Bismuth(III) chloride-catalyzed one-pot Mannich reaction: three-component synthesis of β-amino carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.09.131

A simple and efficient method has been developed for the one-pot Mannich reaction of β-amino carbonyl compounds from aromatic aldehydes, aromatic ketones and aromatic amines in the presence of a catalytic amount of bismuth trichloride.

Full text of DOI:10.1016/j.tetlet.2009.09.131

Tetrahedron Letters 50 (2009) 6858–6860
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bismuth(III) chloride-catalyzed one-pot Mannich reaction: three-component
synthesis of b-amino carbonyl compounds
*
Hua Li, Hong-yao Zeng, Hua-wu Shao
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2009
Revised 18 September 2009
Accepted 22 September 2009
Available online 25 September 2009
A simple and efficient method has been developed for the one-pot Mannich reaction of b-amino carbonyl
compounds from aromatic aldehydes, aromatic ketones and aromatic amines in the presence of a cata-
lytic amount of bismuth trichloride.
Ó 2009 Elsevier Ltd. All rights reserved.
The Mannich reaction is one of the most important carbon–car-
bon bond forming reactions in organic synthesis1 because it affords
synthetically and biologically important b-amino carbonyl com-
pounds which are important intermediates for the construction of
various nitrogen-containing natural products and pharmaceuti-
cals.2 Due to the drastic reaction conditions, severe side-reactions,
substrate limitations and the long reaction time, the classical
intermolecular Mannich reaction is plagued.3 To overcome the
drawbacks of the classic method, the Lewis acid-catalyzed conden-
sation between silyl enol ethers or silyl ketene acetals and pre-
formed imines has been developed.4 Recently, some Bronsted acid
or Lewis aicd-catalyzed one-pot Mannich reactions of unmodified
aldehydes, ketones and amines have been catalyzed by HCl,5 pro-
line,6 p-dodecyl benzene sulfonic acid (DBSA),7 polymer-support
sulfonic acid (PS-SO3H),8 Lewis acids9 as well as Silica-AlCl3.10 How-
ever, the long reaction time, costly catalysts and requirement of spe-
cial effort for catalyst preparation cannot be avoided. Therefore, it
has attracted continuous interest to develop methods for the syn-
thesis of b-amino carbonyl compounds.
sive. In this Letter, we report a rapid and efficient method for
one-pot Mannich reaction of aldehydes, ketones and amines in
the presence of BiCl3 (Scheme 1).
Initially, we screened different common Lewis acids for their
ability to catalyze the three-component Mannich reaction and ace-
tophenone, benzaldehyde and aniline were selected as models. As
shown in Table 1, the common Lewis acids such as ZnCl2, ZnSO4,
CuCl2, LaCl3 and FeCl3 did not furnish the desired product (Table 1,
entries 2–6). InCl3 and p-TsOH afforded the desired product but only
in moderate yield (Table 1, entries 7 and 8). However, BiCl3 could
efficiently catalyze the Mannich reaction to afford the desired prod-
ucts in high yields in relatively short time (Table 1, entries 10–14).
Next, the amount of the catalyst was examined: we found that
5 mol % BiCl3 was sufficient to drive the reaction completely in
95% yield. The less amount gave a low yield even after a prolonged
reaction time, and the more amount could not cause the obvious in-
crease for the yield of product but could shorten the reaction time.
In addition, Mannich reaction was very sensitive to the reaction
temperature: the high temperature could improve the reaction
rate and shorten the reaction time but favour side reactions and
the oxygenolysis of aldehyde and amine. It was found that the
room temperature was an appropriate condition for BiCl3-cata-
lyzed one-pot three-component Mannich reaction.
In recent years, bismuth chloride (BiCl3) has attracted much
attention because of its diverse applicability as catalysts in organic
synthesis.11 Compared with transition-metal complexes, bis-
muth(III) salts are stable in air, relatively nontoxic and inexpen-
R3
NH2
R3
O
O
HN
CHO
R2
BiCl3, 5 mol%
EtOH, r.t.
CH3
+
+
R2
R1
R1
Scheme 1.
* Corresponding author.
E-mail address: annalee@yeah.net (H. Shao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.131

H. Li et al. / Tetrahedron Letters 50 (2009) 6858–6860
6859
Table 1
perature (Scheme 2). The results of this study are summarized in
Table 2.
Conditions optimization of the direct Mannich reaction under different conditionsa
Yieldb (%)
In general, the three-component Mannich reaction proceeded
smoothly to give the corresponding products in high yields. Vari-
ous aldehydes bearing different substitutes, such as para-Me,
MeO, OH, Me2N, Cl and NO2 on the aryl rings were all suitable to
the reaction. Aromatic ketones bearing para-Me, NO2 and Cl gave
high yields too. In addition, aromatic amines bearing para-Me,
MeO, NO2, F, Cl, Br, COOH, NO2, and meta-Me, Br on the aryl rings
were also favourable to the reaction. It is worth noting that 4-nitro-
benzaldehyde or 4-nitro acetophenone catalyzed by HCl failed to
give the desired Mannich base5 whereas aromatic ketone and aro-
matic amine bearing electron-withdrawing substituents such as
NO2 could give the desired adducts in good yields (Table 2, entries
15 and 18). Although meta- and para-substituted aromatic amines
both bearing electron-withdrawing substituents and electron-
donating substituents gave good results, ortho-substituted aro-
matic amines such as ortho-nitroaniline and ortho-anisidine (Table
2, entries 25 and 26) failed to yield any products because of large
steric hindered effect.9,10
In conclusion, we have demonstrated a very simple, efficient
and practical method for the one-pot Mannich reaction of b-amino
carbonyl compounds from aldehydes, ketones and amines in the
presence of catalytic amount of bismuth(III) chloride. The major
advantage of this method is that it is truly a one-pot procedure
which does not require a separate step to prepare an imine for sub-
sequent use. The significant features of the protocol include oper-
ational simplicity, inexpensive reagents, mild condition and high
yields of the products.
Entry
Catalyst (mol %)
Solvent
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
No cat. (—)
ZnCl2 (10)
ZnSO4 (10)
CuCl2 (10)
LaCl3 (10)
FeCl3 (10)
InCl3 (10)
p-TsOH (10)
I2 (10)
BiCl3 (2)
BiCl3 (4)
BiCl3 (5)
BiCl3 (8)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
48
20
20
20
20
20
20
20
20
11
11
11
11
11
11
11
11
11
11
NRc
NR
NR
NR
NR
NR
56
75
80
75
84
95
88
79
81
62
66
63
84
BiCl3 (10)
BiCl3 (5)
BiCl3 (5)
BiCl3 (5)
BiCl3 (5)
DMF
CH3CN
DCM
H2O
BiCl3 (5)
a
Reaction conditions: acetophenone (2.2 mmol), benzaldehyde (2 mmol), aniline
(2 mmol), rt.
b
Isolated yield.
No reaction.
c
To explore the scope and generality of the present method, dif-
ferent aromatic ketones, aromatic aldehydes and aromatic amines
were selected to undergo one-pot Mannich reaction in the pres-
ence of catalytic amount (5 mol %) of BiCl3 in ethanol at room tem-
Table 2
BiCl3-catalyzed direct Mannich reaction of various acetophenone, aldehydes and aminesa
R3
NH2
O
O
HN
CHO
BiCl3, 5 mol%
EtOH, r.t.
CH3
+
+
R2
R1
R1
R3
R2
4
2
3
1
Scheme 2
Entry
R1
R2
R3
Productb
Time (h)
Yieldc (%)
Mp (°C(lit))
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CH3
3-CH3
4-OCH3
4-F
4-Cl
3-Br
4-NO2
4-COOH
H
H
H
H
H
H
H
H
H
3-Br
4-Cl
4-Br
4-Cl
4-Cl
3-Br
2-NO2
2-OCH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
11
12
12
14
13
9
10
10
11
12
4
95
93
91
89
95
92
90
88
86
90
95
87
91
87
91
93
88
87
86
85
92
90
84
89
—
169–170
167–168
131–132
166–167
162–163
170–171
128–129
185–1869b
161–162
129–130
220–221
142–143
202–203
114–115
105–1069a
139–1409b
119–1209b
114–1169b
126–12710
158–160
147–1495b
136–137
146–147
74–75
H
4-CH3
4-OH
4-OCH3
4-N(CH3)2
4-Cl
4-NO2
H
16
4
12
20
10
19
20
16
13
11
11
11
11
24
24
4-CH3
4-Cl
4-NO2
H
H
H
4-Cl
4-OCH3
H
4-OCH3
4-CH3
4-Cl
H
4s
4t
H
4-CH3
4-CH3
4-Cl
4-CH3
H
4u
4v
4w
4x
4y
4z
—
—
H
H
—
a
b
c
Reaction conditions: acetophenone (2.2 mmol), benzaldehyde (2 mmol), aniline (2 mmol), ethanol (3 mL), BiCl3 (5 mol %) at rt.
Products are characterized by melting point, IR, 1H NMR and comparison with literature.
Isolated yield.

6860
H. Li et al. / Tetrahedron Letters 50 (2009) 6858–6860
Angew. Chem., Int. Ed. 2003, 42, 975–978; (d) Hayashi, Y.; Tsuboi, W.; Ashimine,
Typical procedure for the synthesis of 4. To a mixture of aro-
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(e) Kantam, M. L.; Rajasekhar, C. V.; Gopikrishna, G.; Reddy, K. R.; Choudary, B.
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matic ketones (2.2 mmol), aromatic aldehydes (2.0 mmol) and aro-
matic amines (2.0 mmol) in anhydrous ethanol (3 mL) was added
BiCl3 (5 mol %). The mixture was stirred at room temperature for
the specified time (Table 2) indicated by TLC. After the reaction
was completed, saturated NaHCO3 solution (10 mL) was added,
and the precipitated solid was collected by filtration, washed with
ethanol. The crude product was purified by recrystallization from
acetone/ethanol (2:3) to afford the pure products 4a–x.12–14
7. (a) Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001, 57, 2537–2544; (b)
Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965–1967.
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Acknowledgements
11. For comprehensive reviews: (a) Postel, M.; Dunach, E. Coord. Chem. Rev. 1996,
155, 127–144; (b) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002,
58, 8373–8397; (c) Vidal, S. Synlett 2001, 1194–1195; (d) Hua, R. M. Curr. Org.
Synth. 2008, 5, 1–27.
12. Compound 4e: 3-[(4-fluorophenyl)amino]-1,3-diphenylpropan-1-one: white
solid; mp 162–163 °C; 1H NMR (600 MHz, CDCl3): d = 3.42 (dd, J = 7.6 Hz,
J = 16.3 Hz, 1H), 3.49 (dd, J = 4.9 Hz, J = 16.3 Hz, 1H), 4.91 (dd, J = 7.6 Hz,
J = 4.9 Hz, 1H), 6.49–6.52 (m, 2H), 6.78 (t, J = 8.7 Hz, 2H), 7.24 (t, J = 7.4 Hz, 2H),
7.32 (t, J = 7.6 Hz, 2H), 7.41 (m, J = 8.0 Hz, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.91 (d,
J = 7.4 Hz, 2H). 13C NMR (150 MHz, CDCl3): d = 46.3, 55.7, 115.2, 115.5, 115.6,
126.4, 127.5, 128.2, 128.7, 128.9, 133.5, 136.7, 142.6, 143.1, 198.2. IR (KBr)
We acknowledge the financial support from Chengdu Institute
of Biology, Chinese Academy of Sciences. We are also grateful to
the Analytical and Testing Center of Chengdu Institute of Biology
for supports in NMR and MS analyses.
References and notes
1. (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102–112; (b) Kobayashi, S.; Ishitani, H.
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Angew. Chem., Int. Ed. 1998, 37, 1044–1070; (d) Mannich, C.; Krosche, W. Arch.
Pharm. 1912, 250, 674.
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184–187; (b) Bohme, H.; Haake, M.. In Taylor, E. C., Ed.; Advances in Organic
Chemistry; John Wiley and Sons: New York, 1976; p 107.
3. For comprehensive reviews: (a) Tramontini, M.; Angiolini, L. Mannich-Bases
Chemistry and Uses; CRC: Boca Raton, FL, 1994. and references cited therein; (b)
Volkmann, R. A.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 1, p 355. and references cited therein.
4. (a) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124,
5640–5641; (b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002,
4, 143–145; (c) Periasamy, M.; Suresh, S.; Ganesan, S. S. Tetrahedron Lett.
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m
= 3386, 1671, 1595, 1511, 1449, 1289, 1220, 815, 701, 684. ESI HRMS exact
mass calcd for (C21H18F1N1O1þNa)+ requires m/z 342.1265; found: 342.1268.
13. Compound 4v: 3-(4-chlorophenylamino)-3-(4-methoxyphenyl)-1-p-tolylpro-
pan-1-one: white solid; mp 136–137 °C; 1H NMR (600 MHz, CDCl3): d = 2.39
(s, 3H), 3.34 (dd, J = 7.6 Hz, J = 16.1 Hz, 1H), 3.43 (dd, J = 5.0 Hz, J = 16.1 Hz, 1H),
3.77 (s, 3H), 4.63 (br s, 1H), 4.87 (dd, J = 5.1 Hz, J = 7.6 Hz, 1H), 6.46 (d, J = 8.7 Hz,
2H), 6.84 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.32 (d,
J = 8.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H); 13C NMR (150 MHz, CDCl3): d = 21.6, 46.1,
54.5, 55.2, 114.3, 115.0, 122.4, 127.4, 128.3, 128.8, 129.4, 134.3, 134.5, 144.4,
145.6, 158.9, 197.9; IR (KBr) m = 3381, 1665, 1603, 1513, 1463, 1370, 1289, 1255,
1175, 1032, 808, 734. ESI HRMS exact mass calcd for (C21H18F1N1O1þNa)+
requires m/z 402.1231; found: 402.1229.
14. Compound 4w: 1-(4-chlorophenyl)-3-(4-chlorophenylamino)-3-p-tolylpropan-
1-one: yellowish solid; mp 146–147 °C; 1H NMR (600 MHz, CDCl3): d = 2.18 (s,
3H), 3.37 (dd, J = 7.3 Hz, J = 16.4 Hz, 1H), 3.41 (dd, J = 5.4 Hz, J = 16.4 Hz, 1H),
4.46 (br s, 1H), 4.93 (t, J = 6.4 Hz, 1H), 6.45 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.0 Hz,
2H), 7.26 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H),
7.81(d, J = 8.3 Hz, 2H); 13C NMR (150 MHz, CDCl3): d = 20.3, 46.0, 54.4, 114.1,
127.5, 127.8, 128.9, 129.1, 129.5, 129.7, 133.0, 134.9, 140.1, 141.5, 144.2,
5. (a) Xu, X. J.; Chen, G. X. Acta Chem. Sinica 1982, 40, 463–468. in Chinese; (b) Yi,
L.; Lei, H. S.; Zou, J. H.; Xu, X. J. Synthesis 1991, 9, 717–718; (c) Yang, D. C.;
Zhang, G. L.; Yang, Y.; Zhong, Y. G. Chem. J. Chinese U (in Chinese) 2000, 21,
1694–1696.
6. (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827–833; (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337; (c) Duthaler, R. O.
196.7; IR (KBr)
m = 3408, 1671, 1617, 1587, 1568, 1520, 1488, 1402, 1365, 1285,
1218, 1093, 991, 825, 804, 722. ESI HRMS exact mass calcd for
(C21H18F1N1O1þNa)+ requires m/z 406.0736; found: 406.0728.