A competent pot and atom-efficient synthesis of Betti bases over nanocrystalline MgO involving a modified Mannich type reaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.075

A simple, efficient, and eco-friendly method for the synthesis of 1-(α-aminoalkyl) naphthols, the Betti bases, has been carried out over a basic nanocrystalline MgO catalyst in aqueous condition. The method has been applied for the synthesis of a range of compounds with variable functionalities in excellent yield and selectivity.

Full text of DOI:10.1016/j.tetlet.2011.07.075

Tetrahedron Letters 52 (2011) 4957–4960
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A competent pot and atom-efficient synthesis of Betti bases over nanocrystalline
MgO involving a modified Mannich type reaction
Bikash Karmakar a, Julie Banerji b,
⇑
a Gobardanga Hindu College, Department of Chemistry, Khantura, North 24 Parganas 743273, India
b Centre of Advanced Studies on Natural Products Including Organic Synthesis, Department of Chemistry, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient, and eco-friendly method for the synthesis of 1-(a-aminoalkyl) naphthols, the Betti
Received 24 June 2011
Revised 13 July 2011
Accepted 17 July 2011
Available online 23 July 2011
bases, has been carried out over a basic nanocrystalline MgO catalyst in aqueous condition. The method
has been applied for the synthesis of a range of compounds with variable functionalities in excellent yield
and selectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent synthesis
Betti base
Nanocrystalline MgO
Heterogeneous
Water chemistry
In recent years multicomponent reactions (MCR) have become a
powerful tool for atom efficient and waste-free synthesis of
complex building blocks of ‘drug-like’ motifs.1 Generally MCR
strategy affords time and cost advantageous, environmentally be-
nign pathways leading to the synthesis of a library of compounds.
In the history of multicomponent one-pot reactions, the Strecker
The classical synthesis of Betti bases generally involves a mod-
ified Mannich pathway by the condensation of 2-naphthol,
aldehydes, and ammonia. However, modifications have been made
to prepare Betti base derivatives by using other naphthols, quili-
nols, and akylamines replacing ammonia.13 Addition of naphthols
to preformed iminium salts has also been carried out.14 However,
these reported methods either take longer reaction time or involve
heating conditions. Moreover the catalysts used in these methods
are not user friendly and non-recoverable. Recently, Kumar et al.
reported an efficient method for the preparation of N,N-dialkyl
derivatives of Betti bases in a surfactant mediated condition in
water.15 However, there are no reports available for the synthesis
of Betti bases over heterogeneous catalysts.
synthesis was the first to be studied leading to
a
-aminonitriles.2
Subsequently, there has been a stupendous development of this
MCR protocol. Mention may be made of the Biginelli,3 Passerini,4
Ugi5 and Mannich6 reactions.
Compounds bearing 1,3 arrangements of amino and oxygenated
functional groups are frequently found in various biologically ac-
tive natural products.7 The importance lies in their capacity to bind
Lewis acidic sites making a stable six membered ring. Another
Nanocrystalline metal oxides find excellent application as active
adsorbent for gases, for destruction of hazardous chemicals,16 and
as catalyst in various organic reactions.17 In continuation of our
efforts for the development of synthetic methodologies for the
important class of such compounds is the 1-(a-aminoalkyl)-2-
naphthols, the ‘so-called’ Betti bases (Fig. 1).8 These compounds
can be transformed into derivatives having antibacterial, hypoten-
sive, and bradycardiac activities.9 The phenolic hydroxyl, and
amino groups can be utilized in developing several synthetic build-
ing blocks.10 Optically active Betti bases can be used as ligands to
chelate with organometallic reagents in different reactions to
provide highly efficient asymmetric induction.11 Reaction of Betti
bases with aldehydes produces 1,3-oxazines, an important biolog-
ically active scaffold.10,12
R
R1
N
R2
OH
⇑
Corresponding author. Tel.: +91 33 2350 8386; fax: +91 33 2351 9755.
E-mail address: juliebanerji47@gmail.com (J. Banerji).
Figure 1. Structure of a general Betti base.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.075

4958
B. Karmakar, J. Banerji / Tetrahedron Letters 52 (2011) 4957–4960
R
N
Ar
R'
OH
OH
O
H
N
nano MgO
water, rt
+
+
R
Ar
H
R'
1
2
3
4a-µ
Scheme 1. Synthesis of Betti bases over nanocrystalline MgO catalyst.
Table 1
Screening of solvents in the synthesis of Betti basesa
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
THF
8
8
8
12
12
2
33
72
65
57
n.r.
88
CH3CN
CH2Cl2
Toluene
Hexane
Water
a
Reactions and conditions: benzaldehyde/pyrrolidine/2-naphthol = 1.2:1.0:1.0, 50 mg catalyst,
room temperature.
b
Isolated yield.
Table 2
Synthesis of Betti bases over nanocrystalline MgO catalysta
Entry
1
Aldehyde
Amine
Product
Time (h)
2
Yieldb (%)
88
CHO
4a
N
H
CHO
2
3
4b
4c
3
90
90
N
H
CHO
O
2.5
N
H
CHO
CHO
CHO
NH2
4
5
6
4d
4e
4f
3.5
3
85
78
81
NH2
NH2
3
CHO
CHO
7
4g
2.5
87
N
H
O2N
8
9
4h
4i
3.5
3
84
88
N
H
Me
Cl
CHO
N
H
CHO
N
H
10
4j
2
92
NO2

B. Karmakar, J. Banerji / Tetrahedron Letters 52 (2011) 4957–4960
4959
Table 2 (continued)
Entry
Aldehyde
Amine
Product
Time (h)
4
Yieldb (%)
CHO
CHO
11
12
4k
86
82
N
H
OMe
N
H
4l
3.5
3
MeO
MeO
OMe
OMe
CHO
N
H
13
14
4m
4n
85
90
MeO
O
CHO
O
2
N
H
CHO
15
16
4o
4p
4r
3
88
89
87
N
H
Cl
CHO
3
N
H
NC
CHO
17
18
2.5
N
H
NO2
CHO
NH2
4s
4
6
<20
n.r
CHO
19
4u
N
H
COOH
a
Reaction and conditions: aldehyde/amine/2-naphthol = 1.2:1.0:1.0, 50 mg MgO, water; rt.
Isolated yield.
b
Bronsted base(surface hydroxyls)
OH
O
O2-
O2-
O2-
O2-
O2-
Lewis acid (Mg2+
)
Lewis base (internal oxide anions)
OH
O
Lewis base (external oxide anions)
Figure 2. Reactive sites of nanocrystalline MgO.
production of various biologically important moieties using meso-
porous heterogeneous catalysts,18 we wish to report for the first
time the use of nanocrystalline MgO catalyzed one-pot three
component synthesis of Betti bases and their derivatives in water
at ambient conditions (Scheme 1).
A very simple protocol was followed in the reaction process.19
A
mixture of pyrrolidine (1.0 mmol), benzaldehyde (1.2 mmol) and
2-naphthol (1.0 mmol) was stirred in water at room temperature
over nanoporous MgO catalyst. The progress was checked by TLC
and after work-up excellent yields of the product were obtained.
No other additive was necessary to promote the reaction.
However, prior to this generalization, feasibility of the reaction
conditions was investigated. Optimization was done with variation
of the reaction medium. The results have been summarized in Table
1. The difference in results indicated the influence of solvent on
reaction mechanism. Different conventional organic solvents like
Figure 3. TEM image of the nano MgO.

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B. Karmakar, J. Banerji / Tetrahedron Letters 52 (2011) 4957–4960
3. Bose, A. K.; Pednekar, S.; Ganguly, S. N.; Chakraborty, G.; Manhas, M. S.
Tetrahedron Lett. 2004, 45, 8351.
4. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842.
5. Kobayashi, K.; Matoba, T.; Irisawa, S.; Matsumoto, T.; Morikawa, O.; Konishi, H.
Chem. Lett. 1998, 551.
6. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6, 75.
7. Knapp, S. Chem. Rev. 1995, 95, 1859.
8. Cardellicchio, C.; Capozzi, M. A. M.; Naso, F. Tetrahedron: Asymmetry 2010, 21,
507.
9. Shen, A. Y.; Tsai, C. T.; Chen, C. L. Eur. J. Med. Chem. 1999, 34, 877.
10. (a) Szatmari, I.; Hetenyi, A.; Lazar, L.; Fulop, F. J. Heterocycl. Chem. 2004, 41, 367;
(b) Heydenreich, M.; Koch, A.; Klod, S.; Szatmari, I.; Fulop, F.; Kleinpeter, E.
Tetrahedron 2006, 62, 11081.
11. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortorella, P. Tetrahedron
1999, 55, 14685.
12. (a) Betti, M. Gazz. Chim. Ital. 1900, 30, 310; (b) Smith, H. E.; Cooper, N. E. J. Org.
Chem. 1970, 35, 2212.
13. (a) Phillips, J. P.; Barrall, E. M. J. Org. Chem. 1956, 21, 692; (b) Phillips, J. P. Chem.
Rev. 1956, 56, 271; (c) Saidi, M. R.; Azizi, N.; Naimi-Jamal, M. R. Tetrahedron
Lett. 2001, 42, 8111; (d) Mukhopadhyay, C.; Rana, S.; Butcher, R. J. ARKIVOC
2010, x, 291.
THF, CH3CN, CH2Cl2, and toluene afforded low to moderate yields
(33–72%). In hexane no reaction was observed. The best result
was achieved in aqueous condition when it furnished the coupled
product in high yield (88%). The reaction failed in the absence of
any catalyst. Notably, there was no need for creating an inert atmo-
sphere and the reactions were done at ambient conditions only.
In order to study the scope and limitations of this procedure, a
series of reactions were carried out with 2-naphthol using variety
of aromatic aldehydes and aliphatic amines. The results have been
shown in Table 2. The reactions worked well with almost all the
aldehydes. However, aromatic aldehydes bearing groups like –
NO2, –CN, –OMe, and –Cl showed better reactivity and the reac-
tions were completed in shorter time. Even the heteroaryl
aldehyde, 2-furfural, afforded the desired product in high yield.
The same course of the reactions continued with the aliphatic
amines which showed excellent reactivity affording very good
yields. Surprisingly, the reaction was not successful with aromatic
amines which might be due to its reduced nucleophilicity. Simi-
larly, proline also failed to produce the corresponding Betti base.
After the reaction the crude reaction mixtures were purified
through column chromatography using neutral alumina and
appropriate mixtures of EtOAc/hexane as eluent. The isolated prod-
ucts were then characterized from 1H NMR, 13C NMR, IR, and
elemental analysis.
Nanocrystalline MgO has a polyhedral crystalline structure
containing a number of anionic oxidic Lewis basic (O2À, OÀ) and
hydroxylic Bronsted basic (OH) sites along with Mg2+ as Lewis acid
site (Fig. 2). Moreover, the high surface concentrations of edge/cor-
ner and various exposed crystal planes (such as 0 0 2, 0 0 1 and
1 1 1), lead to inherently high surface reactivity per unit area. The
crystalline nature of the material is evident from the TEM image
(Fig. 3). Particle size of the nano MgO20 was found to be around
20–22 nm. The enhanced surface area due to small particle size is
an added advantage for its reactivity. All these important factors
are responsible for the high accessibility of the substrate molecules
on the catalyst surface. The reaction involves the initial formation of
imines by condensation of aldehydes and amines and these then
14. Katrizky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Belyakov, S. A.;
Ghiviriga, I.; Steel, P. J. J. Org. Chem. 1999, 64, 6071.
15. Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett. 2010, 51, 1582.
16. (a) Lucas, E.; Decker, S.; Khaleel, A.; Seitz, A.; Fultz, S.; Ponce, A.; Li, W.; Carnes,
C.; Klabunde, K. J. Chem. Eur. J. 2001, 7, 2505; (b) Schlogl, R.; Abd Hamid, S. B.
Angew. Chem., Int. Ed. 2004, 43, 1628; (c) Bell, A. T. Science 2003, 299, 1688; (d)
Carnes, C. L.; Klabunde, K. J. Langmuir 2000, 16, 3764.
17. (a) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.; Mahendar, k.; Sreedhar,
B. J. Am. Chem. Soc. 2004, 126, 3396; (b) Choudary, B. M.; Ranganath, K. V. S.;
Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167; (c)
Choudary, B. M.; Ranganath, K. V. S.; Yadav, J.; Kantam, M. L. Tetrahedron Lett.
2005, 46, 1369; (d) Choudary, B. M.; Mahendar, K.; Ranganath, K. V. S. J. Mol.
Catal. A: Chem. 2005, 234, 25; Choudary, B. M.; Mahendar, K.; Kantam, M. L.;
Ranganath, K. V. S.; Athar, T. Adv. Synth. Catal. 2006, 348, 1977; (f) Kantam, M.
L.; Ranganath, K. V. S.; Mahendar, K.; Chakrapani, L.; Choudary, B. M.
Tetrahedron Lett. 2007, 48, 7646.
18. (a) Karmakar, B.; Nayak, A.; Chowdhury, B.; Banerji, J. ARKIVOC 2009, xii, 209;
(b) Postole, G.; Chowdhury, B.; Karmakar, B.; Pinki, K.; Banerji, J.; Auroux, A. J.
Catal. 2010, 269, 110; (c) Karmakar, B.; Chowdhury, B.; Banerji, J. Catal.
Commun. 2010, 11, 601; (d) Karmakar, B.; Banerji, J. Tetrahedron Lett. 2010, 51,
3855; (e) Karmakar, B.; Sinhamahapatra, A.; Panda, A. B.; Banerji, J.;
Chowdhury, B. Appl. Catal. A: Gen. 2010, 392, 111.
19. Representative experimental procedure: A mixture of 2-naphthol (1.0 equiv),
amine (1.0 equiv), and aldehyde (1.2 equiv) was stirred at room temperature in
water in presence of 50 mg MgO catalyst for certain period as indicated in
Table 2. After completion of the reaction as indicated by TLC (After elusion the
silica gel precoated aluminum plates were visualized under UV light and
charred in alkaline KMnO4 solution), the reaction mixture was extracted with
ethyl acetate (3 Â 10 mL). The extract was concentrated under reduced
pressure and purified by column chromatography using 100–200 mesh silica
gel with ethyl acetate/hexane (6–10%) as eluent. The isolated compounds were
characterized by mp, IR, 1H NMR, 13C NMR and elemental analysis (C, H, and N).
Spectral data of some representative products are provided below.
react with 2-naphthol at the
pathway to produce the 1-(
a
-position following a Mannich type
a
-aminoalkyl)-2-naphthols.
From the context of green chemistry this reaction is highly
significant as the reactions are extremely atom-efficient and have
been performed in water avoiding the use of harmful organic
solvents.
An efficient, clean, step economic, and one-pot procedure for
the synthesis of Betti bases has been developed by the three-com-
ponent coupling of aldehyde, amine, and 2-naphthol over the high
surface area of nanocrystalline MgO catalyst under aqueous condi-
tion. Mild reaction conditions, short reaction time, excellent yields
of the products make this methodology highly significant.
l-(
180 °C; IR (KBr): 3449.9, 2967.0, 1841.3, 1510.3, 1591.8, 1456.9, 1236.0,
1095.6, 950.5, 823.5, 748.8, 699.5 cmÀ1 1H NMR (CDCl3, 300 MHz): d 1.83 (br
a-N-pyrrolidobenzyl)-2-naphthol (4a, entry1, Table 2). White solid; mp
;
s, 4H), 2.3–2.5 (m, 4H), 5.11 (s, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.16–7.25 (m, 5H),
7.34 (1H, J = 7.7 Hz, 1H), 7.58 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 9.3 Hz, 1H), 7.67 (d,
J = 9.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz): d 23.4, 53.5,
70.8, 116.6, 119.9, 121.09, 122.36, 126.37, 127.85, 128.49, 128.59, 128.69,
128.87, 129.5, 131.87, 141.15, 155.5; Anal. Calcd for C21H21NO: C, 83.17; H,
6.93; N, 4.62. Found: C, 83.08; H, 6.87; N, 4.69.
l-(
solid; mp 131–133 °C; IR (KBr): 3311.9, 3054.6, 2922.9, 1592.9, 1460.3, 1238.1,
1085.8, 975.8, 827.9, 747.8, 698.8 cmÀ1 1H NMR (CDCl3, 300 MHz): d 0.92 (m,
a-N-butylaminobenzyl)-2-naphthol (4e, entry 5, Table 2). Crystalline white
;
Acknowledgments
3H), 1.39 (m, 2H), 1.55–1.66 (m, 2H), 2.8–2.86 (m, 2H), 3.64 (m, 1H), 5.68 (s,
1H), 7.14 (d, J = 9.04 Hz, 1H), 7.24–7.29 (m, 5H), 7.31 (m, 2H), 7.36 (d, J = 7.5 Hz,
2H), 7.47–7.74 (m, 3H); 13C NMR (CDCl3, 75.5 MHz): d 13.85, 20.32, 48.96,
64.42, 109.4, 113.4, 120.12, 121.14, 122.35, 123.32, 126.39, 127.73, 128.06,
128.26, 128.6, 128.82, 129.09, 129.63, 130.54, 141.7, 156.84; Anal. Calcd for
Thanks are accorded to Sri S. Chatterjee and Sri S. Bhowmick,
Organic Instrumentation Laboratory, Department of Chemistry,
University of Calcutta, for technical assistance. B.K. acknowledges
UGC for financial assistance under minor research project.
C
21H23NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 82.71; H, 7.53; N, 4.51.
20. Procedure for the synthesis of nanocrystalline MgO: The catalyst was prepared by
non-hydrothermal sol-gel approach. Anhydrous MgCO3 was used as the Mg
source. The salt was dissolved in triethanolamine solvent with stirring at room
temperature. Deionised water was added dropwise to form a gel. Then triethyl
ammonium hydroxide was added to the mixture to maintain a pH of 12. This
was aged at room temperature for 24 h to obtain a white gel. The gel was dried
at 120 °C for another 24 h and finally the cake was calcined at 600 °C for 12 h to
obtain a fine white powder.
References and notes
1. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123; (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168.
2. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.