An unusual Mannich type reaction of tertiary aromatic amines in aqueous micelles

Article abstract of DOI:10.1016/j.tetlet.2008.07.019

An efficient, unusual Mannich type reaction of tertiary aromatic amines, formaldehyde and 1,3-dicarbonyl compounds is described in aqueous micelles catalyzed by boric acid to afford dialkylaminoarylated 1,3-dicarbonyls. In this unusual Mannich type reacti

Full text of DOI:10.1016/j.tetlet.2008.07.019

Tetrahedron Letters 49 (2008) 5471–5474
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An unusual Mannich type reaction of tertiary aromatic amines
in aqueous micelles q
*
Atul Kumar , Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, unusual Mannich type reaction of tertiary aromatic amines, formaldehyde and 1,3-dicar-
bonyl compounds is described in aqueous micelles catalyzed by boric acid to afford dialkylaminoarylated
1,3-dicarbonyls. In this unusual Mannich type reaction, tertiary aromatic amines react with formalde-
hyde to generate an N-alkyl-N-(4-methylenecyclohexa-2,5-dienylidene)alkylaminium intermediate
(aza quinone methide), which undergoes nucleophilic addition with 1,3-dicarbonyl compounds. The
reaction is highly regioselective, and exclusively para functionalized products are formed in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 April 2008
Revised 26 June 2008
Accepted 3 July 2008
Available online 6 July 2008
Keywords:
Unusual Mannich type reaction
Aza quinone methide
Boric acid
Aqueous micelles
Tertiary aromatic amines
1,3-Dicarbonyl compounds
The Mannich reaction is a powerful synthetic method for the
preparation of b-amino carbonyl compounds, an important class
of building blocks of pharmaceutically relevant compounds.1 Due
to its atom-economy, the Mannich reaction has received increasing
attention, and is applied widely as a key step in the synthesis of
numerous pharmaceuticals and natural products.2 Mannich reac-
tions are very useful for generation of diversity in order to optimize
lead compounds.
The Mannich reaction proceeds with initial formation of an
iminium salt (intermediate 3) via reaction of amine 1 and aldehyde
2 (Scheme 1). The intermediate 3 then reacts with various nucleo-
philes to give products 4, which are known as ‘Mannich bases’.
Under typical Mannich reaction conditions, simple tertiary amines
cannot be employed because the iminium salt 3 cannot be gener-
ated from the aldehyde during the first step of the Mannich
reaction.
Nu
R
R
R
Nu
N
N
NH
+
CH2O
Nu
R
R1
R1
R1
Nu
N
4
1
2
3
R1
The Mannich reaction
7
(Major)
R
R
R1
N
R1
N
+
N
CH2O
R1
R1
N
5
2
R
6
R
5
(aza quinone methide)
9 (Minor)
Scheme 1. Unusual Mannich type reaction.
q
CDRI Com. No. 7372.
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405/2623938.
E-mail address: dratulsax@gmail.com (A. Kumar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.019

5472
A. Kumar, R. A. Maurya / Tetrahedron Letters 49 (2008) 5471–5474
However, in the present unusual Mannich type reaction, an
acid (PTSA) or methane sulfonic acid (MSA), led to simplified reac-
tion (TLC), and two major products (7a and 9a) were isolated in
varying ratios. Boric acid was found to be better than other acidic
catalysts. Using 20 mol % of boric acid as catalyst, 7a was obtained
with high selectivity. Decreasing the amount of catalyst resulted in
a poor yield of 7a and also poor selectivity of 7a over 9a. The
results of this study are shown in Table 1.
intermediate (N-alkyl-N-(4-methylenecyclohexa-2,5-dienylidene)
alkylaminium 6, as equivalent iminium salt of 3, is suggested to
form on reaction of tertiary aromatic amines (N,N-dimethylaniline)
with a non-enolizable aldehyde such as formaldehyde.3,4 This
intermediate 6 can be attacked by a number of nucleophiles to
generate Mannich type products.
We report here a facile and regioselective unusual Mannich
type coupling reaction of tertiary aromatic amines, formaldehyde
and 1,3-diketones in the presence of boric acid in aqueous micelles
via aza quinone methide intermediate 6.
We also studied the effect of solvent on the boric acid catalyzed
coupling reaction of ethyl acetoacetate, formaldehyde and N,N-
dimethylaniline. In less polar solvents such as dichloromethane
and tetrahydrofuran, poor yields of 7a were obtained with signifi-
cant formation of 9a. However, in more polar solvents such as
methanol and ethanol, 7a was obtained with better selectivity. In
neat water, the reaction gave a poor yield of 7a but in aqueous
micelles of sodium dodecyl sulfate SDS, product 7a was formed
in high selectivity. The role of SDS appears to form aqueous
micelles, which increases the solubility of reactants and thus
minimizes the formation of side products. The results of this study
are shown in Table 2.
We studied the scope of the boric acid catalyzed unusual Man-
nich type reaction in aqueous micelles (Scheme 3). A number of
tertiary aromatic amines reacted smoothly to yield condensed
products 7a–n.12,13
We carried out the reaction with cyclic and acyclic 1,3-dicar-
bonyl compounds. Reactions with acyclic 1,3-dicarbonyl com-
pounds resulted in the formation of dimer 9a in minor amounts,
however, with cyclic 1,3- dicarbonyls 7a was obtained exclusively.
In all cases the reaction was carried out with 20 mol % boric acid in
aqueous SDS (0.1 g/ml). The results of this study are shown in
Table 3.
Boric acid is a useful catalyst for a number of synthetic transfor-
mations, for example, the aza Michael addition in water,5 the thia
Michael addition in water,6 Biginelli reaction,7 transesterification
of ethyl acetoacetate8 and decarboxylation of cyclic b-enamino-
ketoesters.9 It offers milder conditions relative to common mineral
acids. The selection of boric acid as catalyst was made because of
one of its most fundamental properties, namely it produces a
Brønsted acid ½BðOHÞ þ H2O ¼ Hþ þ BðOHÞ4ꢀꢁ on reaction with
3
water. The use of water as a reaction medium in organic synthesis
has received much attention.10 Water as a reaction medium con-
veys many important advantages; it is cheap, safe and environ-
mentally benign. Moreover, the application of water as a solvent
has led to observed differences in both reactivity and selectivity
to those found in common organic solvents.11 Thus, boric acid in
water is expected to be a useful reagent for Mannich type addi-
tions. As a part of our continued efforts towards the development
of environmentally friendly synthetic procedures for multi-compo-
nent reactions, we report here a boric acid catalyzed unusual Man-
nich type coupling reaction in aqueous micelles.
Initial experiments focused on finding an efficient catalyst for
coupling N,N-dimethylaniline, formaldehyde and ethyl acetoace-
tate (Scheme 2).
When no catalyst was used, the reaction yielded a complex mix-
ture. Using acidic catalyst such as CF3COOH, para toluene sulfonic
In conclusion, we have developed a boric acid catalyzed unusual
Mannich type reaction of tertiary aromatic amines, formaldehyde
and 1,3-dicarbonyl compounds in aqueous micelles with high
regioselectivity. The reaction conditions are mild, and good to
excellent yields of products are obtained in short reaction times.
Further development of this unusual Mannich type reaction and
its application to the synthesis of bioactive compounds are in
progress.
O
O
Catalyst
N
+
CH2O
+
SDS, Water
OEt
Table 2
Solvent effect on the coupling of ethyl acetoacetate, formaldehyde and N,N-
8a
dimethylanilinea
5a
Entry
Solvent
Yield 7ab (%)
Yield 9ab (%)
N
O
OEt
N
N
1
2
3
4
5
CH2Cl2
THF
MeOH
EtOH
25
30
70
73
84
54
38
22
19
<5
+
O
SDS–water (0.1 g/ml)
7a
9a
a
Reaction conditions: ethyl acetoacetate (1 mmol), formaldehyde (1 mmol), N,N-
Scheme 2.
dimethylaniline (1 mmol), boric acid (20 mol %), reflux, 0.5 h.
b
Isolated yield.
Table 1
Screening of catalysts for coupling of ethyl acetoacetate, formaldehyde and N,N-
dimethylanilinea
R1
R
R1
R
N
O
Boric acid
N
CH2O
+
Entry
Catalyst
Catalyst (mol %)
Yield 7ab (%)
Yield 9ab (%)
O
SDS, Water
1
2
3
4
5
6
None
CF3COOH
PTSA
MSA
H3BO3
H3BO3
—
<10
50
59
53
85
70
80
40
41
35
<5
25
20
20
20
20
10
Reflux
0.5 h
O
O
5a-d
8a-e
7a-n
a
Reaction conditions: ethyl acetoacetate (1 mmol), formaldehyde (1 mmol), N,N-
dimethylaniline (1 mmol), SDS–water (1 ml, concn = 0.1 g/ml), 90 °C, 0.5 h.
b
Isolated yield.
Scheme 3.

A. Kumar, R. A. Maurya / Tetrahedron Letters 49 (2008) 5471–5474
5473
Table 3
Boric acid catalyzed three-component coupling of tertiary aromatic amines, formaldehyde and 1,3-dicarbonyl compounds in aqueous micellesa
Entry
Aromatic amine
1,3-Dicarbonyl compound
Product
Time (min)
Yieldb (%)
N
O
O
O
O
O
N
1
5a
8a
8b
8c
8d
8e
8a
8d
8c
8d
7a
40
84
OEt
Ph
O
EtO
Ph
N
O
N
2
3
4
5
6
7
8
9
5a
7b
30
30
30
40
40
30
30
30
84
86
82
84
81
84
85
78
O
O
N
O
N
O
N
N
5a
7c
N
O
N
O
O
O
N
O
O
N
5a
7d
O
O
O
O
O
N
N
5a
7e
N
N
N
O
O
O
N
N
N
5b
5b
5b
5c
7f
OEt
O
EtO
O
O
O
7g
7h
O
O
O
O
N
O
N
N
N
O
O
O
N
O
O
N
7i
O
O
O
O
N
N
N
O
N
N
N
10
11
5c
5c
8c
7j
30
30
84
79
N
O
O
N
O
O
O
O
8b
7k
Ph
Ph
(continued on next page)

5474
A. Kumar, R. A. Maurya / Tetrahedron Letters 49 (2008) 5471–5474
Table 3 (continued)
Entry
Aromatic amine
1,3-Dicarbonyl compound
Product
Time (min)
Yieldb (%)
O
N
O
N
12
13
5d
8e
7l
30
82
O
O
O
N
O
N
5d
8d
7m
30
30
85
81
O
O
O
N
O
N
N
O
N
14
5d
8c
7n
N
O
N
O
O
a
Reaction conditions: 1,3-diketone (1 mmol), formaldehyde (1 mmol), tertiary aromatic amine (1 mmol), boric acid (20 mol %), SDS–water (1.5 ml, c = 0.1 g/ml), reflux.
Isolated yield.
b
(CDCl3, 50 MHz) d 14.0, 29.6, 33.2, 40.6, 61.2, 61.6, 112.8, 125.7, 129.3, 149.4,
Acknowledgements
169.3, 203.0. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.30; H, 7.92; N, 5.20. 2-(4-(dimethylamino)benzyl)-1-phenylbutane-1,3-dione
7b: ESI-MAS (m/z) = 296 (M+H)+. IR (KBr, cmꢀ1): 3064, 2925, 1720, 1677, 1597,
1523, 1447, 1358, 1228, 756, 694. 1H NMR (CDCl3, 200 MHz): d 2.12 (s, 3H),
2.87 (s, 6H), 3.20 (m, 2H), 4.77 (t, J = 7.1 Hz, 1H), 6.60 (d, J = 8.7 Hz, 2H), 7.04 (d,
J = 8.7 Hz, 2H), 7.42–7.55 (m, 3H), 7.91–7.95 (m, 2H). 13C NMR (CDCl3, 50 MHz)
d 29.0, 34.4, 41.1, 65.7, 113.3, 126.5, 128.6, 129.1, 129.8, 130.6, 134.0, 137.0,
149.9, 196.4, 204.1. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.16; H, 7.12; N, 4.60. 5-(4-Dimethylamino-benzyl)-1,3-dimethyl-
pyrimidine-2,4,6-trione 7c: Mp 236 °C. ESI-MAS (m/z) = 290 (M+H)+. IR (KBr,
cmꢀ1): 2928, 2815, 1683, 1613, 1526, 1449, 1381, 1360, 1301, 821, 754. 1H
NMR (CDCl3, 200 MHz): d 2.87 (s, 6H), 3.02 (s, 6H), 3.10 (m, 3H), 6.46 (d,
J = 8.6 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d 28.6, 40.8,
49.6, 56.8, 112.4, 121.0, 130.0, 150.6, 150.7, 172.2. Anal. Calcd for C15H19N3O3,
C, 62.27; H, 6.62; N, 14.52. Found: C, 62.18; H, 6.56; N, 14.46. 2-(4-
Dimethylamino-benzyl)-5,5-dimethyl-cyclohexane-1,3-dione 7d: Mp 155 °C. ESI-
MAS (m/z) = 274 (M+H)+. IR (KBr, cmꢀ1): 2959, 2928, 2874, 2547, 1569, 1522,
1451, 1378, 1252, 1214, 1154, 1042, 946, 802, 599, 487. 1H NMR (CDCl3,
200 MHz): d 1.03 (s, 6H), 2.26 (s, 4H), 2.85 (s, 6H), 3.15 (s, 2H), 6.59 (d,
J = 8.6 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz): d 26.7, 28.8,
32.3, 41.3, 47.2, 54.5, 113.2, 114.9, 129.4, 130.6, 149.1. Anal. Calcd for
R.A.M. is thankful to CSIR New Delhi for the award of a senior
research fellowship. Authors also acknowledge SAIF-CDRI for
providing analytical and spectral data.
References and notes
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Chen, L. Chem. Soc. Rev. 2006, 35, 68; (e) Lindstrom, U. M., Ed.Organic Reactions
in Water; Blackwell Publishing: Oxford, 2007.
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12. General experimental procedure for the unusual Mannich type reaction: In a 25 ml
round-bottomed flask, N,N-dimethylaniline (0.121 g, 1 mmol), 37% aqueous
formaldehyde (0.081 ml, 1 mmol), ethyl acetoacetate (0.130 g, 1 mmol), boric
acid (0.013 g, 20 mol %) and SDS–water (1.5 ml, c = 0.1 g/ml) were taken. The
reaction mixture was refluxed for half an hour. The reaction was followed by
TLC monitoring. After completion, the reaction mixture was diluted with 25 ml
water and extracted with ethyl acetate (25 ꢂ 2). The organic layer was dried
over sodium sulfate and concentrated to give a crude. The crude was subjected
to column chromatography to yield compound 7a (0.22 g, 84%).
13. Physical data for selected compounds: ethyl 2-(4-(dimethylamino)benzyl)-3-
oxobutanoate 7a: Physical state: oily. ESI-MAS (m/z) = 264 (M+H)+. IR (Neat,
cmꢀ1): 2942, 1722, 1698, 1363. 1H NMR (CDCl3, 200 MHz): d 1.22 (t, J = 7.1 Hz,
3H), 2.17 (s, 3H), 2.89 (s, 6H), 3.05 (d, J = 7.5 Hz, 2H), 3.72 (t, J = 7.5 Hz, 1H),
4.12–4.14 (m, 2H), 6.65 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H). 13C NMR
C
17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.61; H, 8.36; N, 5.02. 2-(4-
Dimethylamino-benzyl)-cyclohexane-1,3-dione 7e: Mp 140 °C. ESI-MAS (m/
z) = 246 (M+H)+. IR (KBr, cmꢀ1): 3440, 3045, 2923, 1590, 1529, 1431, 1370,
1295, 1267, 1172, 998, 803. 1H NMR (CDCl3, 200 MHz):
d 1.85 (quintet,
J = 6.1 Hz, 2H), 2.35 (t, J = 6.1 Hz, 4H), 2.85 (s, 6H), 3.05 (s, 1H), 3.45 (s, 2H), 6.56
(d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz): d 20.0,
26.1, 31.6, 38.4, 46.7, 117.6, 120.9, 134.4, 135.5, 153.9. Anal. Calcd for
C
15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.31; H, 7.69; N, 5.64. 2-(4-
(Diethylamino)benzyl)-5,5-dimethylcyclohexane-1,3-dione 7g: ESI-MAS
(m/z) = 302 (M+H)+. IR (KBr, cmꢀ1): 2966, 2872, 1617, 1570, 1519, 1378, 1308,
1250, 1042. 1H NMR (CDCl3, 200 MHz): d 1.04–1.26 (m, 12H), 2.28 (s, 4H),
3.22–3.33 (m, 4H), 3.43–3.57 (m, 3H), 6.58 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz,
2H). Anal. Calcd for C19H27NO2: C, 75.71; H, 9.03; N, 4.65. Found: C, 75.63; H,
8.94; N, 4.76. 5-(4-Diethylamino-benzyl)-1,3-dimethyl-pyrimidine-2,4,6-trione
7h: Mp 145 °C. ESI-MAS (m/z) = 318 (M+H)+. IR (KBr, cmꢀ1): 2967, 2927,
1680, 1613, 1521, 1442, 13691355, 1267, 196, 1155, 1099, 811. 1H NMR
(CDCl3, 200 MHz): d 1.07 (t, J = 7.0 Hz, 6H), 2.99 (s, 6H), 3.22–3.33 (m, 7H), 6.46
(d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz): d 12.9,
28.4, 44.7, 44.8, 62.2, 112.2, 122.1, 130.5, 147.5, 151.0, 172.0. Anal. Calcd for
C
17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C, 64.22; H, 7.17; N, 13.16. 4,40-
Methylenebis(N,N-dimethylaniline) 9a: ESI-MAS (m/z) = 255 (M+H)+. IR (KBr,
cmꢀ1): 3007, 2888, 2806, 1614, 1521, 1445, 1345, 1230, 1166, 1070, 947, 796.
1H NMR (CDCl3, 200 MHz): d 2.81 (s, 12H), 3.73 (s, 2H), 6.58 (d, J = 8.5 Hz, 4H),
6.96 (d, J = 8.5 Hz, 4H). 13C NMR (CDCl3, 50 MHz): d 40.3, 41.4, 113.5, 129.8,
130.8, 149.5. Anal. Calcd for C17H22N2: C, 80.27; H, 8.72; N, 11.01. Found: C,
80.20; H, 8.66; N, 11.12.