Mannich-type reactions of aromatic aldehydes, anilines, and methyl ketones in fluorous biphase systems created by rare earth (III) perfluorooctane sulfonates catalysts in fluorous media

Article abstract of DOI:10.1016/j.jfluchem.2006.07.009

Rare earth (III) perfluorooctane sulfonates (RE(OPf)₃) catalyze the three-component Mannich-type reactions of different ketones with various aromatic aldehydes and aromatic amines in fluorous media to give various β-arylamino ketones in good yields. By simple separation of the fluorous phase containing only catalyst, reaction can be repeated several times.

Full text of DOI:10.1016/j.jfluchem.2006.07.009

Journal of Fluorine Chemistry 127 (2006) 1515–1521
www.elsevier.com/locate/fluor
Mannich-type reactions of aromatic aldehydes, anilines, and methyl
ketones in fluorous biphase systems created by rare earth (III)
perfluorooctane sulfonates catalysts in fluorous media
*
Wen-Bin Yi, Chun Cai
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing 210094, China
Received 2 May 2006; received in revised form 3 July 2006; accepted 6 July 2006
Available online 16 July 2006
Abstract
Rare earth (III) perfluorooctane sulfonates (RE(OPf)3) catalyze the three-component Mannich-type reactions of different ketones with various
aromatic aldehydes and aromatic amines in fluorous media to give various b-arylamino ketones in good yields. By simple separation of the fluorous
phase containing only catalyst, reaction can be repeated several times.
# 2006 Published by Elsevier B.V.
Keywords: Mannich reaction; Fluorous biphasic catalysis; Rare earth (III) perfluorooctanesulfonates; Perfluorocarbon
1. Introduction
Kobayashi reported that dodecylbenzenesulfonic acid [4] or
supported sulfonic acid [5] can catalyze the Mannich reaction
of ketones with aldehydes and amines in good to excellent yield
in water. However, the recovery of the catalyst from aqueous
solution in such protocol is not an economic process. Quite
recently, it was found that ytterbium triflate (Yb(OTf)3) was a
highly efficient catalyst for the same type of reaction [6].
However, reusing of this catalyst required tedious work up
procedures such as filtration, purification and drying.
Mannich and related reactions provide one of the most basic
and useful methods for synthesis of b-amino carbonyl
compounds, which constitute various pharmaceuticals, natural
products, and versatile synthetic intermediates [1]. However,
due to the drastic reaction conditions, severe side-reactions and
substrate limitations, the classical intermolecular Mannich
reaction is plagued by a number of serious disadvantages [1].
The Lewis acid-catalyzed condensation of silyl enol ethers or
silyl ketene acetals to pre-formed imines is an excellent variant
of the classical Mannich reaction [2]. However, this Lewis acid-
catalyzed three-component reaction of aldehydes, amines, and
silyl enolates in the same vessel has to be carried out under strict
anhydrous conditions because many of the imines are unstable
in water. In addition, most Lewis acids cannot be used in this
one-pot reaction because of the presence of free amines and
water produced in the imine formation. From atom economical
and environmental points of view, therefore, it is desirable to
develop a new efficient system for Mannich-type reactions in
which the parent carbonyl compounds are directly used and
environment-friendly solvent is used as a solvent [3].
Recently, a new kind of Lewis acids of rare earth (III)
perfluorooctanesulfonates (RE(OSO2C8F17)3, RE(OPf)3, RE =
Sc, Y, La–Lu) has been of special interest in that they have
characteristic features such as low hygroscopicity, ease of
handling, robustness for the recycling using and high solubility
in fluorous solvent [7]. On the other hand, perfluorocarbon
solvents, one of most important environment-friendly solvents,
especially perfluoro-alkanes have some unique properties
which make them attractive alternatives for conventional
organic solvents [8]. The compounds functionalized with
perfluorinated groups often dissolve preferentially in fluorous
solvents and this property can be used to extract fluorous
components from reaction mixtures [9]. Shi et al. used
RE(OPf)3 as catalysts in the reaction of arylaldehydes with
aromatic amines and (1-methoxy-2-methylpropenyloxy)-tri-
methylsilane in fluorous media [2i]. As a part of our studies to
explore the utility of lanthanide perfluorooctanesulfonates
catalyzed reactions in fluorous solvents [10], we decided to
* Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: c.cai@mail.njust.edu.cn (C. Cai).
0022-1139/$ – see front matter # 2006 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2006.07.009

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investigate RE(OPf)3-catalyzed the three-component one-pot
Mannich-type reactions of aldehydes, amines, and ketones.
2. Results and discussion
Scheme 1.
The reaction of benzaldehyde, aniline, and acetophenone in
the presence RE(OPf)3 in fluorous media was selected as a
model reaction. Based on the general concept of fluorous
phase chemistry [9], we also used toluene as a co-solvent for
the reaction. It was found that, upon heating at 60 8C, the
organic phase is miscible with fluorous phase and the reaction
system became homogenous. Among these catalysts (Table 1,
entries 1–16), Sc(OPf)3 and Yb(OPf)3 are the most efficient
catalysts for the reaction. This would be ascribed to the higher
Lewis acidity of Sc(OPf)3 and Yb(OPf)3 than those of other
RE(OPf)3 [11]. The control experiment elucidates that no
product of Mannich reaction could be obtained in the absence
of catalyst and fluorous solvent. In addition, we found that a
catalyst loading of only 0.4 mol% was required when using
fluorous phase technology, which is more effective than the
5 mol% of Yb(OTf)3 required to catalyzed the reaction. Next,
the effect of fluorous solvents such as, perfluorohexane
(C6F14), perfluoromethylcyclohexane (C7F14), perfluoroto-
luene (C7F8), perfluorooctane (C8F18), perfluorooctyl bromide
(C8F17Br), and perfluorodecalin (C10F18, cis and trans-
mixture) was examined for the Mannich reaction (Table 1,
entries 16–21). The results showed that yields of the desired
products in perfluorooctane (C8F18) and perfluorooctyl
bromide (C8F17Br) are lower than other solvents. The fluorous
solvents perfluorohexane (C6F14) and perfluorotoluene (C7F8)
are in fact miscible with aromatic compounds at room
temperature. Thus, it is impossible to recover fluorous phase
by phase-separation. At the same time, we found that during
repeated Mannich reactions the loss of fluorous solvent is very
serious when using perfluoromethylcyclohexane (C7F14) as a
fluorous solvent because it is very volatile (bp 76 8C).
Therefore, perfluorodecalin (C10F18, cis and trans-mixture) is
the best fluorous solvent for the reaction.
In order to seek out a practical, useful ‘one-pot’ Manncih
reaction process, we decided to use the relatively cheap and
similarly active catalyst Yb(OPf)3 and perfluorodecalin
(C10F18, cis and trans-mixture) as a fluorous solvent for
reaction of a variety of acetophenones, aromatic aldehydes,
and aromatic amines (Scheme 1). The reaction proceeds
typically through the imine formation of the aldehyde and the
amine, protonation of the imine, and the attack of the enol
derived from the ketone to the protonated imine. The
following features are noteworthy in these reactions. (1)
The reaction was not affected by the electronic effect of
substituent groups of aniline. When o-substituted anilines
were performed as substrate, the reaction gave no desired
product due to the hindrance of ortho substituents. (2) In the
investigation of various benzaldehydes, it was found that p-
methylbenzaldehyde is most active for the reaction. This is
because substituents on benzaldehyde have remarkable
influence on the intermediate ‘RC6H4C+HNHC6H5’ derived
from the aldehyde and the amine: rich electron-donating
substituents such as ‘–OCH3’ result in low stability of the
intermediate, furthermore, difficulty to formation of the
intermediate; rich electron-withdrawing ones such as ‘–NO2’
degrades the activity of the intermediate which does not
favor the following reaction. Similarly, the reaction suffer
remarkably from the hindrance of ortho substituents. (3)
The reactivity order of the aromatic amines is p-nitroaceto-
phenone > p-chloroacetophenone > acetophenone > p-
methyl-acetophenone, indicating the importance of the
electronic nature of the aromatic ketone.
Table 1
Reaction of benzaldehyde, aniline, and acetophenone
Entry
Catalyst
Fluorous solvent
Yield (%)a
b
1
2
Sc(OPf)3
Y(OPf)3
C10F18
96
82
73
82
71
85
73
85
79
70
79
88
91
79
78
96
90
98
95
84
82
C10F18
3
La(OPf)3
Ce(OPf)3
Pr(OPf)3
Nd(OPf)3
Sm(OPf)3
Eu(OPf)3
Gd(OPf)3
Tb(OPf)3
Dy(OPf)3
Ho(OPf)3
Er(OPf)3
Tm(OPf)3
Lu(OPf)3
Yb(OPf)3
Yb(OPf)3
Yb(OPf)3
Yb(OPf)3
Yb(OPf)3
Yb(OPf)3
C10F18
4
C10F18
5
C10F18
6
C10F18
7
C10F18
8
C10F18
9
C10F18
10
11
12
13
14
15
16
17
18
19
20
21
C10F18
C10F18
C10F18
In order to ascertain the scope and limitation of this
catalyzed Mannich reaction, the use of the catalytic systems
was extend to the reaction of aliphatic ketones, various
aldehydes and amines (Scheme 1; Table 2). In the case of
cyclopentanone and cyclohexanone, the reactions were finished
within 12–24 h and good yields (76–94%) of b-amino ketones
were obtained, regardless of the kind of substituent group on
benzaldehydes and anilines. The purity of the products thus
obtained was consistently high, probably because the perflates-
catalyzed reactions took place under neutral conditions, as
opposed to the acid system, which may result in decomposition
of Mannich base at 60 8C or higher reaction temperature [6].
Notably, not only benzaldehyde but also hetero-aromatic
C10F18
C10F18
C10F18
C10F18
CF3(CF2)4CF3
C6F5CF3
C6F13CF3
CF3(CF2)6CF3
CF3(CF2)6CF2Br
Reaction conditions: benzaldehyde (0.01 mol), aniline (0.01 mol), acetophe-
none (0.01 mol), RE(OPf)3 (0.4 mol%), fluorous solvent (2 ml), toluene (4 ml),
60 8C.
a
Isolated yields.
b
.

W.-B Yi, C. Cai / Journal of Fluorine Chemistry 127 (2006) 1515–1521
1517
Table 2
Mannich-type reactions of different ketones with various aromatic aldehydes and aromatic amines
Entry
Ketone (R1)
Amine (R2)
Aldehyde (R3)
Time (h)
Yield (%)a
1
Ph
4-O2NC6H4–
4-CH3C6H4–
4-ClC6H4–
4-CH3OC6H4–
4-HOOCC6H4–
4-CH3CH2OOCC6H4–
3-O2NC6H4–
2-O2NC6H4–
2-ClC6H4–
Ph
Ph
8
16
12
14
10
10
10
24
24
12
12
12
12
12
12
12
12
16
18
18
18
24
24
18
12
16
18
32
32
24
48
36
36
96
87
92
89
90
91
94
–
2
Ph
Ph
3
Ph
Ph
4
Ph
Ph
5
Ph
Ph
6
Ph
Ph
7
Ph
Ph
8
Ph
Ph
9
Ph
Ph
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Ph
4-CH3C6H4–
99
89
81
92
–
Ph
Ph
4-CH3OC6H4–
Ph
Ph
4-O2NC6H4–
Ph
Ph
4-ClC6H4–
Ph
Ph
2-HOC6H4–
4-CH3C6H4–
4-O2NC6H4–
4-ClC6H4–
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclopentanone
Cyclopentanone
Cyclopentanone
Cyclopentanone
Propiophenone
CH3CH2–
CH3CH2CH2–
CH3–
Ph
Ph
86
99
97
88
91
93
84
86
81
82
83
78
76
72
81
79
–
Ph
Ph
Ph
Ph
Ph
Ph
4-CH3C6H4–
4-ClC6H4–
4-ClC6H4–
Ph
Ph
Ph
4-CH3OC6H4–
2-Furfural
Ph
2-Pyridinecarbaldehyde
Ph
Ph
4-ClC6H4–
3-O2NC6H4–
4-ClC6H4–
4-ClC6H4–
4-CH3C6H4–
Ph
Ph
Ph
4-CH3OC6H4–
Ph
Ph
Ph
4-CH3C6H4–
CH3(CH2)2CH2–
PhCH2–
(CH3)2CHCH2–
Ph
Ph
Ph
–
Ph
–
Reaction conditions: aldehyde (0.01 mol), amine (0.01 mol), ketone (0.01 mol), Yb(OPf)3 (0.4 mol%), perfluorodecalin (2 ml), toluene (4 ml), 60 8C, 12 h.
Isolated yields.
a
aldehydes such as 2-furfural and 2-pyridine-carbaldehyde
worked well for the Mannich reaction with cyclohexanone and
aniline. The reaction of propiophenone with p-chloroaniline
and benzaldehyde gave corresponding b-amino ketones in 72%
yield. In the reactions of unsymmetrical aliphatic ketones such
as 2-butanone and 2-pentanone, the adduct aminoalkylated at
C1 was formed preferentially. The catalyst Yb(OPf)3 system
appeared to show no catalytic activity for the reaction in which
the aliphatic amines such as butylamine and benzylamine, and
aliphatic aldehydes such as isovaleraldehyde were performed as
substrates.
3. Experimental
3.1. General
MPs were obtained with Shimadzu DSC-50 thermal
analyzer. IR spectra were recorded on a Bumem MB154S
infra-red analyzer. 1H NMR and 19F NMR spectra were
measured on Bruker Advance RX500. UV–vis spectra was
achieved by UV-1601 apparatus. Mass spectra were recorded
with a Saturn 2000GC/MS instrument. Inductively coupled
plasma (ICP) spectra were measured on Ultima2C apparatus.
Elemental analyses were performed on a Yanagimoto
MT3CHN corder. Commercially available reagents were used
without further purification.
When the reaction was finished, the reaction mixture was
cooled to room temperature. The fluorous phase with
RE(OPf)3 catalyst separates from the organic layer and
returns to the bottom layer [8]. Based on the 19F NMR and
UV–vis spectroscopic data and GC–MS, no loss of catalyst or
fluorous solvent to the organic phases can be detected. Use of
fluorous phase, recycled without purification was equally
effective. For example, in the Yb(OPf)3-catalyzed reaction of
acetophenone, aniline, and benzaldehyde, the yields of
reaction from the first run to the fifth run are 96, 94, 94, 93,
and 92%, respectively.
3.2. Typical procedure for preparation of RE(OPf)3
RE(OPf)3 was prepared according to the literatures [10].
(Method A): The mixture of PfOH solution (aqueous) and
YbCl3ꢀ6H2O solution (aqueous) was stirred at room tempera-
ture. (Method B): The mixture of PfOH solution (aqueous) and
Yb2O3 powder was stirred at boiling. In both methods, the

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W.-B Yi, C. Cai / Journal of Fluorine Chemistry 127 (2006) 1515–1521
resulting gelatin-like solid was collected, washed and dried at
150 8C in vacuo to give a white solid, which does not have a
clear melting point up to 500 8C, but shrinks around 380 and
450 8C. IR (KBr) y 1237 (CF3), 1152 (CF2), 1081 (SO2), 1059
(SO2), 747 (S–O) and 652 (C–S) cmꢁ1. ICP: calcd for
C24O9F51S3Yb: Yb, 10.30%. Found: Yb, 9.88%. Anal. calcd for
C24O9F51S3YbꢀH2O: C, 17.21%; H, 0.10%. Found: C, 17.03%;
H, 0.18%.
3.3.5. 1,3-Diphenyl-3-( p-methoxyphenylamino)-1-
propanone (Table 2, entry 4)
A yellowlish solid; mp 166–167 8C (literature [3d] 184–
186 8C) IR (KBr) y 3390, 1675, 1500, 1287, 812, 709 cmꢁ1. 1H
NMR (500 MHz, TMS, CDCl3) d 2.42 (s, 3H), 3.38–3.55 (m,
2H), 4.93 (t, J = 6.4 Hz, 1H), 6.48 (d, 2H), 6.85 (d, 2H), 7.23 (t,
1H), 7.33 (t, 2H), 7.42–7.47 (m, 4H), 7.52 (t, 1H), 7.91 (d, 2H).
MS (EI) m/z 331 (M+).
3.3. Typical procedure for the Mannich reaction of
aldehydes, ketones, and amines
3.3.6. 1,3-Diphenyl-3-( p-carboxylphenylamino)-1-
propanone (Table 2, entry 5)
A yellow solid; mp 162–163 (literature [6] 162–163 8C) IR
1
A mixture of Yb(OPf)3 (34 mg, 0.02 mmol), benzaldehyde
(0.50 ml, 5 mmol), acetophenone (0.58 ml, 5 mmol), aniline
(0.46 ml, 5 mmol), toluene (4 ml), and perfluorodecalin
(C10F18, cis and trans-mixture, 2.0 ml). The mixture was
stirred at 60 8C for 12 h. Then, the fluorous layer on the
bottom was separated for the next condensation. The reaction
mixture (organic phase) was cooled to 0 8C. The crystalline
product was further washed cold ethanol (10 ml) and dried to
give the product 1,3-diphenyl-3-phenylamino-1-propanone
(1.45 g, 96%).
(KBr) y 3379, 1701, 1280, 815 cmꢁ1. H NMR (500 MHz,
TMS, CDCl3) d 3.65–3.71 (q, J = 9.0 Hz, 1H), 5.05–5.11 (m,
1H), 6.52 (d, 2H), 7.00 (d, 1H), 7.22 (t, 1H), 7.30 (t, 2H), 7.47
(d, 2H), 7.50 (t, 2H), 7.58 (d, 2H), 7.62 (t, 1H), 7.88 (d, 2H). MS
(EI) m/z 345 (M+).
3.3.7. 1,3-Diphenyl-3-( p-carbethoxyphenylamino)-1-
propanone (Table 2, entry 6)
Awhite solid; mp 150–152 8C (literature [6] 150–151 8C) IR
1
(KBr) y 3406, 1679, 1521, 712 cmꢁ1. H NMR (500 MHz,
TMS, CDCl3) d 3.45–3.57 (m, 4H), 3.82 (t, J = 4.3 Hz, 3H),
5.10 (t, J = 6.3 Hz, 1H), 5.78 (br, 1H), 6.82–6.86 (m, 1H), 7.20
(t, 2H), 7.29–7.34 (m, 3H), 7.42–7.47 (m, 5H), 7.62 (t, 1H),
7.81 (d, 2H). MS (EI) m/z 373 (M+).
3.3.1. 1,3-Diphenyl-3-phenylamino-1-propanone
(production for Table 1)
A white solid; mp 169–170 8C (literature [3d] 169–171 8C)
IR (KBr) y 3200, 1681, 1610, 1500, 1300, 756, 512 cmꢁ1. 1H
NMR (500 MHz, TMS, CDCl3) d 3.47 (d, J = 4.8 Hz, 2H), 5.03
(t, J = 6.1 Hz, 1H), 6.58 (s, 2H), 6.68 (s, 1H), 7.09 (s, 2H), 7.20
(s, 2H), 7.32 (s, 2H), 7.45 (s, 4H), 7.56 (s, 1H), 7.92 (d, 2H). MS
(EI) m/z 301 (M+).
3.3.8. 1,3-Diphenyl-3-(3-nitrophenylamino)-1-propanone
(Table 2, entry 7)
A yellow solid; mp 140–142 8C (literature [6] 138–139 8C)
IR (KBr) y 3406, 1679, 1521, 712 cmꢁ1. 1H NMR (500 MHz,
TMS, CDCl3) d 3.44–3.57 (m, 2H), 5.10 (s, 1H), 6.80–6.85 (m,
1H), 7.20 (t, 1H), 7.27 (t, 2H), 7.32–7.36 (m, 3H), 7.42–7.47
(m, 5H), 7.62 (t, 1H), 7.90 (d, 2H). MS (EI) m/z 346 (M+).
3.3.2. 1,3-Diphenyl-3-( p-nitrophenylamino)-1-propanone
(Table 2, entry 1)
Ayellow solid; mp 183–185 8C (literature [3d] 184–186 8C)
1
IR (KBr) y 3381, 1710, 1454, 1600, 1210 cmꢁ1. H NMR
3.3.9. 1-Phenyl-3-( p-methylphenyl)-3-phenylamino-1-
propanone (Table 2, entry 10)
(500 MHz, TMS, CDCl3) d 3.57 (d, J = 5.0 Hz, 2H), 5.13 (t,
J = 6.2 Hz, 1H), 5.58 (brs, 2H), 6.58 (d, 2H), 7.27 (t, 1H), 7.30
(t, 2H), 7.42 (d, 2H), 7.47 (t, 2H), 7.42 (d, 2H), 7.47 (t, 2H), 7.58
(t, 1H), 7.88 (d, 2H), 7.99–8.10 (m, 2H). MS (EI) m/z 346 (M+).
Awhite solid; mp 131–132 8C (literature [6] 131–132 8C) IR
(KBr) y 3400, 1678, 1600, 1520, 810 cmꢁ1 1H NMR
.
(500 MHz, TMS, CDCl3) d 3.47–3.59 (m, 2H), 3.73 (s, 3H),
5.78 (t, J = 6.8 Hz, 1H), 6.52 (d, 2H), 6.69 (t, 1H), 6.85 (d, 2H),
7.09 (t, 2H), 7.39 (d, 2H), 7.45 (t, 2H), 7.57 (t, 1H), 7.90 (d, 2H).
MS (EI) m/z 316 (M+).
3.3.3. 1,3-Diphenyl-3-( p-methylphenylamino)-1-
propanone (Table 2, entry 2)
A white solid; mp 168–170 8C (literature [3d] 170–171 8C)
IR (KBr) y 3400, 1682, 1520, 807 cmꢁ1. 1H NMR (500 MHz,
TMS, CDCl3) d 3.50 (d, J = 5.0 Hz, 2H), 5.03 (t, J = 5.3 Hz,
1H), 6.66 (d, 2H), 6.80 (d, 2H), 7.24 (t, 1H), 7.32 (t, 2H), 7.46 (t,
4H), 7.57 (t, H), 7.92 (d, 2H). MS (EI) m/z 315 (M+).
3.3.10. 1-Phenyl-3-( p-methoxyphenyl)-3-phenylamino-1-
propanone (Table 2, entry 11)
A white solid; mp 151–152 8C (literature [3d] 150–152 8C)
IR (KBr) y 3380, 1680, 1598, 803 cmꢁ1. 1H NMR (500 MHz,
TMS, CDCl3) d 3.37–3.52 (m, 2H), 3.70 (s, 3H), 5.02 (t,
J = 6.7 Hz, 1H), 6.58 (d, 2H), 6.69 (t, 1H), 6.85 (d, 2H), 7.12 (t,
2H), 7.38 (d, 2H), 7.43 (t, 2H), 7.58 (t, 1H), 7.89 (d, 2H). MS
(EI) m/z 332 (M+).
3.3.4. 1,3-Diphenyl-3-( p-chlorophenylamino)-1-
propanone (Table 2, entry 3)
A white solid; mp 170–171 8C (literature [3d] 170–171 8C)
IR (KBr) y 3380, 1680, 1611, 1532, 812 cmꢁ1 1H NMR
.
(500 MHz, TMS, CDCl3) d 3.47–3.49 (m, 2H), 4.93 (t,
J = 6.4 Hz, 1H), 6.48 (d, 2H), 7.02 (d, 2H), 7.27 (t, 1H), 7.31 (t,
2H), 7.39–7.49 (m, 4H), 7.57 (t, 1H), 7.90 (d, 2H). MS (EI) m/z
336–338 (M+).
3.3.11. 1-Phenyl-3-( p-nitrophenyl)-3-phenylamino-1-
propanone (Table 2, entry 12)
A white solid; mp 107–110 8C (literature [3c] 108–109 8C)
IR (KBr) y 3410, 1623, 1605, 1512, 748 cmꢁ1. 1H NMR (500

W.-B Yi, C. Cai / Journal of Fluorine Chemistry 127 (2006) 1515–1521
1519
MHz, TMS, CDCl3) d 3.52 (d, J = 6.1 Hz, 2H), 5.12 (t,
3.3.18. 2-[10-(N-p-chlorophenylamino)-10-
phenyl]methylcyclohexane (Table 2, entry 20)
J = 6.1 Hz, 1H), 6.72 (d, 2H), 6.70 (t, 1H), 7.11 (t, 2H), 7.49 (t,
2H), 7.59 (t, 1H), 7.65 (d, 2H), 7.87 (d, 2H), 8.18 (d, 2H). MS
(EI) m/z 346 (M+).
A yellowlish solid; mp 137–138 8C (literature [3c] 136–
138 8C) IR (KBr) y 3378, 1676, 1609, 1510, 800 cmꢁ1. H
1
NMR (500 MHz, TMS, CDCl3) d 1.60–1.92 (m, 6H), 2.29–2.32
(m, 2H), 2.65 (m, 1H), 3.54 (s, 3H), 4.57 (br, 1H), 4.67 (d,
J = 5.5 Hz, 5H), 6.51 (m, 2H), 6.60 (m, 2H), 7.21–7.55 (m, 5H).
MS (EI) m/z 343–345 (M+).
3.3.12. 1-Phenyl-3-( p-chloroophenyl)-3-phenylamino-1-
propanone (Table 2, entry 13)
A white solid; mp 117–118 8C (literature [3h] 118–119 8C)
IR (KBr) y 3390, 1688, 1604, 1510, 792 cmꢁ1 1H NMR
.
(500 MHz, TMS, CDCl3) d 3.48 (d, J = 5.8 Hz, 2H), 5.18 (t,
J = 5.9 Hz, 1H), 6.60 (d, 2H), 6.68 (t, 1H), 7.12 (t, 2H), 7.52 (t,
2H), 7.54 (t, 1H), 7.60 (d, 2H), 7.82 (d, 2H), 7.90 (d, 2H). MS
(EI) m/z 336–338 (M+).
3.3.19. 2-[10-(N-p-chlorophenylamino)-10-( p-
methoxyphenyl)]methylcyclohexane (Table 2, entry 21)
A yellowlish solid; mp 133–134 8C (literature [3c] 132–
1
134 8C) IR (KBr) y 3321, 1702, 1610, 1510, 800 cmꢁ1. H
NMR (500 MHz, TMS, CDCl3) d 1.14–2.65 (m, 9H), 3.08 (s,
1H), 3.61 (s, 3H), 4.62 (d, J = 4.9 Hz, 1H), 6.31–6.82 (m, 3H),
7.09–7.35 (m, 5H). MS (EI) m/z 374–376 (M+).
3.3.13. 1-( p-Methylphenyl)-3-phenyl-3-phenylamino-1-
propanone (Table 2, entry 15)
A white solid; mp 138–139 8C (literature [3i] 139–140 8C)
1
IR (KBr) y 3380, 1625, 1600, 1502, 758 cmꢁ1. H NMR
3.3.20. 2-[10-(2-Furyl)-10-N-
(500 MHz, TMS, CDCl3) d 2.40 (s, 3H), 3.42 (d, J = 5.9 Hz,
1H), 3.49 (d, 1H), 4.91 (d, J = 6.1 Hz, 1H), 6.42 (d, 2H), 6.79
(d, 2H), 7.12–7.42 (m, 7H), 7.79 (d, 2H). MS (EI) m/z 316
(M+).
phenylamino]methylcyclohexane (Table 2, entry 22)
A white solid (literature [4]); mp 107–108 8C. IR (KBr) y
3362, 2938, 1673, 1597, 1500 cmꢁ1 1H NMR (500 MHz,
.
TMS, CDCl3) d 1.60–2.40 (m, 8H), 2.89–2.96 (m, 1H), 4.57 (br,
1H), 4.85 (d, J = 5.0 Hz, 1H), 6.21 (m, 2H), 6.65 (m, 3H), 7.11–
7.30 (m, 3H). MS (EI) m/z 269 (M+).
3.3.14. 1-( p-Nitrophenyl)-3-phenyl-3-phenylamino-1-
propanone (Table 2, entry 16)
A yellow solid; mp 144–146 8C (literature [3d]) IR (KBr) y
3.3.21. 2-[10-N-phenylamino-10-(2-
3400, 1678, 1510, 808 cmꢁ1
.
1H NMR (500 MHz, TMS,
pyridyl)]methylcyclohexane (Table 2, entry 23)
A white solid (literature [4]); mp 141–142 8C. IR (KBr) y
CDCl3) d 3.44–3.57 (m, 2H), 5.10 (s, 1H), 6.80–6.83 (m, 1H),
7.20 (t, 1H), 7.30 (t, 2H), 7.32–7.39 (m, 3H), 7.42–7.50 (m,
5H), 7.62 (t, 1H), 7.92 (d, 2H). MS (EI) m/z 346 (M+).
1
3390, 2924, 1692, 1590, 1486 cmꢁ1. H NMR (500 MHz,
TMS, CDCl3) d 1.61–2.51 (m, 8H), 3.21–3.33 (m, 1H), 4.78
(d, J = 3.9 Hz, 1H), 5.09 (br, 1H), 6.63 (d, 2H), 6.65 (t, 1H),
7.11–7.40 (m, 4H), 7.59 (t, 1H), 8.59 (d, 1H). MS (EI) m/z
280 (M+).
3.3.15. 1-( p-Chlorophenyl)-3-phenyl-3-phenylamino-1-
propanone (Table 2, entry 17)
A yellowlish solid; mp 119–120 8C (literature [3d] 119–
1
120 8C) IR (KBr) y 3380, 1685, 1610, 1520, 808 cmꢁ1. H
3.3.22. 2-[10-(N-phenylamino)-10-
NMR (500 MHz, TMS, CDCl3) d 3.47–3.50 (m, 2H), 4.92 (t,
J = 6.3 Hz, 1H), 6.48 (d, 2H), 7.08 (d, 2H), 7.27 (t, 1H), 7.34 (t,
2H), 7.39–7.49 (m, 4H), 7.60 (t, 1H), 7.89 (d, 2H). MS (EI) m/z
336–338 (M+).
phenyl]methylcyclopentanone (Table 2, entry 24)
A white solid; mp 164–165 8C (literature [3c] 164–166 8C)
IR (KBr) y 3411, 1730, 1690, 1608, 1521, 806 cmꢁ1. 1H NMR
(500 MHz, TMS, CDCl3) d 1.61–2.41 (m, 7H), 3.66 (s, 1H),
4.41 (d, J = 4.8 Hz, 1H), 6.51–6.66 (m, 3H), 6.82–7.19 (m, 7H).
MS (EI) m/z 295 (M+).
3.3.16. 2-[1’0-(N-phenylamino)-10-
phenyl]methylcyclohexane (Table 2, entry 18)
A white solid; mp 139–140 8C (literature [3c] 138–140 8C)
3.3.23. 2-[10-(N-p-chlorophenylamino)-10-
IR (KBr) y 3380, 1685, 1610, 1520, 808 cmꢁ1
.
1H NMR
phenyl]methylcyclopentanone (Table 2, entry 25)
Ayellow solid; mp 144–147 8C (literature [3c] 144–146 8C)
IR (KBr) y 3410, 1728, 1688, 1608, 1513, 800 cmꢁ1. 1H NMR
(500 MHz, TMS, CDCl3) d 1.63–2.44 (m, 7H), 3.69 (s, 1H),
4.40 (d, J = 5.2 Hz, 1H), 6.58–6.76 (m, 3H), 6.92–7.32 (m, 6H).
MS (EI) m/z 329–311 (M+).
(500 MHz, TMS, CDCl3) d 1.61–1.88 (m, 6H), 2.31–2.45 (m,
2H), 2.71 (m, 1H), 4.51 (br, 1H), 4.68 (d, J = 7.3 Hz, 5H), 6.49
(m, 2H), 6.63 (m, 2H), 7.19–7.40 (m, 5H). MS (EI) m/z 309
(M+).
3.3.17. 2-[10-(N-p-methylphenylamino)-10-
phenyl]methylcyclohexane (Table 2, entry 19)
A white solid; mp 116–118 8C (literature [3c] 116–118 8C)
3.3.24. 2-[10-(N-3-nitrophenylamino)-10-
phenyl]methylcyclopentanone (Table 2, entry 26)
Ayellow solid; mp 165–166 8C (literature [3c] 166–168 8C)
IR (KBr) y 3397, 1736, 1708, 1600, 1510, 796 cmꢁ1. 1H NMR
(500 MHz, TMS, CDCl3) d 1.43–2.94 (m, 7H), 3.49 (s, 1H),
4.30 (d, J = 5.3 Hz, 1H), 6.33–6.76 (m, 3H), 6.88–7.22 (m, 6H).
MS (EI) m/z 340 (M+).
IR (KBr) y 3382, 1680, 1610, 1509, 800 cmꢁ1 1H NMR
.
(500 MHz, TMS, CDCl3) d 1.60–1.91 (m, 6H), 2.29–2.42 (m,
2H), 2.70 (m, 1H), 3.60 (s, 3H), 4.52 (br, 1H), 4.65 (d,
J = 5.2 Hz, 5H), 6.50 (m, 2H), 6.63 (m, 2H), 7.19–7.35 (m, 5H).
MS (EI) m/z 323 (M+).

1520
W.-B Yi, C. Cai / Journal of Fluorine Chemistry 127 (2006) 1515–1521
3.3.25. 2-[10-(N-p-nitrophenylamino)-10-( p-
Synthesis, vol. 2, Pergamon Press, New York, 1991, Chapter 4.1 and
references cited therein;
methoxyphenyl)]methylcyclopentanone (Table 2, entry 27)
Ayellow solid; mp 127–129 8C (literature [3c] 127–128 8C).
IR (KBr) y 3418, 1726, 1678, 1600, 1510, 803 cmꢁ1. 1H NMR
(500 MHz, TMS, CDCl3) d 1.46–2.64 (m, 7H), 3.31 (s, 1H),
3.60 (s, 1H), 4.45 (d, J = 4.9 Hz, 1H), 6.39–6.68 (m, 2H), 6.92–
7.42 (m, 6H). MS (EI) m/z 329–311 (M+).
(c) M. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 37 (1998)
1044–1070, and references cited therein.
[2] (a) M. Onaka, R. Ohno, N. Yanagiya, Y. Izumi, Synlett (1993) 141–
143;
(b) O. Ishihra, M. Funahashi, N. Hanaki, M. Miyata, H. Yamamoto,
Synlett (1994) 963–966;
(c) S. Kobayashi, M. Araki, M. Yasuda, Tetrahedron Lett. 36 (1995)
5773–5776;
3.3.26. 2-Methyl-1,3-diphenyl-3-( p-chlorophenylamino)-
1-propanone (Table 2, entry 28)
(d) P.G. Cozzi, B.D. Simone, A. Umani-Ronchi, Tetrahedron Lett. 37
(1996) 1691–1694;
(e) K. Manabe, Y. Mori, S. Kobayashi, Synlett (1999) 1401–
1402;
A white solid; mp 170–171 8C (literature [3a]) IR (KBr) y
3379, 1676, 1613, 1528, 809 cmꢁ1. 1H NMR (500 MHz, TMS,
CDCl3) d 3.25 (d, J = 7.0 Hz, 3H), 3.47–3.49 (m, 1H), 4.90 (t,
J = 5.5 Hz, 1H), 6.34 (d, 2H), 7.06 (d, 2H), 7.25 (t, 1H), 7.28 (t,
2H), 7.39–7.51 (m, 4H), 7.56 (t, 1H), 7.90 (d, 2H). MS (EI) m/z
350–352 (M+).
(f) T.-P. Loh, Sarah.B.K.W. Liung, K.-L Tan, L.-L Wei, Tetrahedron 56
(2000) 3227–3237;
(g) K. Manabe, S. Kobayashi, Tetrahedron Lett. 40 (1999) 3773–
3776;
(h) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 119 (1997)
10049–10053;
(i) M. Shi, S.-C. Cui, Y.-H. Liu, Tetrahedron 61 (2005) 4965–4970.
[3] HCl-catalyzed, HCl-catalyzed cases in EtOH have been reported.
(a) A.H. Blatt, N. Gross, J. Org. Chem. 29 (1964) 3306–3311;
(b) X.-J. Xu, G.-X. Chen, Acta Chim. Sinica 40 (1982) 463–468;
(c) L. Yi, J.-H. Zou, H.-S. Lei, X. Lin, M. Zhang, Org. Prep. Proced. Int.
23 (1991) 673–676;
3.3.27. 1-Ethyl-3-phenyl-3-phenylamino-1-propanone
(Table 2, entry 29)
A white solid; mp 110–112 8C (literature [3e] 112–114 8C)
IR (KBr) y 3200, 1681, 1610, 1500, 1300, 756, 512 cmꢁ1. 1H
NMR (500 MHz, TMS, CDCl3) d 1.24–2.55 (m, 5H), 3.50 (d,
J = 4.6 Hz, 2H), 5.02 (t, J = 5.9 Hz, 1H), 6.54 (s, 2H), 6.66 (s,
1H), 7.09 (s, 2H), 7.32 (s, 1H), 7.45 (s, 2H), 7.56 (s, 1H), 7.90
(d, 2H). MS (EI) m/z 253 (M+).
(d) L. Yi, H.-S. Lei, J.-H. Zou, X.-J. Xu, Synthesis (1991) 717–
718;
(e) J.-H. Zou, Synth. Commun. 28 (1996) 618–622;
(f) J.-H. Zou, Org. Prep. Proced. Int. 28 (1996) 618–622;
(g) J.-H. Zou, Chin. J. Org. Chem. 16 (1996) 218–222;
(h) S.Y. Xiao, Q.-W. Zeng, Z.-T. Chen, Z.-N. Xia, Z.-L. Li, J.
Chongqing Univ. (Nat. Sci.) 23 (2000) 65–69;
(i) D.-C. Yang, G.-L. Zhang, N. Yang, Y.-G. Zhong, Chem. J. Chin.
Univ. 21 (2000) 1694–1695.
3.3.28. 1-Propyl-3-phenyl-3-phenylamino-1-propanone
(Table 2, entry 30)
A white solid; mp 87–88 8C (literature [3e] 87–88 8C) IR
1
(KBr) y 3219, 1680, 1613, 1505, 1308, 756 cmꢁ1. H NMR
[4] K. Manabe, S. Kobayashi, Org. Lett. 1 (1999) 1965–1967.
[5] S. Limura, D. Nobutou, K. Manabe, S. Kobayashi, Chem. Commun.
(2003) 1644–1645.
(500 MHz, TMS, CDCl3) d 0.72 (t, 3H), 1.43 (m, 2H), 2.20 (t,
2H), 2.80 (d, 2H), 3.63 (br, J = 5.8 Hz, 1H), 6.54 (s, 2H), 6.66
(s, 1H), 7.10 (s, 2H), 7.24 (s, 1H), 7.36 (s, 1H), 7.44 (s, 2H),
7.76 (s, 1H). MS (EI) m/z 267 (M+).
[6] L.-M. Wang, J.-W. Han, J. Sheng, Z.-Y. Fan, H. Tian, Chin. J. Org. Chem.
25 (2005) 591–594.
[7] (a) S. Kobayashi, I. Hachiya, T. Takahori, M. Araki, M. Ishitani, Tetra-
hedron Lett. 33 (1992) 6815–6818;
(b) S. Kobayashi, H. Ishitani, I. Hachiya, M. Araki, Tetrahedron 50 (1994)
11623–11636;
4. Conclusions
(c) T. Hanamoto, Y. Sugimoto, Y.Z. Jin, J. Inanaga, Bull. Chem. Soc. Jpn.
70 (1997) 1421–1426;
In conclusion, RE(OPf)3 are demonstrated to be new and
highly effective catalysts for the one-pot Mannich-type reactions
of methyl ketones with aromatic aldehydes and aromatic amines
in fluorous media. By simple separation of the fluorous phase
containing only catalyst, reaction can be repeated several times.
The simple procedures as well as easy recovery and reuse of this
novel catalytic system are expected to contribute to the
development of more benign Mannich reaction.
(d) K. Manabe, H. Oyamada, K. Sugita, S. Kobayashi, J. Org. Chem. 64
(1999) 8054–8057;
(e) T. Kitazume, H. Nakano, Green Chem. (1999) 179–181;
(f) S. Kobayashi, A. Kawada, S. Mitamura, J. Matsuo, T. Suchiya, Bull.
Chem. Soc. Jpn. 73 (2000) 2325–2333;
(g) S. Kobayashi, I. Komoto, J. Matsuo, Adv. Synth. Catal. 343 (2001)
71–74;
(h) M. Shi, S.-C. Cui, Chem. Commun. (2002) 994–995;
(i) M. Shi, S.-C. Cui, J. Fluorine Chem. 116 (2002) 143–147.
[8] (a) D.W. Zhu, Synthesis (1993) 953–954;
(b) E.D. Wolf, G.V. Koten, B. Deelman, J. Chem. Soc. Rev. 28 (1999) 37–
41.
Acknowledgements
We thank the National Defence Committee of Science and
Technology (40406020103) for financial support. We also
thank the Zhen-Ya Rare Earth Co., Ltd. for providing several
kinds of rare earth oxides.
[9] (a) I.T. Horvath, J. Rabai, Science 266 (1994) 72–75;
(b) R.P. Huhges, H.A. Trujillo, Organometllics 15 (1996) 286–
294;
(c) G. Pozzi, F. Montanari, S. Quici, Chem. Commun. (1997) 69–
70;
(d) R.H. Fish, Chem. Eur. J. 5 (1999) 1677–1680;
(e) J.J.J. Juliette, I.T. Horvath, J.A. Gladysz, Angew. Chem. Int. Ed.
Engl. 36 (1997) 1610–1612;
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