Highly stereoselective facile synthesis of β-amino carbonyl compounds via a Mannich-type reaction catalyzed by γ-Al2O 3/MeSO3H (alumina/methanesulfonic acid: AMA) as recyclable, efficient, and versatile heterogeneous catalyst

Article abstract of DOI:10.1139/V09-141

Mannich reaction of ketones, aromatic aldehydes, and aromatic amines catalyzed efficiently by g-Al2O3/MeSO3H (alumina/methanesulfonic acid: AMA) as a heterogeneous catalyst, which were carried out in EtOH at ambient temperature to afford the corresponding b-amino ketones in good yields and high stereoselectivities in favor of the anti isomer, was described for the first time. It was found that this catalyst could be completely recovered and reused without loss of its catalytic activities and is thus environmentally conscious. Furthermore, the use of g-Al2O3/CH3SO3H (AMA) catalyst is feasible because of its easy preparation, easy handling, stability, easy recovery, reusability, good activity, stereoselectivity, and eco-friendliness. The use of this method provides a novel and improved modification of the three-component Mannich reaction in terms of mild reaction conditions and clean reaction profiles, using a very small quantity of catalyst and a simple workup procedure.

Full text of DOI:10.1139/V09-141

14
Highly stereoselective facile synthesis of b-amino
carbonyl compounds via a Mannich-type reaction
catalyzed by g-Al2O3/MeSO3H
(alumina/methanesulfonic acid: AMA) as a
recyclable, efficient, and versatile heterogeneous
catalyst
Hashem Sharghi and Mahboubeh Jokar
Abstract: Mannich reaction of ketones, aromatic aldehydes, and aromatic amines catalyzed efficiently by
g-Al2O3/MeSO3H (alumina/methanesulfonic acid: AMA) as a heterogeneous catalyst, which were carried out in EtOH at
ambient temperature to afford the corresponding b-amino ketones in good yields and high stereoselectivities in favor of
the anti isomer, was described for the first time. It was found that this catalyst could be completely recovered and reused
without loss of its catalytic activities and is thus environmentally conscious. Furthermore, the use of g-Al2O3/CH3SO3H
(AMA) catalyst is feasible because of its easy preparation, easy handling, stability, easy recovery, reusability, good activ-
ity, stereoselectivity, and eco-friendliness. The use of this method provides a novel and improved modification of the
three-component Mannich reaction in terms of mild reaction conditions and clean reaction profiles, using a very small
quantity of catalyst and a simple workup procedure.
Key words: Mannich reaction, b-amino ketones, methanesulfonic acid, g-Al2O3/MeSO3H (alumina/methanesulfonic acid:
AMA), steroselectivity, recyclable catalysis
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Resume : Operant a la temperature ambiante, en solution dans l’ethanol, on a effectue des reactions de Mannich de ceto-
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nes, d’aldehydes aromatiques et d’amines aromatiques catalysees efficacement par un catalyseur heterogene forme de
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g-Al2O3/MeSO3H (alumine/acide methanesulfonique: AAM) qui conduisent a la formation des b-aminocetones correspon-
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dantes, avec de bons rendements et par la premiere fois a des stereoselectivites elevees en faveur de l’isomere anti. On a
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observe que le catalyseur peut etre recupere completement sans perte de son activite catalytique et qu’il est ecologique.
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De plus, l’utilisation du catalyseur g-Al2O3/MeSO3H (alumine/acide methanesulfonique) est possible en raison de sa faci-
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lite de preparation, de manutention, de recuperation et de reutilisation ainsi que de sa bonne activite, de sa stereoselectivite
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et de son caractere ecologique. L’utilisation de cette methode donne acces a une modification nouvelle et amelioree de la
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reaction de Mannich a trois composants en termes de conditions reactionnelles douces, avec des profils reactionnels pro-
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pres, qui n’utilisent que de tres faibles quantites de catalyseur et une methode simple de recuperation des produits.
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Mots-cles : reaction de Mannich, b-aminocetones, acide methanesulfonique, g-Al2O3/MeSO3H (alume/acid methanesulfo-
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nique: AAM), stereoselectivite, catalyseur recyclable
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[Traduit par la Redaction]
and polyketides.1,2 b-Amino carbonyl compounds and their
derivatives are used for the synthesis of amino alcohols,
peptides, and lactams, and as precursors for optically active
amino acids. Therefore, the development of new synthetic
methods leading to b-amino carbonyl compounds or their
derivatives has attracted much attention. However, the clas-
sic Mannich reaction has limited applications. To overcome
the drawbacks of the classic method, numerous modern ver-
sions of the Mannich reaction using electrophiles, such as
imines and stable nucleophiles, such as enolates, enol ethers,
and enamines,3 have been developed. But the preferred route
is to use a one-pot, three-component strategy that opens a
wide range of structural variations. Furthermore, only a few
one-pot procedures on the use of unmodified aldehydes or
ketones have been reported in the literature and a variety of
Introduction
Mannich-type reactions are very important C–C bond-
forming reactions in organic synthesis and one of the most
widely utilized chemical transformations for the formation
of b-amino ketones and other b-amino carbonyl compounds,
which in turn are important synthetic intermediates for vari-
ous pharmaceuticals and natural products, such as alkaloids
Received 15 March 2009. Accepted 16 September 2009.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 11 December 2009.
H. Sharghi1 and M. Jokar. Department of Chemistry, College
of Sciences, Shiraz University, Shiraz, 71454, Iran.
1Corresponding author (e-mail: shashem@chem.susc.ac.ir).
Can. J. Chem. 88: 14–26 (2009)
doi:10.1139/V09-141
Published by NRC Research Press

Sharghi and Jokar
15
Scheme 1. One-pot, three-component Mannich reaction with cyclohexanone or cyclopentanone.
Table 1. Catalyzed Mannich reaction of benzaldehyde (2.0 mmol),
aniline (2.0 mmol), and cyclohexanone (2.2 mmol) in EtOH at
room temperature.
catalysts, such as Zn(OTf)2,4 H3PW12O40,5 ZrOCl2Á8H2O,6
(S)-serine,7 DBSA,8 SDS–HCl,9–11 Bi(OTf)3Á4H2O,12 sodium
tetrakis(3,5-trifluoromethylphenyl) borate,13 PS-SO3H,14
L-proline,3h NbCl5,15 HClO4-SiO2,16a and silica sulfuric
acid,16b have been investigated.
AMA (mol% MeSO3H
on 0.1 g g-alumina)
Entry
Yields (%)a
Time (h)
Anti/synb
However, most Lewis acids cannot be used in this one-pot
reaction because of the presence of free amines and H2O
produced in the imine formation.
1
2
3
4
5
6
7
None
0.02
0.03
0.05
0.08
0.15
0.30
0
56
67
10
10
6
4
6
—
90/10
89/11
97/3
85/15
85/15
88/12
98, 97, 97, 96c
Within recent years, the use of reusable heterogeneous
catalysts has received considerable importance in organic
synthesis because of their environmental, economical, and
industrial aspects.6b,17 Up to now several reusable and heter-
ogeneous catalysts have been designed and used in various
reactions. Metal colloides,18a mineral clays,18b and supported
reagent on silica gel,18c,18d alumina,19 and other solid sup-
ports are some common examples of heterogeneous catalysts
that have extensive applications in organic transformations.
Aluminum oxides constitute an important technological
material that can be widely used in catalytic processes. In
particular, g-Al2O3 is used as both a catalyst and support be-
cause of its acid–base properties and mechanical and high-
temperature resistance.6b This study is part of our ongoing
interest in a mixture of the g-Al2O3/MeSO3H (alumina/
methanesulfonic acid: AMA) catalyst in the Fries rearrange-
ment,19 Beckmann rearrangement,20 direct conversions of ar-
omatic aldehydes to the corresponding glycol monoesters,21
hydration of nitriles into amides,22 syntheses of macrocyclic
polyether-diesters,23 syntheses of new hydroxythioxanthone
derivatives,24 direct sulfonyltion of phenoles with p-toluen-
sulfonic acid,25a and synthesis of coumarin derivatives.25b
We report herein our results in the three-component
g-Al2O3/MeSO3H (AMA) catalysed Mannich-type reaction.
89
81
80
1.5
1
aYield of isolated products.
bAnti/syn ratio was determined by H NMR.
1
cThe same catalyst was used for each of the four runs.
Fig. 1. A plot of the yield of 2-[anilino(phenyl)methyl]cyclohexa-
none (4a) versus the amount of g-alumina/methanesulfonic acid
(AMA) as catalyst using benzaldehyde (2.0 mmol), aniline
(2.0 mmol), and cyclohexanone (2.2 mmol) in ethanol at room
temperature.
Results and discussion
In this research, we report a new, simple, mild, and effec-
tive procedure for the one-pot synthesis of b-amino carbonyl
compounds via a multicomponent reaction between aryl al-
dehydes, anilines, and cyclohexanone or cyclopentanone in
the presence of g-Al2O3/MeSO3H (AMA) as catalyst
(Scheme 1).
To establish the optimum conditions for this reaction, ini-
tially, the three-component Mannich reaction of benzalde-
hyde (2.0 mmol), aniline (2.0 mmol), and cyclohexanone
(2.2 mmol) was examined. To find out the optimum quantity
of g-Al2O3-supported methanesulfonic acid (AMA), the
Mannich reaction was carried out at room temperature using
different quantities of the catalyst (Table 1 and Fig. 1).
The reaction does not proceed if no catalyst is employed,
despite prolonged reaction times (Table 1, entry 1). It should
be noted that the optimal catalyst loading effect obtained
from towards the b-amino carbonyl compounds peaked at a
concentration of 0.05 mol% (Table 1, entry 4). A lower cat-
alyst loading gave decreased yields (Table 1, entries 2 and
3), and increasing the catalyst loading also led to decreased
yields (Table 1, entries 5–7). Thereafter, the reaction was
carried out by varying the amount of cyclohexanone and
aniline. The optimum ratio of benzaldehyde, cyclohexanone,
and aniline was found to be 2:2.2:2, respectively, and 0.1 g
AMA (equal to 0.05 mol% H+). Entry 4 of Table 1 de-
scribed the yields of four consecutive reactions leading to
Published by NRC Research Press

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Can. J. Chem. Vol. 88, 2009
Table 2. Investigation of various solvent effects on the synthesis
of b-amino carbonyl compounds via Mannich reaction of ben-
zaldehyde (2.0 mmol), aniline (2.0 mmol), and cyclohexanone
(2.2 mmol) and g-Al2O3/CH3SO3H (AMA) (0.05 mol% H+) at
room temperature.
2-[anilino(phenyl)methyl]cyclohexanone (4a). In these ex-
periments, the reaction mixture was diluted with AcOEt,
and the catalyst was removed by filtration and washed with
hot EtOH. The filtrate was dried at 120 8C for 24 h to give
recycled AMA. Thus, the recovered catalyst, which always
works the same, begins reloading with fresh reagents for fur-
ther runs. No significant decrease in the yield was observed
demonstrating the efficiency of AMA as a catalyst in the
synthesis of b-amino carbonyl compounds.
Entry
1
2
3
4
5
6
7
8
Solvent
MeCN
CH2Cl2
Et2O
MeOH
Toluene
CHCl3
1,4-Dioxane
THF
Yields (%)a Time (h) Anti/synb
55
58
68
75
53
45
27
48
—
98
5
5
5
5
5
5
5
5
5
4
93/7
85/15
74/26
69/31
63/37
83/17
65/35
70/30
—
With AMA as an effective catalyst for the Mannich-type
reaction, conditions using various solvents such as MeCN,
1,4-dioxane, Et2O, THF, toluene, CHCl3, and EtOH were
examined (Table 2). Benzaldehyde, aniline, and cyclohexa-
none were chosen as representative substrates. Interestingly,
the Mannich reaction showed an intriguing solvent effect,
and it was found that the solvent has an important role in
terms of reaction rate, yields, and stereoselectivity. Among
various solvents tested, toluene, MeCN, Et2O, CH2Cl2, and
MeOH gave moderate yields of the expected product
(Table 2, entries 1–5) and the reaction in 1,4-dioxane af-
forded a very poor yield (Table 2, entry 7, 27%). Excellent
anti selectivity was observed in MeCN whereas the yield of
the reaction exhibited was low (Table 2, entry 1, 55%) com-
pared to EtOH that showed a high yield and excellent ster-
eoselectivity. Obviously, EtOH is the solvent of choice with
its fast reaction rate, high yield, excellent anti selectivity,
cheapness, and environmental acceptability. According to
step II of the mechanism for this reaction, which involves
the formation of a Schiff base, we expected EtOH to stand
out as the favorite solvent, since EtOH has proved to be
one of the suitable solvents for the synthesis of Schiff
bases.26
To optimize the temperature we carried out a model study
with benzaldehyde (2 mmol), aniline (2 mmol), and cyclo-
hexanone (2.2 mmol) using a catalyst (0.1 g, equal to
0.05 mol % H+) in EtOH at various temperatures (Table 3).
Increasing the temperature to 80 8C favored side reactions
and the formation of deeply colored products. If the reaction
runs at refluxing temperature, no Mannich-reaction bases (4)
can be isolated. Decreasing the temperature decreases the
rates of the reaction, and also the rates of the side reactions.
Table 3 clearly demonstrates that room temperature is an ef-
fective temperature in terms of reaction time and yield ob-
tained.
c
9
10
H2O
EtOH
98/2
aYield of isolated products.
1
bAnti/syn ratio was determined by H NMR.
cMain product was imine.
Table 3. Investigation of various temperature effects on the
synthesis of b-amino carbonyl compounds via Mannich re-
action of benzaldehyde (2.0 mmol), aniline (2.0 mmol), and
cyclohexanone (2.2 mmol) and g-Al2O3/CH3SO3H (AMA)
(0.05 mol% H+) in EtOH.
Entry
Temperature (8C)
10
RT
40
50
60
70
80
Reflux
Time (min)
900
480
240
110
105
90
80
120
Yield (%)a
1
2
3
4
5
6
7
8
63
98
91
88
85
81
74
0
aYields refer to the pure isolated products.
substrates like 4-cyanobenzaldehyde also reacted in high
yields without the formation of any side products (Table 4,
entry 13). Heteroaryl aldehydes, such as 2-thiophenecarbox-
aldehyde (Table 4, entry 10), was well-tolerated in these
mild conditions. The highly electron-deficient 4-nitroaniline
1
almost did not work (Table 4, entry 15). By using H NMR
to monitor the reaction, we realized that the imine inter-
mediate, 4-nitrobenzylidenephenylamine, was not formed
during the reaction. Furthermore, the use of alkyl aldehydes
(such as butylaldehyde) also failed to give the desired prod-
uct, which implies that this reaction is limited to nonenoliz-
able imines (Table 4, entry 16). A three-component reaction
of benzaldehyde, aniline, and cyclopentanone did not pro-
duce the desired adduct, probably because of the polyami-
noalkylation of cyclopentanone,27 and in this case, another
procedure was adopted in which benzaldehyde and aniline
were first mixed to produce imine in situ before ketone was
added. As is shown in Table 4, the desired adduct was gen-
erated with very good yields and excellent diastereoselectiv-
ities.
Encouraged by the remarkable results obtained with the
above reaction conditions, and to show the generality and
scope of this new protocol, we used various aldehydes and
amines (Table 4). A variety of aromatic aldehydes, including
electron-withdrawing and electron-donating groups, were
tested using our new method in EtOH in the presence of
AMA. It was found that the electronic effect of substitutes
had an influence on the yields. In this case, both the elec-
tron-rich and the electron-deficient benzaldehydes gave
good to excellent anti selectivity at room temperature
(Table 4, entries 1–14). However, when aryl aldehyde bear-
ing an electron-withdrawing substituent was subjected to the
reaction under standard conditions, there was a lower yield
of desired adducts formed (Table 4, entry 9). An important
feature of this procedure was the survival of a variety of
functional groups, such as ethers, nitro, hydroxyl, halides,
cyanide, etc., under the reaction conditions. Acid-sensitive
With the help of different probe molecules, surface prop-
erties of g-Al2O3 have been the object of many experimental
works.28a Under atmospheric conditions, the surfaces adsorb
Published by NRC Research Press

Sharghi and Jokar
17
Table 4. Catalyzed Mannich reaction of aromatic aldehyde (2.0 mmol), aniline (2.0 mmol), and cyclohexanone or cyclopentanone
(2.2 mmol) and AMA (0.1 g equal to 0.05 mol% H+) in EtOH (4–6 mL) at room temperature.
water both molecularly28b,28c and dissociatively, giving rise
to surface hydroxyls that persist even at temperatures higher
than 1000 8C.28d,28e Surface characterization experiments
have been monitored by IR28f and DRIFTS28g spectroscopies
that show the presence of different hydroxyl groups, which
are assigned primarily to the different possibilities for coor-
dination of surface aluminum cations and, for a given coor-
dination number, to the different environments of the site
(Fig. 2).6b,28h,28i
With regard to the latest articles about adsorption of some
alcohols such as methanol, ethanol, propanol, and isopropa-
nol on the g-alumina surface,28j,28k we assume that methane-
sulfonic acid (MeSO3H) chemisorbs to the alumina surface
with hydrogen bonding when they come close to the surface
with suitable orientation between the OH hydrogen of
MeSO3H with a surface oxygen atom of g-alumina, which
is in turn close to a cation vacancy.
To explore the mechanism of the reaction, we monitored
aldehyde consumption by GC analysis and found that the
Schiff base is formed (within the first 20 min of the begin-
ning of the reaction) and the rate determining step (RDS)
was found to be the attack of in situ generated enolate I on
the in situ generated aldimine II as shown in Scheme 2.6a,6b
AMA, used in catalytic amounts, is recycled in the reaction
and can be reused for subsequent reactions.
High anti selectivity was obtained with various substituted
benzaldehydes (Table 4, entries 1–14). The two most stable
possible transition states are shown in Scheme 2. Transition
state III (Scheme 2) provides the anti isomer, whereas the
syn isomer forms via V (Scheme 2). In V (Scheme 2), the
Published by NRC Research Press

18
Can. J. Chem. Vol. 88, 2009
Fig. 2. Dry g-Al2O3 where small circles: Al+3, gray and white cir-
cles: O–2, and black circles: OH–2 (8i).
The reaction worked well with a variety of aldehydes in-
cluding those bearing electron-withdrawing groups, and the
corresponding b-amino ketones (6) were obtained in good
yields (Table 5, entries 2, 3, and 7). Several electron-rich ar-
omatic aldehydes led to the desired products in very good
yields (Table 5, entries 4, 5, 8, 9, and 15).
The presented method has the ability to tolerate other
functional groups such as methoxy, halides, and nitro on
aryl aldehyde (Table 5).
The scope of our method could be extended to substi-
tuted anilines. Although para-substituent aromatic amines
gave good results, ortho-substituent aromatic amines such
as 2-methylaniline (Table 5, entry 12) failed to yield any
product because of the steric effects. Furthermore, amines
with electron-withdrawing groups, such as 4-chloroaniline,
4-flouroaniline, and 4-bromoaniline, gave the desired prod-
uct in good yields (Table 5, entries 10, 11, and 14).
To show the simplicity and efficiency of the over pre-
sented catalyzed Mannich reaction of benzaldehydes, ani-
lines, and ketones, including acetophenones and
cycloalkanones, they are compared with the reported works
in Table 6.
two phenyl groups of aldimine are syn to each other, so they
are unfavorable. Also in V (Scheme 2), steric repulsion ex-
ists between the hydrogen atoms of cyclohexanone’s meth-
ylene and phenyl groups. The phenyl groups of aldimine in
III (Scheme 2) are anti to each other; therefore, III
(Scheme 2) should be more stable than V (Scheme 2) and
is the most stable transition state that produces the anti iso-
mer.16,17,29
Conclusion
In conclusion, the present procedure provides an efficient
and improved modification of Mannich type reactions. This
new catalytic method provides a protocol that enables the
synthesis of b-amino carbonyl compounds in a highly ster-
eoselectivity pure form, while displaying good functional
group tolerance. No toxic reagent(s) or byproduct(s) were
involved. This procedure is ideally suited for automated ap-
plication since the entire synthetic sequence can be carried
out at room temperature in the presence of a reusable and
heterogeneous catalyst. Mild reaction condition, low loading
of catalyst, ease of workup, high yields, stability and recy-
clability of the catalyst, general applicability of both acyclic
and cyclic ketones and aldehydes, large-scale synthesis, and
simple procedure are features of this new protocol. Quite a
number of products are insoluble in EtOH, which can be ob-
tained by filtration and recrystallization. This simple work-
up procedure is also beneficial in this method. These condi-
tions are also environmentally friendly, cost effective, and
possess high generality, making our methodology a valid
contribution to the existing processes in the field of b-amino
ketone synthesis. Further applications of this catalyst to
other transformations are currently under investigation.
1
The anti/syn ratio was determined by H NMR, using the
intensity of the Ha (Scheme 3). The JHa,Hb signal of the anti
isomer is higher than that of the syn isomer. According to
1
the H NMR spectrum, the Ha signal for the anti isomer has
a lower d value than that for the syn isomer. For instance, in
1
the H NMR spectra of 2-[anilino(phenyl)methyl]cyclohexa-
none (4a), the signal at d = 4.63 ppm (J = 7.1 Hz) is contrib-
uted by the anti isomer, while the one at 5.4 ppm (J =
3.6 Hz) is contributed by the syn isomer.6,16,17
To access the feasibility of applying this method in a
preparative scale, we carried out the one-pot, three-compo-
nent Mannich reaction of benzaldehyde with aniline and cy-
clohexanone on a 100 mmol scale (Table 4, entry 17). As
expected, the reaction proceeded similarly to the case in
Table 4 (entry 1) in a smaller scale , and the desired b-
amino ketone was obtained in 98% isolated yield in
100 min.
The reaction proceeded not only for cycloalkanones but
also for acyclic ketones such as acetophenones. As illus-
trated in Scheme 4, AMA did catalyze the Mannich reaction
of acetophenones, substituted benzaldehydes, and anilines to
yield the desired b-amino ketone products.
The optimum ratio of benzaldehyde, acetophenone, and
aniline was found to be 2:2.2:2, respectively, and 0.2 g
AMA (equal to 0.1 mol% H+). The expected products were
obtained in good-to-high yields under these conditions. Acy-
clic ketones were less reactive than cyclohexanone and
needed much more catalyst and a longer reaction time to af-
ford the desired products (Table 5).
Experimental
Instrumentation, analysis, and starting material
NMR spectra were recorded on a Bruker Avance DPX-
250 (1H NMR 250 MHz and 13C NMR 62.9 MHz) spec-
trometer in pure deuterated solvents with tetramethylsilane
as an internal standard. IR spectra were obtained using a
Shimadzu FTIR 8300 spectrophotometer. Mass spectra were
determined on a Shimadzu GCMS-QP 1000 EX instruments
at 70 or 20 eV. Melting points were determined in open
capillary tubes in a Bu¨chi-535 circulating oil melting point
apparatus. Elemental analyses were performed by Thermo
Finnigan CHNS-O analyzer, 1112 series. The purity deter-
Published by NRC Research Press

Sharghi and Jokar
19
Scheme 2. Proposed reaction mechanism for the Mannich reaction of benzaldehyde, aniline, and cyclohexanone and the possible transition
states leading to the anti isomer.
1
Scheme 3. Identification of anti and syn isomers by H NMR spec-
mination of the substrates and reaction monitoring were ac-
troscopy.
complished by TLC on silica gel PolyGram SILG/UV 254
plates. Column chromatography was carried out on short
columns of silica gel 60 (70–230 mesh) in glass columns
(2–3 cm diameter) using 15–30 g of silica gel per one gram
of crude mixture. Chemical materials were either prepared
in our laboratories or purchased from Fluka, Sigma-Aldrich,
and Merck Companies. Acidic g-alumina (g-Al2O3) type 540
C was purchased from the Fluka Company.
Preparation of AMA (0.1 g, equal to 0.05 mol% H+)
General procedure for synthesis of b-amino carbonyl
compounds 4
Methanesulfonic acid (1.62 mL, 25 mmol) was added
dropwise over a period of 90 min at 40 8C to a mixture of
g-alumina (50 g, 500 mmol) in dichloromethane (30 mL).
After the addition was complete, the mixture was stirred for
2 h and then the solvent was evaporated under reduced pres-
sure. After removal of CH2Cl2 in a rotary evaporator, the
solid powder was kept at 120 8C for 72 h. A white solid of
65.0 g was obtained.
A mixture of the aldehyde (2 mmol), amine (2 mmol),
and a solution of the catalyst (0.1 g, equal to 0.05 mol%
H+) in EtOH (4–6 mL) was placed in a test tube and the re-
action mixture was vigorously stirred at room temperature.
Cyclohexanone or cyclopentanone (2.2 mmol) was then
added to the mixture and after completion of the reaction as
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20
Can. J. Chem. Vol. 88, 2009
Scheme 4. One-pot, three-component Mannich reaction of aromatic aldehydes (2 mmol) and anilines (2.0 mmol) with acetophenones
(2.2 mmol).
indicated by TLC (Table 4), the reaction mixture was di-
luted with ethyl acetate, and the catalyst was removed by
filtration. The organic phases were combined and dried over
Na2SO4. The solvent was removed under reduced pressure to
give the desired products. The residual crude product was
purified by column chromatography on neutral silica gel
(ethyl acetate/petroleum ether 1:5) or by recrystallization
with CH2Cl2/petroleum ether or hexane to give the pure
b-aminoketone as a mixture of diastereoisomers. The syn/anti
ratio was determined by 1H NMR and 13C NMR analysis.
(279.376; %): C 81.68, H 7.58, N 5.01; found: C 81.60, H
7.64, N 5.08.
2-[Anilino(4-methylphenyl)methyl]cyclohexanone (4b)16a
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4b as a colorless powder in a 90% yield; anti/syn 97/3; mp
1
115–118 8C. H NMR (250 MHz, CDCl3) d: 7.26 (2H, d,
J = 7.8 Hz), 7.03–7.15 (4H, m), 6.63 (1H, t, J = 7.3 Hz),
6.54 (2H, d, J = 7.8 Hz), 5.4 (0.02H, d, J = 3.6 Hz), 4.58
(0.98H, d, J = 7.3 Hz), 2.74–2.76 (1H, m), 2.32–2.47 (2H,
m), 2.29 (3H, s), 1.68–1.89 (6H, m). 13C NMR (62.9 MHz,
CDCl3) d: 21.1, 23.5, 27.8, 31.2, 41.6, 57.4, 113.6, 114.1,
117.4, 127.0, 127.1, 127.3, 129.0, 129.1, 136.7, 138.5,
147.2, 149.2, 190, 212. Anal. calcd. for C20H23NO
(293.407; %): C 81.87, H 7.90, N 4.77; found: C 81.91, H
7.89, N 4.82.
General procedure for synthesis of b-amino carbonyl
compounds 6
A mixture of the aldehyde (2 mmol), amine (2 mmol), and
acetophenone (2.2 mmol) was added to a solution of the cat-
alyst (0.2 g, equal to 0.1 mol% H+) in EtOH (4–6 mL) was
placed in a test tube and the reaction mixture was vigorously
stirred at room temperature for the appropriate time
(Table 5). The reaction was monitored by TLC. The products
precipitated from the reaction mixture. The precipitate was
filtered off, dissolved in hot EtOH, and the catalyst was re-
moved by hot filtration. The filtrate was kept at room tem-
perature, was triturated with hexane (10 mL) and then
filtered and was crystallized with EtOH/H2O (2:1).
2-[Anilino(4-chlorophenyl)methyl]cyclohexanone (4c)16a
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4c as a colorless powder in a 90% yield; anti/syn 92/8; mp
1
268–270 8C. H NMR (250 MHz, CDCl3) d: 7.2–7.37 (4H,
Recycling of g-Al2O3/CH3SO3H (AMA)
m), 7.06 (2H, d, J = 7.9 Hz), 6.67 (1H, t, J = 7.5 Hz), 6.52
(2H, d, J = 7.5 Hz), 5.09 (1H, br, s), 4.71 (0.08H, d, J =
4.2 Hz), 4.54 (0.92H, d, J = 7.3 Hz), 2.28–2.52 (2H, m),
1.87–2.28 (3H, m), 1.5–1.73 (4H, m). 13C NMR (62.9 MHz,
CDCl3) d: 20.4, 25.9, 39.1, 41.1, 54.0, 58.4, 113.6, 114.1,
118.1, 118.5, 128.7, 128.9, 129.0, 133.0, 140.2, 147.2,
191.0, 202.1, 218.9. Anal. calcd. for C19H20ClNO
(313.821; %): C 72.72, H 6.42, N 4.46; found: C 72.80, H
6.35, N 4.40.
g-Al2O3/CH3SO3H (AMA) was prepared according to the
abovementioned procedure. The catalyst was separated from
the reaction mixture and washed with EtOH and dried at
120 8C for 24 h to give recycled g-Al2O3/CH3SO3H (AMA).
The remaining catalyst begins reloading with fresh reagents
for further runs. The reaction of benzaldehyde, aniline, and
cyclohexanone was repeated with recycled catalyst and the
yields were found to remain in the range of 96%–97% for
four recycles.
All runs produced b-amino ketones characterized by de-
2-[Anilino(phenyl)methyl]cyclopentanone (4d)31
1
tailed structural data using IR, H NMR, 13C NMR, and ele-
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4d as a colorless powder in a 90% yield; anti/syn 73/26; mp
mental analysis as given below.
2-[Anilino(phenyl)methyl]cyclohexanone (4a)5
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4a as a colorless powder in a 98% yield; anti/syn 97/3; mp
1
166–168 8C. H NMR (250 MHz, CDCl3) d: 7.2–7.4 (5H,
m), 7.0–7.1 (2H, m), 6.65 (1H, t, J = 7.5 Hz), 6.56 (2H, d,
J = 7.8 Hz), 4.9 (1H, br, s), 4.76 (0.17H, d, J = 4.4 Hz),
4.55 (0.73H, d, J = 7.3 Hz), 1.91–2.49 (2H, m), 1.18–1.19
(1H, m), 1.25–1.77 (4H, m). 13C NMR (62.9 MHz, CDCl3,
mixture of diastereoisomeres) d: 20.5, 20.6, 25.8, 26.7, 39.2,
39.8, 53.3, 54.0, 57.7, 59.0, 113.6, 114.2, 117.4, 117.8,
127.1, 127.3, 127.4, 128.5, 128.6, 128.9, 129, 129.6, 141.0,
147.0, 219.0. Anal. calcd. for C18H19NO (265.350; %): C
81.47, H 7.22, N 5.28; found: C 81.55, H 7.30, N 5.20.
1
130–132 8C. H NMR (250 MHz, CDCl3) d: 7.05–7.41 (6H,
m), 6.55–6.68 (3H, m), 5.4 (0.02H, d, J = 3.6 Hz), 4.8 (1H,
br, s), 4.63 (0.98H, d, J = 7.1 Hz), 2.78–2.80 (1H, m),
2.34–2.45 (2H, m), 1.66–1.92 (6H, m). 13C NMR
(62.9 MHz, CDCl3) d: 23.6, 27.1, 31.3, 41.7, 57.3, 58.2,
112.6, 113.8, 117.7, 126.2, 126.5, 127.2, 127.3, 128.4,
128.6, 141.4, 146.8, 191, 212.9. Anal. calcd. for C19H21NO
Published by NRC Research Press

Sharghi and Jokar
21
Table 5. Catalyzed Mannich reaction of aromatic aldehyde (2.0 mmol), aniline (2.0 mmol), and acetophenone (2.2 mmol) and AMA (0.2 g
equal to 0.1 mol% H+) in EtOH (4–6 mL) at room temperature.
Table 6. Catalyzed Mannich reaction of benzaldehydes, anilines, and ketones, including cyclohexanones and acetophenones,
under various conditions.
Entry
1
2
3
4
5
6
7
8
Ketone
Conditions
H3Pmo12O40/H2O/RT5
DBSA/H2O/23 8C8
Time (h)
Yield (%)a Anti/syn
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
18
12
48
8
7
12
9
76
69
81
98
84
95
88
98
84
98
—
—
—
—
86/14
85/15
—
99/1
63/37
97/3
NaBAr4/H2O/30 8C13
0.05 mol% MeSO3H on 0.1 g g-alumina/EtOH/RT
Bi(OTf)3ÁH2O/H2O/RT12
NbCl5/RT15
30
10 mol% Cu-np (18 2) nm methanol, RT, N2
HClO4-SiO2/EtOH/RT16a
2
9
10
H3Pmo12O40/H2O/RT5
3–16
4
0.05 mol% MeSO3H on 0.1 g g-alumina/EtOH/RT
aYields refer to the pure isolated products.
2-[(4-Bromoanilino)(phenyl)methyl]cyclopentanone (4e)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4e as a colorless powder in a 92% yield; anti/syn 98/2; mp
142–144 8C. IR (KBr, cm–1) y: 3375, 2877, 1728, 1598,
1504, 1450, 1315, 817, 702. H NMR (250 MHz, CDCl3) d:
7.2–7.4 (5H, m), 7.14 (2H, d, J = 6.9 Hz), 6.3 (2H, d, J =
7.0 Hz), 5.2 (1H, br, s), 4.67 (0.01H, d, J = 3.7 Hz), 4.45
(0.99H, d, J = 7.5 Hz), 2.1–2.4 (m, 2H), 1.18–1.19 (1H, m),
1.5–1.8 (4H, m). 13C NMR (62.9 MHz, CDCl3) d: 20.4,
26.8, 39.3, 53.8, 59.2, 66.8, 109.6, 115.8, 117.0, 118.1,
127.0, 127.6, 128.7, 131.6, 140.0, 141.0, 146.1, 219.0. MS
m/z (%): 346 (M+ + 2, 0.7), 345 (M+ + 1, 3.6), 344 (M+,
4.0), 279 (7.3), 260 (56.1), 171 (39.5), 149 (79.5), 115
(24.9), 83 (33.1), 57 (100.0). Anal. calcd. for C18H18BrNO
(344.246; %): C 62.80, H 5.27, N 4.07; found: C 62.71, H
5.32, N 4.01.
1
Published by NRC Research Press

22
Can. J. Chem. Vol. 88, 2009
2-[Anilino(4-methylphenyl)methyl]cyclopentanone (4f)6b
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4f as a colorless powder in a 94% yield; anti/syn 97/3; mp
6.02 (0.85H, d, J = 7.5 Hz), 4.94 (1H, br, s), 2.6–2.7 (1H,
m), 2.17–2.21 (1H, m), 1.32–2.02 (5H, m). 13C NMR
(62.9 MHz, DMSO mixture of diastereoisomeres) d: 20.3,
24.1, 25.6, 54.4, 54.9, 55.2, 113.3, 113.6, 116.9, 123.8,
123.8, 128.4, 129.0, 129.1, 129.2, 147.7, 147.8, 150.3,
152.0, 217.2, 217.9. MS m/z (%): 311 (M+ + 1, 0.9), 310
(M+, 2.1), 279 (3.0), 256 (4.4), 227 (59.3), 181 (25.1), 149
(27.1), 129 (14.4), 111 (22.1), 83 (54.1), 57 (100.0). Anal.
calcd. for C18H18N2O3 (310.374; %): C 69.66, H 5.85, N
9.03; found: C 69.70, H 5.91, N 9.07.
1
127–129 8C. H NMR (250 MHz, CDCl3) d: 7.24–7.27 (3H,
m), 7.12 (2H, d, J = 8.5 Hz), 7.05 (2H, d, J = 7.5), 6.68 (1H,
t, J = 7.3 Hz), 6.5 (1H, d, J = 7.8 Hz), 5.0 (1H, br, s), 4.71
(0.02H, d, J = 4.5 Hz), 4.61 (0.98H, d, J = 7.3 Hz), 2.51–
2.55 (1H, m). 2.129–2.48 (4H, m), 2.124–2.129 (1H, m),
1.85–1.91 (2H, m), 1.67–1.77 (2H, m). 13C NMR
(62.9 MHz, CDCl3) d: 20.5, 21.1, 26.6, 39.2, 54.1, 58.7,
114.2, 117.8, 127.0, 127.9, 128.9, 129.0, 129.1, 129.3,
136.9, 138.5, 147.4, 149.2, 161.1, 193.1, 219.4. Anal. calcd.
for C19H21NO (279.376; %): C 81.68, H 7.58, N 5.01;
found: C 81.69, H 7.51, N 5.04.
2-[Anilino(2-thienyl)methyl]cyclopentanone (4j)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4j as a colorless powder in an 86% yield; anti/syn 100/0; mp
175–177 8C. IR (KBr, cm–1) y: 3394, 1689, 1508, 1141,
2-[Anilino(4-chlorophenyl)methyl]cyclopentanone (4g)6b
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4g as a colorless powder in a 94% yield; anti/syn 97/3; mp
1
752, 717, 694, 516. H NMR (250 MHz, CDCl3) d: 7.61
(1H, t, J = 5.5 Hz), 7.49 (1H, d, J = 9 Hz), 7.01–7.11 (3H,
m), 6.85–6.87 (1H, m), 6.58–6.63 (2H, m), 5.01 (1H, br, s),
4.89 (1H, d, J = 7.5 Hz), 2.66–2.97 (3H, m), 1.1.85–1.90
(2H, m), 1.18–1.48 (2H, m). 13C NMR (62.9 MHz, CDCl3)
d: 23.3, 26.9, 54.2, 55.5, 68.1, 114.3, 118.4, 124.5, 126.5,
128.1, 129.0, 130.6, 133.3, 152.7, 199.0, 226.5. MS m/z
(%): 273 (M+ + 2, 6.1), 272 (M+ + 1, 13.4), 271 (M+, 11.6),
236 (10.9), 186 (43.4), 152 (10.9), 135 (24.9), 111 (23.6), 83
(53.1), 57 (100.0). Anal. calcd. for C16H17NOS (271.378;
%): C 70.81, H 6.31, N 5.16, S 11.82; found: C 70.75, H
6.36, N 5.14, S 11.90.
1
162–164 8C. H NMR (250 MHz, CDCl3) d: 7.24–7.37 (4H,
m), 7.07 (2H, d, J = 7.5), 6.67 (1H, t, J = 7.3 Hz), 6.49 (2H,
d, J = 7.8 Hz), 5.10 (1H, br, s), 4.7 (0.03H, d, J = 4.3 Hz),
4.52 (0.097H, d, J = 7.3 Hz), 1.87–2.08 (2H, m), 1.65–1.70
(5H, m). 13C NMR (62.9 MHz, CDCl3) d: 20.4, 26.6, 39.2,
54.0, 58.4, 114.1, 118.1, 127.9, 128.0, 128.3, 128.5, 128.8,
129.0, 133.0, 140.3, 147.2, 190.1, 218.93. Anal. calcd. for
C18H18ClNO (299.794; %): C 72.11, H 6.05, N 4.67; found:
C 72.20, H 5.98, N 4.74.
2-[(4-Bromoanilino)(4-
isopropylphenyl)methyl]cyclopentanone (4k)
2-[Anilino(9-anthryl)methyl]cyclopentanone (4h)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4k as a colorless powder in a 91% yield; anti/syn 96/4; mp
142–144 8C. IR (KBr, cm–1) y: 3379, 2962, 2873, 1732,
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with hexane gave compound 4h as a pale yel-
low powder in a 92% yield; anti/syn 100/0; mp 206–208 8C.
IR (KBr, cm–1) y: 3328, 2873, 1720, 1596, 1492, 1253,
1
1596, 1508, 1485, 1269, 1249, 1126, 1072, 917, 486. H
1
NMR (250 MHz, CDCl3) d: 7.06–7.53 (5H, m), 6.35–6.46
(2H, m), 5.2 (1H, br, s), 4.64 (0.04H, d, J = 4.0 Hz), 4.42
(0.96H, d, J = 7.8 Hz), 2.8–3.1 (1H, m), 1.86–1.91 (3H, m),
1.68–1.72 (4H, m), 1.21–124(6H, m). 13C NMR (62.9 MHz,
CDCl3) d: 20.4, 23.9, 26.9, 33.7, 39.2, 53.8, 58.9, 59.1,
109.4, 110, 115.0, 126.7, 126.9, 130, 131.6, 133, 138.4,
145.3, 146.6, 148.1, 219.5. MS m/z (%): 388 (M+ + 2, 2.9),
387 (M+ + 1, 6.2), 386 (M+, 5.4), 302 (74.8), 288 (13.9),
171 (29.6), 149 (13.6), 129 (18.0), 95 (17.0), 69 (100.0).
Anal. calcd. for C21H24BrNO (386.325; %): C 65.29, H
6.26, N 3.63; found: C 65.20, H 6.31, N 3.70.
1068, 732, 486. H NMR (250 MHz, CDCl3) d: 9.41 (1H, d,
J = 6 Hz), 8.63 (1H, d, J = 8.3 Hz), 8.45 (1H, s), 8.05 (2H,
t, J = 8.0 Hz), 7.47–7058 (4H, m), 6.92 (2H, t, J = 7.5 Hz),
6.55 (m, 3H), 5.97 (1H, d, J = 10.0 Hz), 3.26 (1H, q, J =
9.5 Hz), 2.36–2.43 (2H, m), 1.59–1.89 (1H, m), 1.29–1.46
(3H, m). 13C NMR (62.9 MHz, CDCl3) d: 20.5, 25.1, 39.4,
52.3, 55.4, 114.5, 117.8, 118.2, 123.1, 124.6, 125.0, 125.3,
125.9, 126.2, 126.4, 127.1, 128.6, 128.9, 129.5, 130.0,
131.3, 132.0, 137.9, 148.6, 166.2, 221.2. MS m/z (%): 367
(M+ + 2, 1.3), 366 (M+ + 1, 4.7), 365 (M+, 5.5), 282
(100.0), 255 (18.8), 215 (44.3), 177 (27.8), 104 (20.6), 77
(23.9), 55 (41.7). Anal. calcd. for C26H23NO (365.467; %):
C 85.45, H 6.34, N 3.83; found: C 85.48, H 6.30, N 3.89.
2-[Anilino(2-hydroxy-1-naphthyl)methyl]cyclopentanone
(4l)
2-[Anilino(4-nitrophenyl)methyl]cyclopentanone (4i)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by
recrystallization with hexane gave compound 4i as a color-
less yellow powder in an 80% yield; anti/syn 85/15; mp
150–152 8C. IR (KBr, cm–1) y: 3355, 2989, 1720, 1600,
1523, 1350, 1284, 856, 756, 698. 1H NMR (250 MHz,
DMSO) d: 8.11–8.15 (2H, m), 7.5–7.63 (2H, m), 6.93–6.95
(2H, m), 6.47–6.5 (3H, m), 6.30 (0.15H, d, J = 4.6 Hz),
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with hexane gave compound 4l as a pale brown
powder in a 90% yield; anti/syn 100/0; mp 208–210 8C. IR
(KBr, cm–1) y: 3367, 2980, 1735, 1596, 1496, 1430, 1400,
1226, 1149, 1038, 1014, 933, 817, 748, 694. 1H NMR
(250 MHz, CDCl3) d: 8.0 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J =
8.3 Hz), 7.5–7.72 (3H, m), 7.17–7.3 (2H, m), 7.03 (1H, d, J =
8.8 Hz), 6.69–6.88 (3H, m), 5.18 (1H, br, s), 4.42 (1H, d, J =
Published by NRC Research Press

Sharghi and Jokar
23
6.5 Hz), 3.01–3.17 (1H, m), 2.71–2.79 (2H, m), 1.54–1.64
(1H, m), 1.18–1.64 (3H, m). 13C NMR (62.9 MHz, CDCl3) d:
23.0, 25.1, 26.1, 43.8, 45.7, 113.7, 115.1, 118.0, 119.1, 121.8,
122.9, 123.2, 124.0, 126.5, 127.6, 128.4, 129.6, 130.4, 130.9,
135.3, 199.0, 226.5. MS m/z (%): 333 (M+ + 2, 0.3), 332
(M+ + 1, 1.3), 331 (M+, 4.3), 284 (2.7), 256 (3.1), 219 (20.5),
152 (11.0), 125 (16.3), 97 (38.6), 71 (60.4), 55 (100.0). Anal.
calcd. for C22H21NO2 (331.408; %): C 79.73, H 6.39, N 4.23;
found: C 79.80, H 6.31, N 4.30.
3-Anilino-3-(3-chlorophenyl)-1-phenyl-1-propanone (6b)33
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6b as a colorless powder in an 86% yield; mp
1
120–122 8C. H NMR (250 MHz, CDCl3) d: 7.93 (2H, d,
J = 8.5 Hz), 7.58 (1H, t, J = 8.3 Hz), 7.43 (2H, t, J =
7.0 Hz), 7.21–7.34 (4H, m), 7.08 (2H, t, J = 7.5 Hz), 6.72
(1H, t, J = 7.5 Hz), 6.54 (2H, d, J = 7.8 Hz), 4.97 (1H, t,
J = 6.0 Hz), 4.20 (1H, s), 3.46 (2H, d, J = 5.5 Hz). 13C
NMR (62.9 MHz, CDCl3) d: 46.1, 54.5, 113.9, 118.2, 119.0,
124.7, 126.6, 127.6, 128.2, 128.5, 128.8, 129.2, 130.1,
131.3, 133.6, 134.7, 136.5, 139.1, 145.3, 146.6, 197.7. Anal.
calcd. for C21H18ClNO (335.826; %): C 75.11, H 5.40, N
4.17; found: C 75.19, H 5.48, N 4.21.
4-[Anilino(2-oxocyclopentyl)methyl]benzonitrile (4m)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with CH2Cl2/petroleum ether gave compound
4m as a brown powder in an 84% yield; anti/syn 94/6; mp
126–128 8C. IR (KBr, cm–1) y: 3340, 2225, 1720, 1600,
3-Anilino-3-(4-chlorophenyl)-1-phenyl-1-propanone (6c)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6c as a colorless powder in an 89% yield; mp
128–130 8C (lit. value16a mp 131–132 8C). 1H NMR
(250 MHz, CDCl3) d: 7.89 (2H, d, J = 7 Hz), 7.55–7.64
(2H, m), 7.49 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 9 Hz),
7.29 (1H, d, J = 8.5 Hz), 7.11 (2H, t, J = 8.3 Hz), 6.70 (1H,
t, J = 8.0 Hz), 6.54 (2H, d, J = 7.8 Hz), 4.99 (1H, t, J =
6.5 Hz), 4.59 (1H, s), 3.47 (2H, d, J = 5.8 Hz). 13C NMR
(62.9 MHz, CDCl3) d: 46.1, 54.2, 113.9, 118.1, 122.5,
127.9, 128.2, 128.5, 128.6, 128.8, 128.9, 129.2, 129.6,
132.9, 133.4, 133.5, 136.6, 141.5, 143.2, 146.6, 197.9. Anal.
calcd. for C21H18ClNO (335.826; %): C 75.11, H 5.40, N
4.17; found: C 75.15, H 5.34, N 4.24.
1
1500, 844, 756, 698, 551. H NMR (250 MHz, CDCl3) d:
7.63 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.3 Hz), 7.09
(2H, t, J = 8.3 Hz), 6.66 (1H, t, J = 7.3 Hz), 6.42 (2H, d,
J = 7.8 Hz), 5 (1H, br, s), 4.8 (0.06H, d, J = 4.4 Hz), 4.4
(0.94H, d, J = 7.3 Hz), 1.89–1.97 (2H, m), 1.24–1.67 (5H,
m). 13C NMR (62.9 MHz, CDCl3) d: 20.4, 26.7, 39.1, 53.7,
58.7, 111.4, 114.1, 118.5, 118.7, 127.1, 127.8, 128.0, 129.1,
132.5, 133.1, 146.7, 147.4, 197.2, 218.4. MS m/z (%): 292
(M+ + 2, 0.3), 291 (M+ + 1, 1.9), 290 (M+, 4.5), 207
(100.0), 149 (11.9), 77 (26.9), 55 (23.2). Anal. calcd. for
C19H18N2O (290.359; %): C 78.59, H 6.25, N 9.65; found:
C 78.66, H 6.31, N 9.71.
2-[Anilino(3-hydroxyphenyl)methyl]cyclopentanone (4n)
Purification by column chromatography on neutral silica
gel, eluted with ethyl acetate/petroleum ether (1:5) or by re-
crystallization with hexane gave compound 4n as a colorless
powder in an 84% yield; anti/syn 100/0; mp 176–178 8C. IR
(KBr, cm–1) y: 3309, 3163, 2977, 1724, 1585, 1492, 1230,
752, 694. 1H NMR (250 MHz, DMSO) d: 9.1 (1H, s),
6.70–6.84 (3H, m), 6.26–6.44 (5H, m), 5.86 (1H, d, J =
5.8 Hz), 4.36 (1H, s) 2.26–2.36 (1H, m), 1.18–1.64 (6H,
m). 13C NMR (62.9 MHz, DMSO) d: 19.8, 24.9, 54.1, 56.0,
112.8, 113.8, 113.9, 116.0, 117.9, 118.2, 128.6, 129.1,
142.8, 146.2, 147.6, 157.1, 184.7, 218.2. MS m/z (%): 283
(M+ + 2, 0.5), 282 (M+ + 1, 1.9), 281 (M+, 4.6), 198
(100.0), 104 (19.6), 77 (35.5), 55 (17.9). Anal. calcd. for
C19H18N2O (281.349; %): C 76.84, H 6.81, N 4.98; found:
C 76.82, H 6.88, N 4.94.
3-Anilino-3-(4-isopropylphenyl)-1-phenyl-1-propanone
(6d)13
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6d as a colorless powder in a 96% yield; mp
1
154–156 8C. H NMR (250 MHz, CDCl3) d: 7.80(2H, d,
J = 8.3 Hz), 7.47 (1H, t, J = 8.5 Hz), 7.36 (2H, t, J =
7.8 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.09 (2H, d, J = 8.3 Hz),
7.0 (2H, t, J = 8.3 Hz), 6.58 (1H, t, J = 7.5 Hz), 6.51 (2H, d,
J = 8.5 Hz), 4.91 (1H, t, J = 5.8 Hz), 3.41 (2H, d, J =
5.5 Hz), 2.87 (1H, m), 1.19 (6H, d, J = 6.8 Hz). 13C NMR
(62.9 MHz, CDCl3) d: 23.9, 24.0, 33.7, 46.2, 45.5, 113.8,
114.0, 117.7, 126.3, 126.8, 128.2, 128.6, 129.1, 130.1,
133.3, 134.2, 136.7, 140.1, 145.9, 146.9, 147.9, 149.4,
169.1, 198.4. Anal. calcd. for C24H25NO (343.461; %): C
83.93, H 7.34, N 4.08; found: C 83.89, H 7.30, N 4.12.
3-Anilino-1,3-diphenyl-1-propanone (6a)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6a as a colorless powder in a 98% yield; mp
169–170 8C (lit. value32 mp 170–171 8C). 1H NMR
(250 MHz, CDCl3) d: 7.90 (2H, d, J = 8.5 Hz), 7.55 (2H, t,
J = 7.3 Hz), 7.23–7.47 (6H, m), 7.11 (2H, t, J = 7.5 Hz),
6.76 (1H, t, J = 7.3 Hz), 6.69 (2H, d, J = 7.8 Hz), 5.01
(1H, t, J = 6.5 Hz), 3.60 (2H, d, J = 5.8 Hz). 13C NMR
(62.9 MHz, CDCl3) d: 46.2, 55.0, 95.2, 114.0, 117.8, 118.1,
126.4, 125.2, 127.4, 128.2, 128.7, 128.8, 129.1, 129.3,
133.4, 136.6, 142.7, 146.7, 159.2, 179.2, 198.2. Anal. calcd.
for C21H19NO (301.382; %): C 83.69, H 6.35, N 4.65;
found: C 83.75, H 6.42, N 4.59.
3-Anilino-3-(2,5-dimethoxyphenyl)-1-phenyl-1-propanone
(6e)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6e as a pale yellow powder in a 90% yield; mp
148–150 8C. IR (KBr, cm–1) y: 3344, 2831, 1670, 1600,
1
1492, 1288, 1041, 722, 694, 590, 470. H NMR (250 MHz,
CDCl3) d: 7.97 (2H, d, J = 8.3 Hz), 7.56 (1H, t, J = 8.5 Hz),
7.46 (2H, t, J = 9.0 Hz), 7.11 (2H, t, J = 7.5 Hz), 6.8 (1H, d,
J = 9.0 Hz), 6.6 (4H, d, J = 8.8 Hz), 6.64 (1H, t, J =
8.0 Hz), 5.26 (1H, t, J = 5.0 Hz), 3.89 (3H, s), 3.82 (1H, d,
J = 4.8 Hz), 3.69 (3H, s), 3.36 (1H, m). 13C NMR
(62.9 MHz, CDCl3) d: 44.4, 51.0, 55.6, 55.8, 111.4, 112.4,
Published by NRC Research Press

24
Can. J. Chem. Vol. 88, 2009
113.9, 114.0, 117.9, 123.1, 127.3, 128.4, 128.6, 129.0,
129.2, 131.1, 133.3, 136.6, 146.6, 150.7, 153.9, 155.4,
198.9. MS m/z (%): 363 (M+ + 2, 2.6), 362 (M+ + 1, 3.0),
361 (M+, 4.7), 242 (38.4), 212 (10.9), 149 (27.8), 123
(15.1), 105 (39.8), 69 (100.0). Anal. calcd. for C23H23NO3
(361.434; %): C 76.43, H 6.41, N 3.88; found: C 76.39, H
6.88, N 3.92.
3-Anilino-3-(4-methylphenyl)-1-phenyl-1-propanone (6i)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6i as a colorless powder in a 92% yield; mp
134–135 8C (lit. value34 mp 131–132 8C). 1H NMR
(250 MHz, CDCl3) d: 7.92 (2H, d, J = 7.3 Hz), 7.56 (1H, t,
J = 8.8 Hz), 7.44 (2H, t, J = 7.8 Hz), 7.32 (2H, d, J =
8.0 Hz), 7.06–7.14 (4H, m), 6.64 (1H, t, J = 7.3 Hz), 6.58
(2H, d, J = 8.8 Hz), 4.98 (1H, t, J = 6.0 Hz), 3.50 (2H, d,
J = 5.5 Hz), 2.23 (3H, s, 3H). 13C NMR (62.9 MHz,
CDCl3) d: 21.1, 46.2, 54.7, 114.0, 114.9, 118.0, 124.4,
126.3, 127.3, 127.9, 128.2, 128.6, 129.1, 129.4, 133.2,
136.3, 139.0, 141.7, 145.5, 147.9, 159.0, 199.1. Anal. calcd.
for C22H21NO (315.408; %): C 83.78, H 6.71, N 4.44;
found: C 83.81, H 6.75, N 4.40.
3-Anilino-3-(2-naphthyl)-1-phenyl-1-propanone (6f)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6f as a colorless powder in a 91% yield; mp
133–135 8C. IR (KBr, cm–1) y: 3363, 2893, 1670, 1600,
1
1508, 1288, 744, 686, 742. H NMR (250 MHz, CDCl3) d:
7.89 (2H, t, J = 7 Hz), 7.78–8.0 (4H, m), 7.6 (1H, d, J =
8.0 Hz), 7.53 (4H, d, J = 7.5 Hz), 7.45 (2H, t, J = 8.5 Hz),
7.08 (2H, t, J = 7.3 Hz), 6.64 (3H, t, J = 7.8 Hz), 5.17 (1H,
t, J = 5 Hz), 3.57 (2H, d, J = 5.3 Hz). 13C NMR (62.9 MHz,
CDCl3) d: 46.3, 55.1, 114.1, 118.0, 123.7, 124.6, 125.2,
125.8, 126.1, 127.4, 127.6, 127.8, 127.9, 128.2, 128.5,
128.6, 128.7, 129.1, 131.2, 133.0, 133.5, 140.4, 144.9,
146.9, 198.1. MS m/z (%): 353 (M+ + 2, 0.4), 352 (M+ + 1,
1.6), 351 (M+, 3.6), 236 (25.4), 182 (31.7), 128 (38.1), 105
(36.5), 83 (61.9), 55 (100.0). Anal. calcd. for C25H21NO
(351.440; %): C 85.44, H 6.02, N 3.99; found: C 85.49, H
6.08, N 3.94.
3-(4-Bromoanilino)-1,3-diphenyl-1-propanone (6j)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6j as a colorless powder in a 90% yield; mp
182–184 8C (lit. value32 mp 182–184 8C). 1H NMR
(250 MHz, CDCl3) d: 7.86 (2H, d, J = 8.3 Hz), 7.51 (2H, t,
J = 7.3 Hz), 7.39 (2H, t, J = 7.5 Hz), 7.35 (2H, d, J =
7.5 Hz), 7.20–7.28 (4H, m), 6.77 (2H, d, J = 8.8 Hz), 4.99
(1H, t, J = 6.5 Hz), 3.85 (2H, d, J = 6.5 Hz). 13C NMR
(62.9 MHz, CDCl3) d: 43.7, 59.1, 114.0, 114.9, 120.7,
121.2, 124.1, 127.9, 128.1, 128.6, 128.7, 128.9, 132.2,
133.6, 136.2, 137.6, 138.0, 139.3, 144.9, 162.9, 196.6. Anal.
calcd. for C21H18BrNO (380.278; %): C 66.33, H 4.77, N
3.68; found: C 66.29, H 4.70, N 3.71.
3-Anilino-3-(4-nitrophenyl)-1-phenyl-1-propanone (6g)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6g as a pale green powder in an 80% yield; mp
108–110 8C (lit. value34 mp 108–109 8C). 1H NMR
(250 MHz, CDCl3) d: 8.1 (2H, d, J = 8.8 Hz), 7.89 (1H, d,
J = 8 Hz), 7.6 (2H, d, J = 8.5 Hz), 7.57 (2H, t, J = 7.3 Hz),
7.44 (2H, t, J = 7.8 Hz), 7.11 (2H, t, J = 7.5 Hz), 6.70 (1H,
d, J = 7.3 Hz), 6.55 (2H, d, J = 7.8 Hz), 5.1 (1H, t, J =
6.0 Hz), 3.5 (2H, d, J = 6.0 Hz). 13C NMR (62.9 MHz,
CDCl3) d: 45.5, 54.4, 114.1, 118.8, 123.6, 124.1, 124.2,
125.7, 127.5, 128.6, 128.8, 129.3, 129.6, 133.4, 133.8,
136.3, 141.5, 145.9, 147.2, 150.5, 197.1. Anal. calcd. for
C21H18N2O3 (346.379; %): C 72.82, H 5.24, N 8.09; found:
C 72.78, H 5.29, N 8.15.
3-(4-Fluoroanilino)-1,3-diphenyl-1-propanone (6k)35
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6k as a colorless powder in an 89% yield; mp
1
158–160 8C. H NMR (250 MHz, CDCl3) d: 7.89 (2H, d,
J = 7.3 Hz), 7.23–7.56 (8H, m), 6.78 (2H, t, J = 8.8 Hz),
6.49 (2H, d, J = 9.0 Hz), 4.91 (1H, t, J = 7.0 Hz), 3.45
(2H, d, J = 5.3 Hz). 13C NMR (62.9 MHz, CDCl3) d: 46.3,
55.6, 114.9, 115.1, 115.3, 115.7, 116.0, 126.4, 127.5, 128.2,
128.5, 128.7, 128.9, 133.5, 136.6, 142.6, 143.1, 145.1,
154.1, 158.0, 198.2. Anal. calcd. for C21H18FNO (319.372;
%): C 78.98, H 5.68, N 4.39; found: C 78.94, H 6.61, N
4.35.
3-Anilino-3-(4-methoxyphenyl)-1-phenyl-1-propanone
(6h)
3-Anilino-1-(4-chlorophenyl)-3-phenyl-1-propanone (6m)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6m as a colorless powder in a 90% yield; mp
119–120 8C (lit value32 mp 119–120 8C). 1H NMR
(250 MHz, CDCl3) d: 7.74 (2H, d, J = 8.5 Hz), 7.45 (3H, d,
J = 8.3 Hz), 7.1–7.37 (4 H, m), 6.90 (2H, t, J = 8.0 Hz),
6.55 (3H, d, J = 8.3 Hz), 5.02 (1H, t, J = 6.8 Hz), 3.80
(2H, d, J = 6.3 Hz). 13C NMR (62.9 MHz, CDCl3) d: 44.2,
59.0, 111.3, 118.35, 121.5, 122.7, 127.6, 128.3, 128.5,
128.8, 128.9, 129.0, 129.7, 129.9, 130.7, 134.7, 138.6,
139.9, 145.4, 178.9, 195.7. Anal. calcd. for C21H18ClNO
(335.826; %): C 75.11, H 5.40, N 4.17; found: C 75.05, H
5.44, N 4.21.
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6h as a colorless powder in a 91% yield; mp
148–150 8C (lit. value34 mp 150–152 8C). 1H NMR
(250 MHz, CDCl3) d: 7.92 (2H, d, J = 8.3 Hz), 7.88 (1H, t,
J = 8.5 Hz), 7.45 (2H, t, J = 7.8 Hz), 7.34 (2H, d, J =
8.8 Hz), 7.10 (2H, t, J = 7.5 Hz), 6.8 (2H, d, J = 8.8 Hz),
6.68 (1H, t, J = 8.0 Hz), 6.60 (2H, d, J = 7.5 Hz), 4.97
(1H, t, J = 6.5 Hz), 3.80 (3H, s), 3.47 (2H, d, J = 5.8 Hz).
13C NMR (62.9 MHz, CDCl3) d: 46.2, 54.5, 55.2, 114.1,
114.2, 118.0, 123.2, 124.3, 124.9, 127.1, 127.5, 128.2,
128.7, 129.1, 133.3, 134.6, 136.1, 141.2, 145.8, 148.0,
158.8, 198.4. Anal. calcd. for C22H21NO2 (331.408; %): C
79.73, H 6.39, N 4.23; found: C 79.70, H 6.43, N 4.20.
Published by NRC Research Press

Sharghi and Jokar
25
(2) (a) Blicke, F. F. Org. React. 1942, 1, 303; (b) Leinnmann, E.
F. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: New York, 1991; Vol. 2, Chapter 4.1; (c)
Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. Engl. 1998, 37 (8), 1044. doi:10.1002/(SICI)1521-
3773(19980504)37:8<1044::AID-ANIE1044>3.0.CO;2-E.;
(d) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99 (5),
1069. doi:10.1021/cr980414z. PMID:11749440.
(3) (a) Trost, B. M.; Terrell, L. R. J. J. Am. Chem. Soc. 2003,
125 (2), 338. doi:10.1021/ja028782e. PMID:12517138.; (b)
Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125 (16), 4712. doi:10.1021/
ja034787f. PMID:12696881.; (c) Juhl, K.; Gathergood, N.;
Jørgensen, K. A. Angew. Chem. 2001, 113 (16), 3083.
doi:10.1002/1521-3757(20010817)113:16<3083::AID-
3-(4-Bromoanilino)-1-(4-chlorophenyl)-3-phenyl-1-
propanone (6n)
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6n as a pale yellow powder in an 85% yield; mp
139–140 8C (lit value32 mp 139–141 8C). 1H NMR
(250 MHz, CDCl3) d: 7.80 (2H, d, J = 8.5 Hz), 7.32–7.42
(4H, m), 7.27 (3H, t, J = 8.0 Hz), 7.12 (2H, d, J = 8.8 Hz),
6.43 (2H, d, J = 8.8 Hz), 4.92 (1H, t, J = 5.8 Hz), 3.42 (2H,
d, J = 7.3 Hz). 13C NMR (62.9 MHz, CDCl3) d: 46.0, 54.8,
109.7, 111.0, 113.2, 114.5, 115.5, 122.1, 126.3, 127.6,
128.9, 129.0, 129.6, 129.1, 130.4, 131.8, 134.9, 140.1,
142.1, 145.7, 196.9. Anal. calcd. for C21H17BrClNO
(414.723; %): C 60.82, H 4.13, N 3.38; found: C 60.89, H
4.07, N 3.41.
ANGE3083>3.0.CO;2-C.; (d) List, B. J. Am. Chem. Soc.
2000, 122 (38), 9336. doi:10.1021/ja001923x.; (e) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124 (5), 827. doi:10.1021/ja0174231. PMID:
3-Anilino-3-(2-methoxyphenyl)-1-phenyl-1-propanone
(6o)
´
11817958.; (f) Cordova, A.; Notz, W.; Zhong, G.; Betancort,
The filtrate was triturated with hexane (10 mL), filtered,
and then recrystallization with EtOH/H2O (2:1) gave com-
pound 6o as a pale green powder in an 85% yield; mp
122–124 8C. IR (KBr, cm–1) y: 3375, 1681, 1600, 1519,
J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124 (9),
1842. doi:10.1021/ja017270h. PMID:11866583.; (g) Kobaya-
shi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002,
124 (20), 5640. doi:10.1021/ja026094p. PMID:12010028.;
(h) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.;
Shoji, M.; Sakai, K. Angew. Chem. Int. Ed. 2003, 42 (31),
3677. doi:10.1002/anie.200351813.
1
1234, 748, 690, 574. H NMR (250 MHz, CDCl3) d: 7.91
(2H, d, J = 8.5 Hz), 7.39 (3H, t, J = 9.0 Hz), 7.21 (2H, t,
J = 9.0 Hz), 7.05 (2H, t, J = 7.5 Hz), 6.84–6.92 (2H, m),
6.63 (1H t, J = 7.5 Hz), 6.53 (2H, d, J = 8.5 Hz), 5.22 (1H,
dd, J1 = 8.5 Hz, J2 = 4.5 Hz), 3.92 (3H, s), 3.64 (1H, dd,
J1 = 15.0 Hz, J2 = 4.8 Hz), 3.20 (1H, dd, J1 = 15.0 Hz, J2 =
8.3 Hz). 13C NMR (62.9 MHz, CDCl3) d: 44.5, 50.7, 55.4,
110.5, 113.5, 113.9, 117.7, 118.0, 121.0, 127.5, 128.33,
128.9, 129.1, 129.7, 129.8, 134.9, 135.0, 139.7, 140.1,
146.9, 156.5, 197.9. MS m/z (%): 333 (M+ + 2, 1.0), 331
(M+ + 1, 3.5), 330 (M+, 1.9), 279 (3.4), 257 (1.8), 241
(2.0), 212 (47.0), 167 (11.3), 149 (37.9), 119, 93 (17.6), 69
(100.0). Anal. calcd. for C22H21NO2 (331.408; %): C 79.73,
H 6.39, N 4.23; found: C 79.70, H 6.35, N 4.29.
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2006, 62 (43), 10079. doi:10.1016/j.tet.2006.08.063.; (b)
Shou, W.-G.; Yang, Y.-Y.; Wang, Y.-G. Tetrahedron Lett.
2006, 47 (11), 1845. doi:10.1016/j.tetlet.2005.12.136.
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2079. doi:10.1021/ol060498v. PMID:16671786.
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Zirak, M. Eur. J. Org. Chem. 2006, 5152. doi:10.1002/ejoc.
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M.; Marquez, A. M.; Calzado, C. J. Int. J. Quantum Chem.
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70:2<359::AID-QUA12>3.0.CO;2-7.
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Chem. Eur. J. 2005, 11 (23), 7024. doi:10.1002/chem.
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We gratefully acknowledge the support of this work by
the Shiraz University Research Council. We are also grate-
ful to Mr. H. Sajedian Fard for helpful cooperation.
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