 8H2O
under solvent-free conditions. Eur. J. Org. Chem. 2006, 22, 5152–5157.

HIGHLY EFFICIENT SYNTHESIS OF b-AMINOKETONES
2843
9. Lee, S. H.; Lee, B. S. Applications of cross-linked poly(4-vinylpyridine=styrene)
copolymer-supported ytterbium(III) triflate in Mannich-type reaction: Three-component
one-pot synthesis of b-aminoketones. Bull. Korean Chem. Soc. 2009, 30, 551–555.
10. Hao, W. J.; Jiang, B.; Tu, S. J.; Gao, X. D.; Wu, S. S.; Yan, S.; Zhang, X. H.; Han, Z. G.;
Shi, F. A new mild base-catalyzed Mannich reaction of hetero-arylamines in water: Highly
efficient stereoselective synthesis of b-aminoketones under microwave heating. Org.
Biomol. Chem. 2009, 7, 1410–1414.
11. Arend, M.; Westermann, B.; Risch, N. Modern variants of the Mannich reaction. Angew.
Chem. Int. Ed. 1998, 37, 1044–1070.
12. Jia, X. D.; Wang, X. E.; Yang, C. X.; Huo, D. D.; Wang, W. J.; Ren, Y.; Wang, X. C.
Synthesis of b-aminoketones and construction of highly substituted 4-piperidones by
Mannich reaction induced by persistent radical cation salts. Org. Lett. 2010, 12, 732–735.
13. Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. A novel catalytic system for Manich-
type reaction of silyl enolate: Stereoselective synthesis of b-aminoketones. Angew. Chem.
Int. Ed. 2000, 39, 1958–1960.
14. Gomtsyan, A. Direct Synthesis of b-aminoketones from amides via novel sequential
nucleophilic substitution=Michael reaction. Org. Lett. 2000, 2, 11–13.
15. Enthaler, S.; Junge, K.; Beller, M. Sustainable metal catalysis with iron: From rust to a
rising star. Angew. Chem. Int. Ed. 2008, 47, 3317–3321.
16. Correa, A.; Mancheno, G. O.; Bolm, C. Iron-catalysed carbon–heteroatom and
heteroatom–heteroatom bond-forming processes. Chem. Soc. Rev. 2008, 37, 1108–1117.
17. Erturk, E.; Demir, A. S. Iron(III) trifluoroacetate [Fe(O CCF ) ]–catalyzed epoxide open-
2
¨
ing with amines. Arkivoc 2008, 160–171.
3 3
18. Adibi, H.; Samimi, H. A.; Beygzadeh, M. Iron(III) trifluoroacetate and trifluoromethane-
sulfonate: Recyclable Lewis acid catalysts for one-pot synthesis of 3,4-dihydropyrimidi-
nones or their sulfur analogues and 1,4-dihydropyridines via solvent-free Biginelli and
Hantzsch condensation protocols. Catal. Commun. 2007, 8, 2119–2124.
19. Iranpoor, N.; Adibi, H. Iron(III) trifluoroacetate as an efficient catalyst for solvolytic
and non-solvolytic nucleophilic ring opening of epoxides. Bull. Chem. Soc. Jap. 2000,
73, 675–680.
20. Li, K.; He, T.; Li, C. Lipase-catalysed direct Mannich reaction in water: Utilization of
biocatalytic promiscuity for C–C bond formation in a ‘‘one-pot’’ synthesis. Green Chem.
2009, 11 (6), 777–779.
21. Wang, L. M. H.; Han, J. W.; Sheng, J.; Tan, H.; Fan, Z. Y. Rare earth perfluorooctanoate
[RE(PFO)3]–catalyzed one-pot Mannich reaction: Three-component synthesis of b-amino
carbonyl compounds. Catal. Commun. 2005, 6, 201–204.
22. Lu, G. P.; Cai, C. Mannich reactions catalyzed by perchloric acid in Triton ꢃ 10 aqueous
micelles. Catal. Commun. 2010, 11, 745–748.
23. Toda, F.; Takumi, H.; Nagami, M.; Tanaka, K. A novel method for Michael addition and
epoxidation of chalcones in a water suspension medium: A completely solvent-free
synthetic procedure. Heterocycles. 1998, 47, 469–479.