Three component synthesis of β-amino carbonyl compounds using indium trichloride-catalyzed one-pot Mannich-type reaction in water

Article abstract of DOI:10.1016/S0040-4020(00)00221-0

The use of indium trichloride as catalyst in a one-pot Mannich reaction in water gives high yields for the formation of β-aminoketones/esters/acids is described. The catalyst can be recycled when the reaction is complete (Loh T.-P.; Wei L.-L. Tetrahedron Lett. 1998, 39, 323). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00221-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3227±3237
Three Component Synthesis of b-Amino Carbonyl Compounds
Using Indium Trichloride-Catalyzed One-pot Mannich-type
Reaction in Water
*
Teck-Peng Loh, Sarah B. K. W. Liung, Kee-Leng Tan and Lin-Li Wei
Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
Received 9 December 1999; revised 25 February 2000; accepted 9 March 2000
AbstractÐThe use of indium trichloride as catalyst in a one-pot Mannich reaction in water gives high yields for the formation of
b-aminoketones/esters/acids is described. The catalyst can be recycled when the reaction is complete (Loh T.-P.; Wei L.-L. Tetrahedron
Lett. 1998, 39, 323). q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
The Mannich reaction is a classical method for the prepara-
tion of b-amino ketones and aldehydes2 and has been one of
the most important basic reactions in organic chemistry for
its use in natural product and pharmaceutical syntheses.
However, due to the drastic reaction conditions and the
long reaction times, the classical intermolecular Mannich
reaction is plagued by a number of serious disadvantages.2
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.3±11 However, this
Lewis acid-catalyzed three component reaction of alde-
hydes, 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.
This Mannich type reaction using silyl enol ethers or silyl
ketene acetals in pure water, to our knowledge, has never
been investigated.1 Nevertheless, we have done so by ®rst
trying the Mannich type reaction in polar organic solvents
such as THF and acetonitrile (Scheme 1).
Table 1 shows that InCl3 can promote this Mannich type
reaction smoothly in both polar organic solvents and pure
water.20 The isolated yields of the product carried out in
different solvent systems are comparable.
Further to our research, we have also successfully employed
a convenient method for similar Mannich type reactions
using aldehydes, amines and ketones at ambient temperature
to give various b-amino ketones in good yields. A preview
of our work is illustrated below (Scheme 2) and detailed
studies are now in progress.
In this article, we propose an ef®cient one-pot method for
the preparation of b-amino esters and ketones from alde-
hydes using InCl3 as catalyst in pure water. We have also
carried out NMR studies to elucidate the role of indium
trichloride.
Due to the numerous advantages of using water as a solvent in
organic reactions,12 the following reactions using various
aldehydes, such as formaldehyde, 2-pyridine carboxaldehyde,
and benzaldehyde with silyl enol ethers B±D and silyl ketene
acetal A, have been performed in pure H2O (Scheme 3).
Scheme 1.
Keywords: one-pot Mannich reaction; b-aminoketones; indium trichloride.
* Corresponding author. Fax: 165-7791691; e-mail: chmlohtp@nus.edu.sg
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00221-0

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T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
Table 1. Mannich reactions in different solvents
benzylamine) also failed to give the desired products
which implies that this reaction is limited to non-enolizable
imines.
Entry
Solvents
Yielda (%)
1
2
3
CH3CN
THF
H2O
80
82
75
During the course of our investigations, the Mukaiyama±
aldol reaction has also been observed in some cases.
Compared to the yields of the desired Mannich reaction,
the yields of Mukaiyama±aldol reactions were much
lower; hence we deduce that in the reaction mixture, free
aldehyde and imine could exist together, since the imine
formation reaction would be in equilibrium, and these
different yields would indicate that the Mannich reaction
is faster than the Mukaiyama±aldol reaction. In order to
justify our proposal, NMR studies were conducted.
a Isolated yield
The catalyst could be recovered and reused after the
reactions were complete. The experimental procedure was
extremely simple: after normal work-up procedure, the
separated aqueous layer could be used for the repeat
reaction.
In addition, glyoxylic acid has also been used for the investi-
gations (Scheme 4). The yields of glyoxylic acid reactions
ranged from low to moderate (Table 3). Nonetheless, these
results demonstrate a convenient method for the preparation
of a-amino acids.
NMR Studies of the InCl3 Catalyzed Mannich-type
Reaction in D2O
Aldimine vs benzaldehyde
We have also attempted reactions using prochiral silyl enol
ethers and discovered that the diastereoselectivities were
poor, with the syn product being the major product. Two
sets of reactions using prochiral silyl enol ethers were
carried out, one with 1-phenyl-1-trimethylsilyloxypropene
C and the other with 1-trimethylsiloxycyclopentene D.
From the results in Table 2, we report that the predominant
isomer obtained was always the syn isomer, regardless of
the stereochemistry of the starting silyl enol ether. Further-
more, the syn selectivity improved when the silyl enol ether
had a predominant E con®guration (refer to Table 2). This
observation is contrary to previous papers15±18 that reported
on the anti selectivity being the major product in the InCl3-
catalysed Mannich reaction.13a,b,14
First, we investigated the Mannich-type reaction of benz-
aldehyde (0.5 mmol) and aniline (0.6 mmol) with 1-phenyl-
1-trimethylsilyloxyethene (1.0 mmol) in D2O (5 mL) with
and without InCl3 (20 mol%). The progress of reaction was
monitored by H NMR in D2O. The reaction mixture was
extracted with CDCl3 and the extract was also examined
directly.
1
Without the addition of InCl3, the spectra of the reaction
mixture in both D2O and CDCl3 (extracted into CDCl3)
showed the progress of the formation of imine (benzalde-
hyde with aniline) and no products from the aldol reaction
and Mannich type reaction were observed.
We probed the reaction further by performing several
experiments involving aliphatic imines derived from alkyl
aldehydes (such as valeraldehydes, carboxylcyclohexalde-
hyde) but found that the yields were poor. Furthermore, the
use of alkyl amines (such as benzylamine and methyl
On the contrary, in the presence of InCl3 (20 mol%), the
ratio of benzaldehyde/imine/Mannich-product in the
Mannich reaction was 28:59:13 after 7 h of mixing. After
22.5 h, the ratio was 21:34:45 and no aldol product was
observed.
Scheme 2.
Scheme 3.
Scheme 4. 1±3: R3ˆR4ˆMe, R5ˆOMe; 1: R2ˆPh; 2: R2ˆ4-ClC6H5; 3: R2 ˆ 4-CH3OC6H5; 4: R2ˆ4-ClC6H5; R3ˆR4ˆH; R5ˆPh:

T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3229
Table 2. Synthesis of b-amino ketones in water
Entry
Aldehyde (R1)
Amine (R2)
Yield (%)a
(syn/anti)b
c
A
B
C
D
1
2
3
4
5
6
7
8
9
H
Ph
2-Py
H
Ph
2-Py
H
Ph
Ph
Ph
30, 8d
54
92
21
91 (88)e
75 (74)e
94
85
60
91
86
40
90
58
46
80 (57:43)
70f (69:31)
78
26 (60:40)
55g (57:43)
41, 5i
68 (59:41)
60 (52:48)
60
17 (74:26)
35 (64:36)
20
4-ClPh
4-ClPh
4-ClPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
23
90
35, 17h
30
90
Ph
2-Py
45 (51:49)
70j (66:34)
11 (76:24)
20 (76:24)
a Isolated yield.
b The diastereoselectivity was determined by 1H NMR.
c E/Zˆ4:1.
d Yield of PhN(CH2C(CH3)2CO2CH3)2.
e Yield (in parenthesis) obtained from separated aqueous layer from previous reaction containing InCl3.
f The yield of aldol product was 10%.
g The yield of aldol products was 23%.
h Yield of 4-CH3OPhN(CH2C(CH3)2CO2CH3)2.
i The yield of 4-CH3OPh(CH2(CH3)CHCOPh)2.
j The yield of aldol product was 11%.
Table 3. Synthesis of a-amino acid in water using glyoxylic acid
were stirred for half an hour in D2O (5 mL) before the
addition of silyl enol ether (0.5 mmol) (Fig. 1). After mixing
all the reactants for 7 h, the ratio of benzaldehyde/imine/
Mannich-product was 62:33:5. After 22 h, the ratio changed
to 47:20:33. Again, no aldol product was observed. For
Entry
Amine (R2)
Yield (%)a
1
comparison purposes, the H NMR spectra of pure aldol
A
B
product, Mannich product and aldimine are presented (Fig.
2). Therefore, these results demonstrated the signi®cance of
InCl3 as a catalyst in the Mannich type reaction of aldimine
over the aldol reaction of benzaldehyde with silyl enol ether.
b
1
2
3
Ph
4-ClPh
4-CH3OPh
,10
31
10
±
63
b
±
a Isolated yield.
b Decomposed.
Aldimine vs 2-pyridine carboxaldehyde
Next, the competitive reaction was carried out in the
presence of excess benzaldehyde. The experimental pro-
cedure is as follows: benzaldehyde (1 mmol), aniline
(0.5 mmol) and InCl3 (0.2 mmol) in the same manner
Next, we employed 2-PyCHO (2-pyridine carboxaldehyde),
a more reactive aldehyde for our studies in the reaction of
the imine (derived from 2-PyCHO and aniline) with silyl
ketene acetal in D2O. The reactions were carried out as
Figure 1. 22 h after mixing benzaldehyde and aniline (extracted into CDCl3 and monitored by 1H NMR).

3230
T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
1
Figure 2. H NMR of the pure products (a), (b) and (c)
follows: 2-PyCHO (0.5 mmol), aniline (0.6 mmol) were
mixed for half an hour in D2O (5 mL) before the addition
of silyl ketene acetal (1 mmol).
17 h of mixing. The ratio of imine and aldol-product was
58:42 and no Mannich product was observed. Nevertheless,
addition of InCl3 (20 mol%) into the reaction mixture
largely converted the 2-PyCHO into the Mannich product
together with a trace amount of the aldol-product in a 95:5
ratio after 17 h of mixing.
In the absence of InCl3, the imine, the aldol product, aniline
and traces of 2-PyCHO were in the reaction mixture after

T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3231
Scheme 5.
Next, the competitive experiment of imine (derived from
2-PyCHO and aniline) using excess 2-PyCHO was carried
out as follows: 2-PyCHO (1 mmol), aniline (0.5 mmol) and
InCl3 (0.2 mmol) were stirred in D2O (5 mL) before adding
silyl ketene acetal (0.5 mmol). Based on NMR studies, the
conversion of aniline to imine was at least 95% complete in
the presence of InCl3 after half an hour of mixing. There-
fore, the ratio of 2-PyCHO and imine was about 50:50 in the
reaction system when silyl ketene acetal (1 equiv.) was
and aldol products were obtained. In the presence of InCl3,
however, the Mannich reaction proceeded smoothly in
water. The results of competitive experiments show that
the use of InCl3 changed the reactivities of imine and alde-
hydes. Thus, InCl3 catalyzes the Mannich reaction of imines
preferentially over the aldol reaction of aldehydes.
b-Amino carbonyl compounds are useful intermediates for
the synthesis of various biologically active compounds.
Therefore the development of new synthetic strategies for
combinatorial synthesis, which will lead to large libraries of
these compounds, is of much interest. In this article, we
have developed a new method for the preparation of
b-amino carbonyl compounds using a Lewis acid-catalyzed
reaction in water. We envisage that these three component
organic reactions in water, where the catalyst remains in the
aqueous layer after the reaction, will be useful for combi-
natorial library construction. According to this method,
large quantities of b-amino ketones and ester can be
prepared (quantities greater than 100 mg).
1
added. From H NMR spectra, the ratio of aldol-product
and Mannich product was 28:72 after 20 h of mixing
(Scheme 5).
This result indicates that even in the presence of excess
aldehyde, the Mannich product is still obtained as the
major product.
It is therefore clear that InCl3 plays an important role in
Mannich type reactions in water. As we have presented
above, in the presence of InCl3, the reaction using an excess
of benzaldehyde preferentially reacts with the silyl enol
ether to give the expected Mannich product without a
trace of the competing aldol product. When a more reactive
aldehyde is used in excess, for example, 2-pyridine carbox-
aldehyde, InCl3 promotes the formation of the Mannich
product preferentially over the aldol product, but without
InCl3 only the aldol product is observed.
Further studies to apply this reaction to the synthesis of
natural products as well as to develop new synthetic
reactions using indium trichloride in conjunction with a
water-soluble ligand as a chiral catalyst are now in progress.
Experimental
Conclusions
General methods and materials
In summary, the synthesis of b-amino ketones from alde-
hydes has been achieved in water using indium trichloride
as catalyst. The catalyst could be recovered after the reac-
tion was complete and could be reused for a repeat reaction
without any signi®cant drop in reactivity. Commercially
available formaldehyde solution and glyoxylic acid mono-
hydrate were used directly to give the corresponding
b-amino ketones in good yields, whilst glyoxylic acid
monohydrate yielded the a-amino acids, which provides a
convenient method of preparing a-amino acids. However,
this methodology is limited to non-enolizable imines. In the
conventional Mannich reaction, deamination of Mannich
bases to produce a,b-unsaturated derivatives resulted in
undesirable side reactions, no deamination occurred with
this reaction. The main side-reactions in this methodology
is the aldol reaction between aldehydes and the silyl enol
ethers and further alkylation of Mannich products but they
were only observed occasionally. The high ef®ciency using
simple starting materials and a catalytic amount of a
reusable catalyst in water is especially noteworthy.
NMR spectra were recorded on a Bruker ACF 300 NMR or
AMX 500 NMR. MS spectra were obtained with a Hewlett±
Packard 5890A gas chromatograph. HR-mass spectra (EI)
were obtained with V.G. Micromass 7035. IR spectra were
measured with a Perkin±Elmer 1600 FTIR spectrometer.
Column chromatography was performed on silica gel,
Merck grade 60 (40±63 mm particle size). All the solvents
were distilled before use. Silyl enol ethers were prepared
according to the references or purchased from Fluka.
Aniline, benzaldehyde and 2-PyCHO were distilled before
used. Formaldehyde, glyoxylic acid monohydrate, amines
and indium trichloride were purchased (Aldrich) and used
directly.
Formaldehyde (46 mL, 0.5 mmol, 37% in water) and indium
trichloride (22.6 mg, 0.1 mmol, 98%) were mixed and stir-
red at room temperature in water (5 mL) for 10 min before
the addition of aniline (distilled, 46.6 mg, 0.6 mmol). The
resulting mixture was stirred at room temperature for
30 min. 1-Methoxy-1-trimethylsilyloxypropene A (183 mg,
1 mmol, 95%) was then added. The suspension was stirred
at room temperature for 1 day and then extracted with ethyl
acetate (25 mL) three times. The organic layers were
NMR studies indicated that InCl3 is essential for this
Mannich-type reaction in water. Without InCl3, only imines

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T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
combined, washed with brine (5 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure. The
corresponding products 1A and 1A0 (see Table 2, footnote
d) were obtained in 30% (31 mg, based on aniline) and 8%
yield (13 mg, based on aniline) separately after silica gel
column chromatography.
MgSO4, and concentrated under reduced pressure. The
corresponding product was obtained in 92% yield
(131 mg) after silica gel chromatography. Yellowish oil;
1
mp 105±1078C; Rf 0.55 (hexane/ethyl acetateˆ2:1); H
NMR (CDCl3): d 8.57±8.54 (m, 1H), 7.59±6.61 (m, 8H),
4.76 (s, 1H), 3.67 (s, 3H), 1.254 (s, 3H), 1.249 (s, 3H); 13C
NMR (CDCl3): d 177.05, 159.22, 148.76, 136.10, 129.09,
123.12, 122.41, 117.73, 113.99, 64.93, 51.98, 47.55, 23.34,
21.59; FTIR (thin ®lm) 1730.8 cm21; MS (m/z, relative
intensity) 284 (24), 183 (99), 101 (2), 78 (45), 42 (8);
HRMS calcd for C17H20N2O2 284.1525, found 284.1514.
Methyl 2,2-dimethyl-3-(phenylamino)propanoate 1A
(Table 2, Entry 1, product of A). Yellowish, wet-solid; Rf
0.61 (hexane/ethyl acetateˆ4:1); 1H NMR (CDCl3): d
7.19±7.13 (m, 2H), 6.71±6.61 (m, 3H), 3.68 (s, 3H), 3.23
(s, 2H), 1.27 (s, 6H); 13C NMR (CDCl3): d 177.40, 148.41,
129.12, 117.29, 112.84, 64.49, 52.60, 51.92, 43.56, 23.45;
FTIR (thin ®lm) 1717.1 cm21; MS (m/z, relative intensity)
207 (61), 106 (100), 101 (2), 77 (64), 59 (13), 29 (7); HRMS
calcd for C12H17NO2 207.1259, found 207.1244.
3-(Methoxycarbonyl)-3-methyl-2-(phenylamino) butanoic
acid 1 (Table 3, Entry 1, product of A). Glyoxylic acid
monohydrate (46 mg, 0.5 mmol) and indium trichloride
(22.6 mg, 0.1 mmol, 98%) were stirred in water (5 mL) at
room temperature for 10 min before aniline (distilled,
93.1 mg, 1.0 mmol) was added. The resulting mixture was
stirred at room temperature for 30 min. 1-Methoxy-1-
trimethylsilyloxypropene A (183 mg, 1 mmol, 95%) was
then added. The suspension was stirred at room temperature
for 1 day. The corresponding product was obtained after the
usual acid±base workup in 10% yield (13 mg). Yellowish,
wet-solid; Rf 0.47 (hexane/ethyl acetate/ HOAcˆ1:2:0.1; 1H
NMR (CDCl3): d 7.22±7.17 (m, 2H), 6.81±6.71 (m, 3H),
4.35 (s, 1H), 3.71 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H); 13C
NMR (Acetone-d6): d 177.21, 149.69, 130.57, 119.62,
115.49, 64.17, 53.00, 47.18, 23.25, 22.88; FTIR (thin ®lm)
1735.1, 1713.6 cm21; MS (m/z, relative intensity) 207 (4),
206 [(M2COOH)1, 7], 160 (52), 102 (36), 77 (59); HRMS
calcd for M C13H17NO4 251.1158, (M2COOH)1 206.1181,
found (M2COOH)1 206.1165.
Methyl 3-{[2-(methoxycarbonyl)-2-methylpropyl]phenyl-
amino}-2,2-dimethylpropanoate 1A0. Dark brown, wet-
solid; mp 48±508C; Rf 0.55 (hexane/ethyl acetateˆ4:1);
1H NMR (CDCl3): d 7.16±7.11 (m, 2H), 6.94±6.91 (m,
2H), 6.70±6.66 (m, 1H), 3.60 (s, 4H), 3.40 (s, 6H), 1.10
(s, 12H); 13C NMR (CDCl3): d 177.50, 148.87, 128.57,
118.52, 118.42, 60.74, 51.47, 45.00, 23.82; FTIR (thin
®lm) 1730.6 cm21; MS (m/z, relative intensity) 321 (35),
290 (10), 262 (5), 220 (92), 115 (50), 77 (60), 59 (100);
HRMS calcd for C18H27NO4 321.1940, found 321.1928.
Methyl 2,2-dimethyl-3-phenyl-3-(phenylamino)propano-
ate 2A. Known19a±d (Table 2, Entry 2, product of A). Benz-
aldehyde (53 mg, 51 mL, 0.5 mmol, distilled) and indium
trichloride (22.6 mg, 0.1 mmol, 98%) were stirred in water
(5 mL) at room temperature for 10 min before aniline
(distilled, 55.9 mg, 0.6 mmol) was added. The resulting
mixture was stirred at room temperature for 30 min before
the addition of 1-methoxy-1-trimethylsilyloxypropene A
(183 mg, 1 mmol, 95%). The suspension was stirred at
room temperature for 1 day and then extracted with ethyl
acetate (25 mL£3). The organic layers were combined,
washed with brine (5 mL), dried over anhydrous MgSO4,
and concentrated under reduced pressure. The correspond-
ing product was obtained in 54% yield (76 mg) after silica
gel chromatography. Yellowish wet-solid; Rf 0.61 (hexane/
ethyl acetateˆ4:1); 1H NMR (CDCl3): d 7.31±7.23 (m, 5H),
7.10±7.03 (m, 2H), 6.65±6.50 (m, 3H), 4.53 (s, 1H), 3.67 (s,
3H), 1.30 (s, 3H), 1.20 (s, 3H); 13C NMR (CDCl3): d 176.97,
146.86, 139.17, 128.95, 128.21, 127.93, 127.38, 117.22,
113.34, 64.30, 52.01, 46.95, 24.48, 20.65; FTIR (thin ®lm)
1715.8 cm21; HRMS calcd for C18H21NO2 283.1572, found
283.1568.
Methyl 3-[(4-chlorophenyl) amino]-2,2-dimethylpropano-
ate 4A (Table 2, Entry 4, product of A). Yield 21%; color-
less wet-solid, mp 113±1158C; Rf 0.55 (hexane/ethyl
1
acetateˆ4:1); H NMR (CDCl3): d 7.10±7.07 (m, 2H),
6.55±6.52 (m, 2H), 3.67 (s, 3H), 3.19 (d, Jˆ6.0 Hz, 2H),
1.26 (s, 6H); 13C NMR (CDCl3): d 177.42, 147.08, 129.01,
121.85, 113.99, 52.79, 52.08, 43.68, 23.54; FTIR (thin ®lm)
1713.4 cm21; MS (m/z, relative intensity) 241 (13), 140
[(M2C6H4NHCH12 ), 99], 59 (15); HRMS calcd for
C12H1635ClNO2 241.0870, found 241.0855.
Methyl 3-[(4-chlorophenyl)amino]-2,2-dimethyl-3-phenyl-
propanoate 5A (Table 2, Entry 5, product of A). Yield
23%; yellowish wet-solid; Rf 0.58 (hexane/ethyl acetateˆ
1
4:1); H NMR (CDCl3): d 7.28±7.25 (m, 5H), 6.99±6.96
(m, 2H), 6.43±6.40 (m, 2H), 4.42 (br, 1H), 3.65 (s, 3H), 1.28
(s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3): d 176.86, 145.42,
138.69, 128.75, 128.13, 128.00, 127.54, 121.82, 114.39,
64.54, 52.02, 46.85, 24.56, 20.62; FTIR (thin ®lm)
1716.1 cm21; MS (m/z, relative intensity) 317 (8), 216
(100), 111 (22), 105 (4), 101 (2), 77 (12); HRMS calcd
for C18H2035ClNO2 317.1183, found 317.1200.
Methyl 2,2-dimethyl-3-(phenylamino)-3-(2-pyridyl)pro-
panoate 3A (Table 2, Entry 3, product of A). 2-Pyridine-
carboxaldehyde (54 mg, 48 mL, 0.5 mmol, 99%) and
indium trichloride (22.6 mg, 0.1 mmol, 98%) were stirred
in water (5 mL) at room temperature for 10 min before
aniline (distilled, 55.9 mg, 0.6 mmol) was added. The
resulting mixture was stirred at room temperature for
30 min before the addition of 1-methoxy-1-trimethylsilyl-
oxypropene A (183 mg, 1 mmol, 95%). The suspension was
stirred at room temperature for 1 day and then extracted
with ethyl acetate (25 mL£3). The organic layers were
combined, washed with brine (5 mL), dried over anhydrous
Methyl 3-[(4-chlorophenyl)amino]-2,2-dimethyl-3-(2-pyri-
dyl) propanoate 6A (Table 2, Entry 6, product of A). Yield
90%; yellowish wet-solid: mp 92±948C; Rf 0.53 (hexane/
ethyl acetateˆ2:1); 1H NMR (CDCl3): d 8.56±8.54 (m, 1H),
7.60±7.55 (m, 1H), 7.26±7.00 (m, 4H), 6.61±6.55 (m, 2H),
4.69 (s, 1H), 3.66 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H); 13C
NMR (CDCl3): d 176.98, 158.73, 148.87, 148.21, 136.21,

T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3233
128.93, 123.16, 122.59, 115.16, 65.16, 52.08, 47.48, 23.55,
21.37; FTIR (thin ®lm) 1723.2 cm21; MS (m/z, relative
intensity) 318 (10), 217 (21), HRMS calcd for
C17H1935ClN2O2 318.1135, found 318.1140.
3-(Methoxycarbonyl)-2-[(4-methoxyphenyl)amino]-3-
methylbutanoic acid 3 (Table 3, Entry 3, product of A).
Yield 10%; dark brown oil; Rf 0.26 (hexane/ethyl acetate/
1
HOAcˆ1/2/0.1); H NMR (CDCl3): d 6.78±6.58 (m, 4H),
3.74 (s, 3H), 3.67 (s, 3H), 3.18 (s, 1H), 1.26 (s, 6H); 13C
NMR (CDCl3): d 177.46, 152.03, 142.71, 114.77, 114.28,
55.76, 53.96, 51.89, 43.52, 23.49; FTIR (thin ®lm)
1713.4 cm21; MS (m/z, relative intensity) 237 (55), 205
(12), 77 (32); HRMS calcd for (M2CO2H)1 C13H18NO3
236.1287, found 236.1282; calcd for (M2CO2)1
C13H19NO3 237.1365, found 237.1352.
2-[(4-Chlorophenyl)amino]-3-(methoxycarbonyl)-3-methyl-
butanoic acid 2 (Table 3, Entry 2, product of A). Yield
31%; yellowish wet-solid; Rf 0.32 (hexane/ethyl acetate/
1
HOAcˆ1:2:0.1); H NMR (CDCl3) d 7.13±7.10 (m, 2H),
6.65±6.62 (m, 2H), 4.28 (s, 1H), 3.69 (s, 3H), 1.32 (s, 3H),
1.31 (s, 3H); 13C NMR (CDCl3) d 176.02, 175.96, 145.53,
129.09, 123.60, 115.22, 63.28, 52.35, 45.82, 22.43, 21.80;
FTIR (thin ®lm) 1715.9 cm21; MS (m/z, relative intensity)
285 (1), 241 (40), 240 (12), HRMS C13H1635ClNO4, calcd
for (M2CO2H)1 C12H1535ClNO2 240.0791, found
240.0788.
1-Phenyl-3-(phenylamino)propan-1-one 1B (Table 2,
Entry 1, product of B). Yield 91%; yellowish oil; mp 11±
1138C; Rf 0.29 (hexane/ethyl acetateˆ4:1); 1H NMR
(CDCl3): d 7.96±7.94 (m, 2H), 7.58±7.44 (m, 3H), 7.19±
7.16 (m, 2H), 6.72±6.64 (m, 3H), 3.62 (t, Jˆ6.1 Hz, 2H),
3.29 (t, Jˆ6.1 Hz, 2H); 13C NMR (CDCl3): d 199.34,
147.74, 136.78, 133.36, 129.36, 128.69, 128.06, 117.64,
113.09, 38.77, 37.71; FTIR (thin ®lm) 1681.5 cm21; MS
(m/z, relative intensity) 225 (90), 148 (12), 133 (51), 120
(80), 119 (54), 105 (98), 92 (60); HRMS calcd for
C15H15NO 225.1154, found 225.1166.
Methyl 3-[4-methoxyphenyl)amino]-2,2-dimethylpropano-
ate 7A (Table 2, Entry 7, product of A). Yield 35%; dark
1
brown wet-solid; Rf 0.47 (hexane/ethyl acetateˆ4:1); H
NMR (CDCl3): d 6.79±6.57 (m, 4H), 3.74 (s, 3H), 3.67
(s, 3H), 3.18 (s, 2H), 1.27 (s, 6H); 13C NMR (CDCl3): d
177.42, 152.04, 142.72, 114.77, 114.28, 55.72, 53.95, 51.84,
43.51, 23.46; FTIR (thin ®lm) 1724.7 cm21; MS (m/z, rela-
tive intensity) 237 (84), 206 (8), 136 (100), 122 (65), 108
(59); HRMS calcd for C13H19NO3 237.1365, found
237.1376.
1,2-Diphenyl-3-(phenylamino)propan-1-one 2B. Known19a±d
(Table 2, Entry 2, product of B). Yield 75%; yellowish oil;
1
mp 168±1708C; Rf 0.52 (hexane/ethyl acetateˆ4:1); H
NMR (CDCl3): d 7.91±7.90 (m, 2H), 7.57±7.07 (m,
10H), 6.67±6.55 (m, 3H), 5.00 (dd, Jˆ5.2, 7.5 Hz, 1H),
4.55 (br, 1H), 3.50 (dd, Jˆ5.2, 16.1 Hz, 1H), 3.42 (dd,
Jˆ7.5, 16.1 Hz, 1H); 13C NMR (CDCl3): d 198.29,
147.00, 142.99, 136.73, 133.42, 129.11, 128.83, 128.70,
128.21, 127.36, 126.38, 117.80, 113.84, 54.83, 46.31;
FTIR (thin ®lm) 1670.6 cm21; HRMS calcd for C21H19NO
301.1467, found 301.1471.
Methyl 3-{[2-(methoxycarbonyl)-2-methylpropyl](4-meth-
oxyphenyl) amino}-2,2-dimethylpropanoate 7A0 (Table
2, Entry 7, see Table footnote h). Yield 17%; dark brown
1
wet-solid; Rf 0.47 (hexane/ethyl acetateˆ4:1); H NMR
(CDCl3): d 6.96±6.71 (m, 4H), 3.73 (s, 3H), 3.43 (s, 4H),
3.36 (s, 6H), 1.09 (s, 12H); 13C NMR (CDCl3): d 177.45,
153.69, 143.26, 123.24, 113.79, 63.77, 55.33, 51.34, 44.81,
23.80; FTIR (thin ®lm) 1731.5 cm21; MS (m/z, relative
intensity) 351 (40), 320 (5), 250 (99), 115 (33), 59 (90);
HRMS calcd for C19H29NO5 351.2046, found 351.2061.
1-Phenyl-3-(phenylamino)-3-(2-pyridyl)propan-1-one 3B
(Table 2, Entry 3, product of B). Yellowish oil; yield
94%; mp 110±1128C; Rf 0.40 (hexane/ethyl acetate/
Methyl
3-[(4-methoxyphenyl)amino]-2,2-dimethyl-3-
1
HOAcˆ1:2:0.1); H NMR (CDCl3): d 8.56±8.55 (m, 1H),
phenylpropanoate 8A (Table 2, Entry 8, product of A).
Yield 30%; dark brown wet-solid; mp 92±948C; Rf 0.50
7.92±7.91 (m, 2H), 7.60±7.40 (m, 5H), 7.15±7.12 (m, 3H),
6.71±6.65 (m, 3H), 5.20 (br, 1H), 4.88 (br, 1H), 3.70
(dd, Jˆ6.5, 16.6 Hz, 1H), 3.60 (dd, Jˆ5.7, 16.6 Hz, 1H);
13C NMR (CDCl3): d 198.89, 161.25, 149.36, 146.73,
136.75, 136.70, 133.29, 129.30, 128.59, 128.22, 122.32,
122.22, 117.90, 113.81, 55.35, 43.95; FTIR (thin ®lm)
1679.9 cm21; MS (m/z, relative intensity) 302 (6), 208
[(M2PhNH)1, 40], 181 (90), 105 (95), 78 (90), 77
(76); HRMS calcd for C20H18N2O 302.1419, found
302.1413.
1
(hexane/ethyl acetateˆ4:1); H NMR (CDCl3): d 7.28±
7.24 (m, 5H), 6.66±6.44 (m, 4H), 4.46 (br, 1H), 3.66 (s,
6H), 1.25 (s, 3H), 1.16 (s, 3H); 13C NMR (CDCl3): d
177.03, 151.84, 141.15, 139.28, 128.26, 127.85, 127.27,
114.62, 114.59, 65.12, 55.57, 51.93, 47.04, 24.37, 20.36;
FTIR (thin ®lm) 1719.2 cm21; MS (m/z, relative intensity)
313 (73), 250 (75), 212 (100), 77 (65); HRMS calcd for
C19H23NO3 313.1678, found 313.1673.
Methyl 3-[(methoxyphenyl)amino]-2,2-dimethyl-3-(2-
pyridyl) propanoate 9A (Table 2, Entry 9, product of A).
Yield 90%; dark brown wet-solid; Rf 0.47 (hexane/ethyl
3-[(4-Chlorophenyl) amino]-1-phenylpropan-1-one 4B
(Table 2, Entry 4, product of B). Yield 85%; colorless oil;
1
1
acetateˆ2:1); H NMR (CDCl3): d 8.56±8.54 (m, 1H),
mp 133±1358C; Rf 0.26 (hexane/ethyl acetateˆ4:1); H
7.55±7.52 (m, 1H), 7.19±7.10 (m, 2H), 6.75±6.59 (m,
4H), 4.67 (s, 1H), 3.67 (s, 6H), 1.24 (s, 3H), 1.22 (s, 3H);
13C NMR (CDCl3): d 177.20, 159.27, 152.36, 148.82,
141.87, 135.97, 122.85, 122.36, 115.72, 114.68, 66.23,
55.69, 52.00, 47.63, 23.42, 21.18; FTIR (thin ®lm)
1729.4 cm21; MS (m/z, relative intensity) 314 (64), 283
(40), 182 (38), 91 (36), 59 (28); HRMS calcd for
C18H22N2O3 314.1631, found 314.1648.
NMR (CDCl3): d 7.95±7.94 (m, 2H), 7.59±7.45 (m, 3H),
7.12±7.11 (m, 2H), 6.58±6.55 (m, 2H), 3.58 (t, Jˆ6.0 Hz,
2H), 3.27 (t, Jˆ6.0 Hz, 2H); 13C NMR (CDCl3): d 199.17,
146.34, 136.68, 133.47, 129.17, 128.73, 128.05, 122.19,
114.15, 38.89, 37.46; FTIR (thin ®lm) 1670.2 cm21; MS
(m/z, relative intensity) 259 (85), 154 ((M2C6H4CO)1,
23], 111 (51), 105 (100), 77 (96), 43 (10); HRMS calcd
for C15H1435ClNO 259.0764, found 259.0766.

3234
T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3-[(4-Chlorophenyl)amino]-1,3-diphenylpropan-1-one 5B
(Table 2, Entry 5, product of B). Yield 60%; yellowish
2-[(4-Chlorophenyl)amino]-4-oxo-4-phenylbutanoic acid
4 (Table 3, Entry 2, product of B). Yield 63%; yellowish
wet-solid; Rf 0.38 (hexane/ethyl acetate/HOAcˆ1:2:0.1);
1H NMR (D2O): d 8.06±8.03 (m, 2H), 7.76±7.62 (m, 3H),
7.27±7.24 (m, 2H), 6.76±6.73 (m, 2H), 4.41 (br, 1H), 3.57
(m, 2H); 13C NMR (D2O): d 205.14, 182.62, 148.92, 139.09,
136.85, 131.77, 131.64, 131.09, 125.24, 118.38, 59.14,
44.47; FTIR (thin ®lm) 1634.4 cm21; MS (m/z, relative
intensity) 254 (32), 176 (42), 105 (70), 77 (64); HRMS
C16H1435ClNO3, calcd for (M2CO22H2)1 C15H1235ClNO
257.0607, found 257.0610.
1
wet-solid; Rf 0.48 (hexane/ethyl acetateˆ4:1); H NMR
(CDCl3): d 7.90±7.89 (m, 2H), 7.58±7.22 (m, 8H), 7.03±
7.00 (m, 2H), 6.48±6.45 (m, 2H), 4.94 (dd, Jˆ5.0, 7.7 Hz,
1H), 3.49 (dd, Jˆ5.0, 16.2 Hz, 1H), 3.40 (dd, Jˆ7.7,
16.2 Hz, 1H); 13C NMR (CDCl3): d 198.17, 145.59, 142.51,
136.65, 133.52, 128.93, 128.91, 128.74, 128.20, 127.51,
126.29, 122.48, 114.98, 54.95, 46.22; FTIR (thin ®lm)
1665.2 cm21; MS (m/z, relative intensity) 335 (45), 258
[(M2C6H5)1, 2)], 216 (86), 111 (77), 105 (78), 77 (88);
HRMS calcd for C21H1835ClNO 335.1077, found 335.1058.
2-Methyl-1-phenyl-3-(phenylamino)propan-1-one 1C
(Table 2, Entry 1, product of C). Yield 58%; colorless
3-[(4-Chlorophenyl)amino]-1-phenyl-3-(2-pyridyl)propan-
1-one 6B (Table 2, Entry 6, product of B). Yield 91%;
yellowish oil; mp 115±1178C; Rf 0.43 (hexane/ethyl
1
wet-solid; Rf 0.53 (hexane/ethyl acetateˆ4:1); H NMR
(CDCl3): d 7.93±7.91 (m, 2H), 7.57±7.43 (m, 3H), 7.17±
7.14 (m, 2H), 6.70±6.59 (m, 3H), 3.88±3.84 (m, 1H), 3.60
(dd, Jˆ7.7, 13.4 Hz, 1H), 3.32 (dd, Jˆ5.2, 13.4 Hz, 1H),
1.27 (d, Jˆ7.1 Hz, 3H); 13C NMR (CDCl3): d 203.47,
147.78, 136.30, 133.16, 129.26, 128.65, 128.30, 117.34,
112.76, 46.47, 40.25, 15.94; FTIR (thin ®lm)
1677.2 cm21; MS (m/z, relative intensity) 239 (28), 133
(7), 106 (100), 105 (74), 77 (71), 27 (5); HRMS calcd for
C16H17NO 239.1310, found 239.1324.
1
acetateˆ2:1); H NMR (CDCl3): d 8.56±8.55 (m, 1H),
7.92±7.90 (m, 2H), 7.61±7.41 (m, 5H), 7.16±7.06 (m,
3H), 6.61±6.57 (m, 2H), 5.14 (br, 1H), 4.95 (br, 1H), 3.66
(dd, Jˆ6.3, 16.7 Hz, 1H), 3.59 (dd, Jˆ5.8, 16.7 Hz, 1H);
13C NMR (CDCl3): d 198.71, 160.83, 149.43, 145.32,
136.79, 136.66, 133.40, 129.13, 128.63, 128.21, 122.47,
122.13, 114.95, 55.53, 43.88; FTIR (thin ®lm)
1686.3 cm21; MS (m/z, relative intensity) 336 (18), 231
(48), 217 (80), 216 (88), 210 (67), 120 (65), 105 (96), 77
(97); HRMS calcd for C20H1735ClN2O 336.1029, found
336.1043.
2-Methyl-1,3-diphenyl-3-(phenylamino)propan-1-one 2C
(Table 2, Entry 2, product of C). Yield 80% (syn/
antiˆ57:43); yellowish oil; mp 108±1108C; Rf 0.55
1
3-[(4-Methoxyphenyl)amino]-1-phenylpropan-1-one 7B.
Known19a±d (Table 2, Entry 7, product of B). Yield 86%;
brownish wet-solid; mp 110±1128C; Rf 0.19 (hexane/ethyl
(hexane/ethyl acetateˆ4:1); H NMR (CDCl3): (syn1anti)
d 7.99±7.04 (m, 12H), 6.68±6.49 (m, 3H), 4.81 (d,
Jˆ5.1 Hz, 1H£0.57), 4.77 (d, Jˆ6.0 Hz, 1H£0.43), 4.07±
3.89 (m, 1H), 1.34 (d, Jˆ7.0 Hz, 3H£0.43), 1.27 (d,
Jˆ6.9 Hz, 3H£0.57); 13C NMR (CDCl3): major d 202.60,
147.20, 141.51, 136.23, 133.22, 128.89, 128.72, 128.21,
127.20, 126.80, 117.55, 113.77, 59.21, 46.90, 11.52;
minor d 204.03, 147.12, 141.80, 137.15, 133.08, 129.01,
128.59, 128.49, 128.11, 126.73, 117.22, 113.42, 61.13,
46.44, 16.65; FTIR (thin ®lm) 1671.9 cm21; MS (m/z, rela-
tive intensity) 315 (6), 182 (87), 133 (19), 105 (99), 77
(100), 27 (37); HRMS calcd for C22H21NO 315.1623,
found 315.1631.
1
acetateˆ4:1); H NMR (CDCl3): d 7.95±7.93 (m, 2H),
7.58±7.44 (m, 3H), 6.80±6.63 (m, 4H), 3.74 (s, 3H), 3.56
(t, Jˆ6.1 Hz, 2H), 3.27 (t, Jˆ6.1 Hz, 2H); 13C NMR
(CDCl3): d 199.43, 152.55, 141.68, 136.79, 133.34,
128.68, 128.05, 115.02, 114.87, 55.83, 40.13, 37.66; FTIR
(thin ®lm) 1674.2 cm21; HRMS calcd for C16H17NO2
255.1259, found 255.1266.
3-[(4-Methoxyphenyl)amino]-1,3-diphenylpropan-1-one
8B. Known19a±d (Table 2, Entry 8, product of B). Yield 40%;
brownish wet-solid; mp 140±1428C; Rf 0.39 (hexane/ethyl
1
acetateˆ4:1); H NMR (CDCl3): d 7.92±7.90 (m, 2H),
2-Methyl-1-phenyl-3-(phenylamino)-3-(2-pyridyl)propan-
1-one 3C (Table 2, Entry 3, product of C). Yield 70% (syn/
7.57±7.21 (m, 8H), 6.69±6.52 (m, 4H), 4.92 (dd, Jˆ5.1,
7.7 Hz, 1H), 3.68 (s, 3H), 3.48 (dd, Jˆ5.1, 16.2 Hz, 1H),
3.42 (dd, Jˆ7.7, 16.2 Hz, 1H); 13C NMR (CDCl3): d 198.44,
152.50, 143.19, 141.12, 136.82, 133.42, 128.84, 128.72,
128.24, 127.37, 126.51, 115.51, 114.77, 55.88, 55.74,
46.44; FTIR (thin ®lm) 1666.3 cm21; HRMS calcd for
C22H21NO2 331.1572, found 331.1588.
1
antiˆ69:31); yellowish oil; H NMR (CDCl3): major d
8.56±8.54 (m, 1H), 8.02±7.99 (m, 2H), 7.56±7.06 (m,
8H), 6.68±6.55 (m, 3H), 5.94 (d, Jˆ6.2 Hz, 1H), 4.65 (br,
1H), 4.34±4.30 (m, 1H), 1.26 (d, Jˆ7.0 Hz, 3H); minor d
8.56±8.54 (m, 1H), 7.82±7.80 (m, 2H), 7.52±6.55 (m,
11H), 5.43 (br, 1H), 4.85 (d, Jˆ5.8 Hz, 1H), 4.44±4.35
(m, 1H), 1.28 (d, Jˆ7.2 Hz, 3H); 13C NMR (CDCl3):
major d 202.98, 160.62, 149.43, 147.29, 136.27, 136.13,
133.03, 129.02, 128.55, 128.42, 122.56, 122.08, 117.67,
113.71, 60.61, 45.79, 12.70; minor d 204.25, 160.94,
149.34, 147.32, 136.96, 136.32, 132.95, 129.05, 128.37,
128.20, 122.06, 121.89, 117.43, 113.49, 62.18, 44.56,
16.03; FTIR (thin ®lm) 1672.3 cm21; MS (m/z, relative
intensity) 316 (38), 183 (75), 133 (46), 105 (78), 92 (47),
91 (61); HRMS calcd for C21H20N2O 316.1576, found
316.1579.
3-[(4-Methoxyphenyl)amino]-1-phenyl-3-(2-pyridyl)-
propan-1-one 9B. Known19a±d (Table 2, Entry 8, product of
B). Yield 90%; dark brown wet-solid; mp 82±848C; Rf 0.29
(hexane/ethyl acetateˆ1:2); 1H NMR (CDCl3): d 8.55±8.54
(m, 1H), 7.92±7.90 (m, 2H), 7.60±7.40 (m, 5H), 7.13±7.11
(m, 1H), 6.74±6.62 (m, 4H), 5.11 (t, Jˆ6.2 Hz, 1H), 4.80
(br, 1H), 3.70 (s, 3H), 3.67 (dd, Jˆ6.4, 16.5 Hz, 1H), 3.57
(dd, Jˆ6.0, 16.5 Hz, 1H); 13C NMR (CDCl3): d 198.94,
161.51, 152.51, 149.35, 140.90, 136.81, 136.65, 133.25,
128.58, 128.21, 122.32, 122.28, 115.50, 114.88, 56.53,
55.71, 44.07; FTIR (thin ®lm) 1673.7 cm21; HRMS calcd
for C21H20N2O2 332.1525, found 332.1511.
3-[(4-Chlorophenyl)amino]-2-methyl-1-phenylpopan-1-
one 4C (Table 2, Entry 4, product of C). Yield 78%;

T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3235
yellowish oil; Rf 0.53 (hexane/ethyl acetateˆ4:1); 1H NMR
(CDCl3): d 7.94±7.90 (m, 2H), 7.59±7.55 (m, 3H), 7.11±
7.07 (m, 2H), 6.53±6.48 (m, 2H), 3.90±3.78 (m, 1H), 3.57
(dd, Jˆ7.8, 13.3 Hz, 1H), 3.28 (dd, Jˆ5.0, 13.3 Hz, 1H),
1.26 (d, Jˆ7.1 Hz, 3H); 13C NMR (CDCl3): d 203.28,
146.38, 136.15, 133.25, 129.02, 128.68, 128.24, 121.76,
113.79, 46.47, 40.11, 15.95; FTIR (thin ®lm)
1677.5 cm21; MS (m/z, relative intensity) 273 (49), 140
(28), 133 (28), 111 (40), 105 (19), 77 (68); HRMS calcd
for C16H1635ClNO 273.0920, found 273.0923.
Entry 7, see Table footnote i). Yield 5%; dark brown oil;
1
Rf 0.42 (hexane/ethyl acetateˆ4:1); H NMR (CDCl3): d
7.83±7.30 (m, 10H), 6.84±6.67 (m, 4H), 3.78 (s, 3H),
3.87±3.78 (m, 2H), 3.65±3.53 (m, 2H), 3.29±3.14 (m,
2H), 1.11 (d, Jˆ6.9 Hz, 6H); 13C NMR (CDCl3): d
203.97, 203.92, 152.56, 152.34, 142.31, 142.05, 136.62,
136.54, 132.89, 132.78, 128.46, 128.31, 128.18, 128.14,
117.15, 116.69, 114.72, 114.69, 56.65, 55.58, 38.86,
38.61, 15.94; FTIR (thin ®lm) 1679.2 cm21; MS (m/z, rela-
tive intensity) 415 (56), 282 (89), 176 (46), 135 (82), 105
(100), 77 (95); HRMS calcd for C27H29NO3 415.2148, found
415.2142.
3-[(4-Chlorophenyl)amino]-2-methyl-1,3-diphenylpropan-
1-one 5C (Table 2, Entry 5, product of C). Yield 26% (syn/
antiˆ60:40); yellowish oil; mp 161±1638C; Rf 0.55
3-[(4-Methoxyphenyl)amino]-2-methyl-1,3-diphenylpro-
pan-1-one 8C (Table 2, Entry 8, product of C). Yield 45%
(syn/antiˆ51:49); dark brown wet-solid; Rf 0.45 (hexane/
1
(hexane/ethyl acetateˆ4:1); H NMR (CDCl3): (syn1anti)
d 7.95±6.94 (m, 12H), 6.48±6.36 (m, 3H), 4.70 (d,
Jˆ4.9 Hz, 1H£0.60), 4.67 (d, Jˆ5.9 Hz, 1H£0.40), 4.00±
3.93 (m, 1H), 1.30 (d, Jˆ7.0 Hz, 3H£0.40), 1.22 (d,
Jˆ7.0 Hz, 3H£0.60); 13C NMR (CDCl3): d 202.54,
203.98, 145.75, 145.72, 141.34, 140.95, 137.02, 136.14,
133.25, 133.12, 128.78, 128.72, 128.68, 128.62, 128.53,
128.47, 128.14, 128.05, 127.33, 126.70, 126.61, 122.24,
121.75, 114.85, 114.46, 61.29, 59.31, 46.74, 46.31, 16.67
(minor), 11.39 (major); FTIR (thin ®lm) 1666.3 cm21; MS
(m/z, relative intensity) 349 (4), 216 (92), 133 (20), 111 (72),
105 (99), 77 (93); HRMS calcd for C22H2035ClNO 349.1234,
found 349.1246.
1
ethyl acetateˆ4:1); H NMR (CDCl3): (syn1anti) d 7.98±
7.15 (m, 10H), 6.70±6.44 (m, 4H), 4.70 (m, 1H), 4.02±3.95
(m, 1H), 3.68 (s, 3H£0.49), 3.67 (s, 3H£0.51), 1.27 (d,
Jˆ7.0 Hz, 3H£0.49), 1.26 (d, Jˆ7.0 Hz, 3H£0.51); 13C
NMR (CDCl3): d 202.80 (major), 203.88 (minor), 152.07,
151.96, 141.95, 141.82, 141.44, 141.34, 137.24, 136.29,
133.16, 133.20, 128.69, 128.53, 128.59, 128.53, 128.50,
128.46, 128.40, 128.20, 128.11, 127.17, 127.15, 126.86,
114.97, 114.91, 114.66, 114.55, 62.18, 60.02, 55.61,
55.59, 46.98, 46.66, 16.50, 11.51; FTIR (thin ®lm)
1681.7 cm21; MS (m/z, relative intensity) 345 (6), 212
(83), 133 (44), 122 (5), 105 (97), 77 (92); HRMS calcd
for C23H23NO2 345.1729, found 345.1733.
3-[(4-Chlorophenyl)amino]-2-methyl-1-phenyl-3-(2-
pyridyl)propan-1-one 6C (Table 2, Entry 6, product of C).
Yield 55% (syn/antiˆ57:43); yellowish oil; mp 129±1318C;
Rf 0.51 (major), 0.42 (minor) (hexane/ethyl acetateˆ2:1);
1H NMR (CDCl3): major d 8.55±8.53 (m, 1H), 7.99±7.96
(m, 2H), 7.57±6.98 (m, 8H), 6.55±6.45 (m, 3H), 4.87 (d,
Jˆ6.1 Hz, 1H), 4.68 (br, 1H), 4.34±4.25 (m, 1H), 1.25 (d,
Jˆ7.0 Hz, 3H); minor d 8.55±8.53 (m, 1H), 7.81±7.78 (m,
2H), 7.52±6.50 (m, 10H), 5.36 (br, 1H), 4.79 (d, Jˆ5.8 Hz,
1H), 4.39±4.30 (m, 1H), 1.25 (d, Jˆ7.1 Hz, 3H); 13C NMR
(CDCl3): major d 202.87, 160.14, 149.50, 145.89, 136.33,
136.03, 133.12, 128.84, 128.57, 128.37, 122.49, 122.22,
114.82, 60.76, 45.73, 12.74; minor d 204.13, 160.48,
149.47, 145.95, 136.82, 136.34, 133.05, 128.88, 128.41,
128.18, 122.20, 121.83, 114.64, 62.44, 44.53, 16.09; FTIR
(thin ®lm) 1670.8 cm21; MS (m/z, relative intensity) 350
(33), 217 (83), 133 (51), 111 (72), 105 (84), 77 (77), 27
(30); HRMS calcd for C21H1935ClN2O 350.1186, found
350.1178.
3-[(4-Methoxyphenyl)amino]-2-methyl-1-phenyl-3-(2-
pyridyl)propan-1-one 9C (Table 2, Entry 9, product of C).
Yield 70% (syn/antiˆ66:34); dark brown solid; mp 113±
1158C; Rf 0.42 (major), 0.36 (minor) (hexane/ethyl ace-
tateˆ2:1); H NMR (CDCl3): major d 8.55±8.54 (m, 1H),
1
8.01±7.98 (m, 2H), 7.54±7.30 (m, 5H), 7.09±7.05 (m, 1H),
6.70±6.48 (m, 4H), 4.83 (d, Jˆ6.2 Hz, 1H), 4.45 (br, 1H),
4.41±4.26 (m, 1H), 3.67 (s, 3H), 1.27 (d, Jˆ7.0 Hz, 3H);
minor d 8.57±8.52 (m, 1H), 7.86±7.83 (m, 2H), 7.53±7.17
(m, 6H), 6.70±6.54 (m, 4H), 4.77 (d, Jˆ6.6 Hz, 1H), 4.36±
4.24 (m, 1H), 3.67 (s, 3H), 1.21 (d, Jˆ7.0 Hz, 3H); 13C
NMR (CDCl3): major d 203.12, 160.95, 152.22, 149.41,
141.46, 136.19, 132.99, 128.53, 128.41, 122.62, 122.01,
115.14, 114.63, 61.71, 55.58, 45.79, 12.69; minor d 204.08,
161.02, 152.20, 149.43, 141.53, 136.20, 132.88, 128.37,
128.21, 122.28, 122.08, 115.23, 114.70, 63.50, 55.58,
44.91, 15.91; FTIR (thin ®lm) 1672.4 cm21; MS (m/z, rela-
tive intensity) 346 (3), 213 (59), 133 (20), 105 (100), 77 (89);
HRMS calcd for C22H22N2O2 346.1681, found 346.1676.
3-[(4-Methoxyphenyl)amino]-2-methyl-1-phenylpropan-
1-one 7C (Table 2, Entry 7, product of C). Yield 41%; dark
1
brown wet-solid; Rf 0.53 (hexane/ethyl acetateˆ4:1); H
2-[(Phenylamino)methyl]cyclopentan-1-one 1D (Table 2,
Entry 1, product of D). Yield 46%; yellowish oil; Rf 0.38
(hexane/ethyl acetateˆ4:1); 1H NMR (CDCl3): d 7.24±7.15
(m, 2H), 6.74±6.63 (m, 3H), 4.19 (br, 1H), 3.34 (dd, Jˆ6.8,
13.0 Hz, 1H), 3.26 (dd, Jˆ6.4, 13.0 Hz, 1H), 2.43±1.62 (m,
7H); 13C NMR (CDCl3): d 220.74, 147.88, 129.17, 117.65,
113.08, 48.18, 43.90, 38.32, 28.05, 20.67; FTIR (thin ®lm)
1726.4 cm21; MS (m/z, relative intensity) 189 (66), 106
(100), 83 (7), 77 (55); HRMS calcd for C12H15NO
189.1154, found 189.1146.
NMR (CDCl3): d 7.94±7.90 (m, 2H), 7.59±7.42 (m, 3H),
6.79±6.54 (m, 4H), 3.74 (s, 3H), 3.89±3.73 (m, 1H), 3.55
(dd, Jˆ7.6, 13.1 Hz, 1H), 3.25 (dd, Jˆ5.2, 13.1 Hz, 1H),
1.26 (d, Jˆ7.0 Hz, 3H); 13C NMR (CDCl3): d 203.53,
152.10, 141.96, 136.33, 133.10, 128.61, 128.24, 114.88,
114.28, 55.70, 47.66, 40.29, 15.90; FTIR (thin ®lm)
1675.2 cm21; MS (m/z, relative intensity) 269 (72), 136
(99), 133 (18), 107 (25), 77 (96), 27 (34); HRMS calcd
for C17H19NO2 269.1416, found 269.1410.
3-[(4-Methoxyphenyl)(2-methyl-3-oxo-3-phenylpropyl)-
amino]-2-methyl-1-phenylpropan-1-one 7C0 (Table 2,
2-[Phenyl(phenylamino)methyl]cyclopentan-1-one 2D
(Table 2, Entry 2, product of D). Yield 68% (syn/

3236
T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
antiˆ59:41); yellowish oil; Rf 0.46 (minor), 0.41 (major)
(major) (hexane/ethyl acetateˆ2:1); 1H NMR (CDCl3):
major d 8.54±8.52 (m, 1H), 7.62±7.56 (m, 1H), 7.25±
7.02 (m, 4H), 6.64±6.58 (m, 2H), 5.40 (d, Jˆ9.0 Hz, 1H),
4.93 (dd, Jˆ4.0, 9.0 Hz, 1H), 2.73±2.65 (m, 1H), 2.33±2.25
(m, 1H), 2.09±1.68 (m, 5H); minor d 8.58±8.55 (m, 1H),
7.71±7.05 (m, 5H), 6.62±6.56 (m, 2H), 5.36 (d, Jˆ6.5 Hz,
1H), 4.90 (m, 1H), 2.83 (m, 1H), 2.33±1.67 (m, 6H); 13C
NMR (CDCl3): major d 219.98, 160.11, 148.83, 145.69,
136.69, 128.86, 122.31, 121.80, 115.27, 58.87, 53.20,
39.18, 25.09, 20.65; minor d 219.91, 159.25, 148.74,
145.22, 136.75, 128.99, 122.45, 122.12, 114.81, 58.16,
1
(hexane/ethyl acetateˆ4:1); H NMR (CDCl3): major d
7.56±7.03 (m, 7H), 6.64±6.56 (m, 3H), 5.38 (br, 1H),
4.75 (d, Jˆ4.4 Hz, 1H), 2.75±2.67 (m, 1H), 2.31±1.60
(m, 6H); minor d 7.54±7.03 (m, 7H), 6.68±6.53 (m, 3H),
5.30 (br, 1H), 4.55 (d, Jˆ7.4 Hz, 1H), 2.75±1.63 (m, 7H);
13C NMR (CDCl3): major d 220.41, 146.65, 140.77, 128.96,
128.42, 127.35, 127.22, 117.38, 113.58, 57.63, 53.23, 39.65,
25.76, 20.55; minor d 219.28, 147.48, 141.63, 128.91,
128.55, 127.25, 127.10, 117.76, 114.09, 58.95, 53.98,
39.13, 26.60, 20.39; FTIR (thin ®lm) 1715.7 cm21; MS
(m/z, relative intensity) 265 (34), 182 (83), 173 (5), 83
(34), 55 (100); HRMS calcd for C18H19NO 265.1467,
found 265.1466.
52.54, 39.01, 25.13, 20.36; FTIR (thin ®lm) 1635.8 cm21
;
MS (m/z, relative intensity) 300 (29), 217 (96), 216 (67),
173 (94), 146 (29), 118 (66), 83 (22), 55 (77); HRMS calcd
for C17H1735ClN2O 300.1029, found 300.1033.
2-[(Phenylamino)-2-pyridylmethyl]cyclopentan-1-one 3D
(Table 2, Entry 3, product of D). Yield 60% (syn/
antiˆ52:48); yellowish oil; Rf 0.40 (minor), 0.33 (major)
2-{[(4-Methoxyphenyl)amino]methyl}cyclopentan-1-one
7D (Table 2, Entry 7, product of D). Yield 20%; yellowish
oil; Rf 0.22 (hexane/ethyl acetateˆ4:1); 1H NMR (CDCl3):
d 6.80±6.75 (m, 2H), 6.64±6.61 (m, 2H), 3.75 (s, 3H), 3.30
(dd, Jˆ6.9, 12.8 Hz, 1H), 3.20 (dd, Jˆ6.3, 12.8 Hz, 1H),
2.39±1.65 (m, 7H); 13C NMR (CDCl3): d 220.91, 152.33,
141.99, 114.79, 114.62, 55.68, 48.03, 45.13, 38.35, 28.06,
1
(hexane/ethyl acetateˆ2:1); H NMR (CDCl3): major d
8.58±8.53 (m, 1H), 7.61±7.55 (m, 1H), 7.29±7.08 (m,
4H), 6.71±6.64 (m, 3H), 5.00 (d, Jˆ3.9 Hz, 1H), 2.76±
2.70 (m, 1H), 2.33±1.69 (m, 6H); minor d 8.58±8.56 (m,
1H), 7.64±7.58 (m, 1H), 7.35±7.33 (m, 1H), 7.19±7.12 (m,
3H), 6.72±6.67 (m, 3H), 5.28 (br, 1H), 5.00 (d, Jˆ5.4 Hz,
1H), 2.92±2.84 (m, 1H), 2.33±1.65 (m, 7H); 13C NMR
(CDCl3): major d 219.93, 160.59, 148.76, 147.09, 136.58,
129.05, 122.15, 121.87, 117.87, 114.13, 58.73, 53.29, 39.18,
25.18, 20.69; minor d 219.97, 159.62, 148.66, 146.64,
136.62, 129.18, 122.28, 122.19, 117.73, 113.69, 57.91,
20.68; FTIR (thin ®lm) 1731.1 cm21
;
MS (m/z,
relative intensity) 219 (60), 136 (87), 122 (19), 108 (88),
97 (8); HRMS calcd for C13H17NO2 219.1259, found
219.1240.
2-{[(4-Methoxyphenyl)amino]phenylmethyl}cyclopentan-
1-one 8D (Table 2, Entry 8, product of D). Yield 11% (syn/
antiˆ76:24); yellowish oil; Rf 0.32 (major), 0.28 (minor)
52.66, 39.01, 25.08, 20.39; FTIR (thin ®lm) 1731.9 cm21
;
MS (m/z, relative intensity) 266 (47), 174 (67), 146 (38),
118 (80), 83 (30), 55 (100); HRMS calcd for C17H18N2O
266.1419, found 266.1414.
1
(hexane/ethyl acetateˆ4:1); H NMR (CDCl3): major d
7.31±7.17 (m, 5H), 6.70±6.53 (m, 4H), 4.71 (d,
Jˆ4.2 Hz, 1H), 3.68 (s, 3H), 2.73±2.66 (m, 1H), 2.31±
1.64 (m, 6H); minor d 7.45±7.21 (m, 5H), 6.68±6.48 (m,
4H), 4.45 (d, Jˆ7.5 Hz, 1H), 3.67 (s, 3H), 2.52±1.65 (m,
7H); 13C NMR (CDCl3): major d 220.38, 152.03, 140.98,
140.83, 128.40, 127.30, 127.15, 115.14, 114.59, 58.53,
55.55, 53.50, 39.62, 25.62, 20.56; minor d 219.47, 152.30,
141.84, 141.63, 128.48, 127.27, 127.16, 115.56, 114.52,
59.91, 55.58, 53.94, 39.11, 26.71, 20.34; FTIR (thin ®lm)
3418.0, 2955.6, 1622.0, 1557.9, 1511.0, 1455.6, 1239.4,
1177.3, 1034.8, 822.2, 756.0, 696.7, 668.0 cm21; MS (m/z,
relative intensity) 295 (16), 264 (12), 212 (72), 55 (100);
HRMS calcd for C19H21NO2 295.1572, found 295.1562.
2-{[4-Chlorophenyl)amino]methyl}cyclopentan-1-one 4D
(Table 2, Entry 4, product of D). Yield 60%; yellowish
1
wet-solid; Rf 0.35 (hexane/ethyl acetateˆ4:1); H NMR
(CDCl3): d 7.12±7.06 (m, 2H), 6.59±6.51 (m, 2H), 3.27
(dd, Jˆ7.0, 13.0 Hz, 1H), 3.20 (dd, Jˆ6.3, 13.0 Hz, 1H),
2.44±1.58 (m, 7H); 13C NMR (CDCl3): d 220.71, 146.52,
128.95, 122.05, 114.10, 47.98, 43.99, 38.29, 27.99, 20.66;
FTIR (thin ®lm) 1726.0 cm21; MS (m/z, relative intensity)
223 (78), 140 (96), 126 (88), 111 (58); HRMS calcd for
C12H1435ClNO 223.0764, found 223.0764.
2-{[(4-Chlorophenyl)amino]phenylmethyl}cyclopentan-
1-one 5D (Table 2, Entry 5, product of D). Yield 17% (syn/
antiˆ74:26); yellowish oil; Rf 0.41 (hexane/ethyl
2-{[(4-Methoxyphenyl)amino]-2-pyridylmethyl}cyclo-
pentan-1-one 9D (Table 2, Entry 9, product of D). Yield
20% (syn/antiˆ76:24); yellowish oil; Rf 0.33 (minor), 0.23
(major) (hexane/ethyl acetateˆ2:1); 1H NMR (CDCl3):
major d 8.54±8.52 (m, 1H), 7.60±6.62 (m, 7H), 4.91 (d,
Jˆ4.0 Hz, 1H), 3.69 (s, 3H), 2.68±2.63 (m, 1H), 2.32±
1.65 (m, 6H); minor d 8.57±8.55 (m, 1H), 7.60±6.62 (m,
7H), 4.87 (d, Jˆ5.7 Hz, 1H), 3.71 (s, 3H), 2.85±1.62 (m,
7H); 13C NMR (CDCl3): major d 220.01, 160.72, 152.45,
148.77, 147.16, 141.28, 136.50, 122.09, 121.93, 115.98,
114.59, 60.17, 55.55, 53.46, 39.17, 25.01, 20.70; minor d
220.19, 159.97, 153.00, 149.90, 148.65, 140.81, 136.61,
122.69, 122.25, 115.27, 114.75, 59.12, 55.60, 52.70,
39.03, 25.16, 20.40; FTIR (thin ®lm) 3442.2, 1633.2,
1507.2, 1244.5, 1178.6, 1037.6, 668.1 cm21; MS (m/z, rela-
tive intensity) 296 (5), 265 (7), 213 (22), 83 (25), 55 (58);
HRMS calcd for C18H20N2O2 296.1525, found 296.1514.
1
acetateˆ4:1); H NMR (CDCl3): mixture d 7.55±6.43 (m,
9H), 4.67 (d, Jˆ4.4 Hz, 1H£0.74), 4.45 (d, Jˆ7.7 Hz,
1H£0.26), 2.73±1.61 (m, 7H); 13C NMR (CDCl3): major
d 220.59, 145.21, 140.16, 128.79, 128.50, 127.35, 127.42,
121.92, 114.64, 57.84, 52.95, 39.68, 25.80, 20.53; minor d
219.28, 145.97, 141.19, 128.68, 128.63, 127.50, 126.96,
122.42, 115.22, 59.24, 53.79, 39.13, 26.77, 20.33; FTIR
(thin ®lm) 1731.8 cm21; MS (m/z, relative intensity) 299
(35), 216 (74), 215 (84), 173 (40), 172 (68), 84 (58), 83
(51), 55 (100); HRMS calcd for C18H1835ClNO 299.1077,
found 299.1054.
2-{[(4-Chlorophenyl)amino]-2-pyridylmethyl}cyclopentan-
1-one 6D (Table 2, Entry 6, product of D). Yield 35% (syn/
antiˆ64:36); yellowish wet-solid; Rf 0.38 (minor), 0.28

T.-P. Loh et al. / Tetrahedron 56 (2000) 3227±3237
3237
13. (a) Loh, T.-P.; Pei, J.; Cao, G.-Q. J. Chem. Soc., Chem.
Commun. 1996, 1819. (b) Loh, T.-P.; Pei, J.; Koh, S.-V. K.; Cao,
G.-Q.; Li, X.-R. Tetrahedron Lett. 1997, 38, 3465; Corrigendum,
Tetrahedron Lett. 1997, 38, 3993±3994. (c) Loh, T.-P.; Wei, L.-L.
Synlett 1998, 4, 975±976. (d) Loh, T.-P.; Wei, L.-L. Tetrahedron,
1998, 26, 7615±7624.
References
1. A preliminary study of this work has been published: Loh, T.-P.;
Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
2. For comprehensive reviews: (a) Risch, N.; Arend, M.;
Westermann, B. Angew. Chem., Int. Ed. Engl. 1998, 37, 1044
and references cited therein. (b) Tramontini, M.; Angiolini, L.
Mannich-Bases, Chemistry and Uses; CRC: Boca Raton, FL,
1994 and reference cited therein. (c) Volkmann, R. A. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, p 355 and references cited
therein.
14. Loh, T.-P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315.
15. (a) Gennari, C.; Venturini, I.; Gislon, F.; Schimperna, G.
Tetrahedron Lett. 1987, 28, 227. (b) Guanti, G.; Narisano, E.;
Ban®, L. Tetrahedron Lett. 1987, 28, 4331. (c) Evans, D. A.;
Nelson, J. V.; Taber T. R. Top. Stereochem. 1982, 13, 1.
16. Heathcock, C. H. In Asymmetric Synthesis, Morrison, J. D.,
Ed.; Academic Press: Orlando, 1984; Vol. 3 (Chapter 2).
17. Manabe, K.; Mori, Y.; Kobayashi, S. Synlett 1999, 1401.
18. Yamaguchi, M. In Comprehensive Organic Synthesis, Trost,
B. M., Ed.; Pergamon: New York, 1991; Vol. 1 (Chapter 1.11).
19. (a) Takahikn Akiyama; Jun Takaya; Hirotaka Kagoshima.
Synlett 1999, 1045±1048. (b) Takahikn Akiyama; Jun Takaya;
Hirotaka Kagoshima. Synlett. 1999, 1426±1428. (c) Pilli, R. A.;
Russowsky, D. J. Chem. Soc., Chem. Commun. 1987, 1053.
(d) Kobayashi, S.; Haruro Ishitani. J. Chem. Soc., Chem. Commun.
1995, 1379.
3. See examples: (a) Danishefsky, S. J.; Chackalamannil, S.;
Harrison, P.; Silvestri, M.; Cole, P. J. Am. Chem. Soc. 1985, 107,
2474. (b) Morin, R. B. In Chemistry and Biology of b-Lactam
Antibiotics; Gorman, M., Ed.; Academic Press: New York, 1982.
4. (a) Ojima, I.; Inaba, S.; Yoshida, K. Tetrahedron Lett. 1977, 18,
3643. (b) Ojima, I.; Inaba, S.; Yoshida, K. Tetrahedron Lett. 1980,
21, 2077±2081. (c) Gennari, C.; Venturini, I.; Gislon, G.;
Schimperna, G. Tetrahedron Lett. 1987, 28, 227. (d) Dubois,
J.-E.; Zxiotis, G. Tetrahedron Lett. 1984, 25, 2143. (e) Cainelli,
G.; Contento, M.; Drusiani, A.; Panunzio, M.; Plessi, L. J. Chem.
Soc., Chem. Commun. 1985, 240.
20. We conducted an experiment to verify that the Mannich-type
reactions are truly catalysed by InCl3 and not through the acidic
hydrates of the indium halide complexes that are generated in
aqueous solutions. The fact that the Mannich-type reaction can
also be carried out under solvent-free conditions as well as in
non-protic solvents (Table 1) has af®rmed our observations in
5. Guanti, G.; Narisano, E.; Ban®, L. Tetrahedron Lett. 1987, 28,
4331.
6. Mukaiyama, T.; Kashiwagi, K.; Matsui, S. Chem. Lett. 1989,
1397.
7. Mukaiyama, T.; Akamatsu, H.; Han, J. -S. Chem. Lett. 1990,
889.
this article.
A brief experimental procedure is described:
8. Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett 1993,
141.
2-PyCHO (54 mg, 48 mL, 0.5 mmol, 99%) was stirred with InCl3
(22.6 mg, 0.1 mmol, 98%) at room temperature for 10 min before
PhNH2 (55.9 mg, 0.6 mmol) was added. Stirring continued for
30 min before 1-phenyl-1-trimethylsiloxyethylene B was added.
The reaction mixture was stirred for 1 day and H2O was added to
quench the reaction. Extraction was carried out using ethyl acetate
(refer to Experimental). The desired product was obtained in 95%
yield after puri®cation by silica gel chromatography.
9. Ishihra, O.; Funahashi, M.; Hanaki, N.; Miyata, M.; Yamamoto,
H. Synlett 1994, 963.
10. Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995,
36, 5773±5776.
11. Cozzi, P. G.; Simone, B. D.; Umani-Ronchi, A. Tetrahedron
Lett. 1996, 37, 1691±1694.
12. See review: Li, C.-J. Chem. Rev. 1993, 93 2023.