Non-ionic surfactant catalyzed synthesis of Betti base in water

Article abstract of DOI:10.1016/j.tetlet.2010.01.056

We have developed an efficient non-ionic surfactant (Triton X-100) catalyzed multicomponent synthesis of Betti base from secondary amine, aromatic aldehydes, and β-naphthol using Mannich-type reaction in water. Lewis and Br?nsted acid catalysts, ionic and non-ionic surfactant have been screened for the reaction. Non-ionic surfactant (Triton X-100) gave the best results and the reaction proceeds through the imine formation, which is stabilized by colloidal dispersion and undergoes nucleophilic addition to afford the corresponding N,N-dialkylated Betti base in excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.01.056

Tetrahedron Letters 51 (2010) 1582–1584
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Non-ionic surfactant catalyzed synthesis of Betti base in water
*
Atul Kumar , Maneesh Kumar Gupta, Mukesh Kumar
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient non-ionic surfactant (Triton X-100) catalyzed multicomponent synthesis
of Betti base from secondary amine, aromatic aldehydes, and b-naphthol using Mannich-type reaction in
water. Lewis and Brønsted acid catalysts, ionic and non-ionic surfactant have been screened for the reac-
tion. Non-ionic surfactant (Triton X-100) gave the best results and the reaction proceeds through the
imine formation, which is stabilized by colloidal dispersion and undergoes nucleophilic addition to afford
the corresponding N,N-dialkylated Betti base in excellent yields.
Received 16 December 2009
Revised 11 January 2010
Accepted 17 January 2010
Available online 29 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Water as solvent has attracted much attention in organic syn-
thesis because of its unique reactivity and selectivity that are not
attained in organic solvents. Water is the cheapest, safest, and
most non-toxic solvent of the chemical world. Water is also consid-
ered as an ideal solvent due to economical and environmental con-
cerns.1 Breslow and co-workers reported acceleration of the Diels–
Alder reaction ‘In Water,’2 while Sharpless and co-workers described
‘On Water,’3 reaction that triggered a more widespread interest in
the field. Initially, the use of water as solvent for organic reactions
was mainly restricted to simple hydrolysis reactions. Recently,
water has been successfully applied to Claisen-rearrangements,4
Aldol reactions,5 allylation reactions,6 Reformatsky-type reactions,7
Mukaiyama Aldol reactions,8 Pinacol coupling,9 Wittig reactions,10
Baylis–Hillman reactions,11 Mannich reactions,12 Heck coupling,13
Suzuki coupling,14 Stille coupling,15 1,3-dipolar cycloaddition reac-
tions,16 and transition-metal-catalyzed cyclization reactions.17
The use of water is preferred over organic solvents to decrease
environmental contamination, easy work-up, and economical.
However, the possibility of using water as solvent is limited be-
cause the majority of reactants are poorly soluble in water which
can be overcome by the use of surfactant.
no)alkyl]benzotriazoles with phenolate anions under refluxing
toluene.23
In continuation of our work on multicomponent reactions
(MCRs)24 for the synthesis of various biologically important het-
erocyclic compounds, we wish to report herein a highly efficient
procedure for the preparation of Betti base and its derivatives via
one-pot three component Mannich-type reaction using non-ionic
surfactant Triton X-100 in aqueous media (Scheme 1). It is impor-
tant to emphasize that Lewis, and Brønsted acid surfactant cata-
lyzed reactions are commonly reported but there are very few
reports where non-ionic surfactants were used as catalyst.25
The non-ionic surfactant Triton X-100 (TR) is one of the most
commonly used detergents in biochemistry as solubilizer with a
wide range of applications to biological systems.26 Solubilization
of lipid membranes triggered by Triton X-100 is a well-described
phenomenon. It is also used as an emulsifier, and complexing agent
in both aqueous and non-aqueous media.
Non-ionic surfactants have the tendency to adsorb at interfaces
and to form micelles beyond their critical micelle concentration
(CMC) similar to the ionic surfactants.27 However, the advantage
of non-ionic surfactants (Triton X-100) is the absence of the electri-
cal double layer as formed by the ionic surfactants. Consequently,
non-ionic surfactants are desirable model adsorbents for interfacial
processes. Therefore, we decided to exploit these properties of
non-ionic surfactant for organic reaction.
Recently, interest in the chemistry of the Betti base18 has inten-
sified due to their attractive catalytic19 and biological20 properties
(Fig. 1). Betti base 1 is generally synthesized by condensation of
2-naphthol, ammonia and benzaldehyde but it is thermally unsta-
ble and therefore, it is not easy to synthesize corresponding N,N-
dialkyl derivatives.21 However, the alkyl derivative of Betti base 2
has been prepared by the original Betti procedure.22 The most
valuable methodology was reported by Katritzky et al. by displace-
H
N
N
H
OH
OH
ment of the benzotriazole moiety from N-[a-(dialkylami-
1
2
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405.
E-mail address: dratulsax@gmail.com (A. Kumar).
Figure 1. Structure of Betti bases.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.056

A. Kumar et al. / Tetrahedron Letters 51 (2010) 1582–1584
1583
Table 2
R1
Triton X-100 catalyzed synthesis of Betti basea
Ar
N
R2
Entry
1
Ar
Amine
Productb
Time (h)
2.5
Yieldc
OH
R2
OH
R1
Water
ArCHO
N
H
Triton-x-100
rt
4a
93
90
N
H
4
1
2
3
Scheme 1. Synthesis of Betti base in water.
2
4b
2.5
N
H
N
H
3
4
4c
2.5
2.0
89
94
Table 1
Screening of various types of catalysts for the synthesis of Betti base
Br
Br
Entry
Catalysta
Time(h)
Yieldb (%)
4d
N
H
1
2
3
4
5
6
7
8
9
TsOH
Boric acid
SDS
TsOH + SDS
SDBS
DBSA
Triton X-100
Tween-20
Triton CF-10
CTAB
4.0
4.5
4.0
5.0
4.5
5.2
2.5
3.0
3.0
5.2
35
15
40
57
50
38
93
90
86
59
5
6
4e
4f
2.0
2.0
90
90
N
H
Br
Br
N
H
10
7
8
9
4g
4h
4i
2.0
2.0
2.0
93
88
86
N
H
a
The reaction was conducted with benzaldehyde (5 mmol), b-naphthol
(3.8 mmol), and pyrrolidine (3.8 mmol) in a mixture of catalyst (5 mol %) and water
(2 ml) at room temperature for given hours.
N
H
b
Isolated yield.
Cl
Cl
N
H
CHO
10
11
4j
2.0
3.0
90
85
N
F
N
H
NH
O
4k
N
H
-H2O
OH
O
N
N
H
12
4l
3.0
88
OH
13
14
4m
4n
3.0
4.5
86
80
N
H
O
N
Figure 2. Micelle-promoted multicomponent Betti base synthesis.
N
H
In our preliminary study, several surfactant, Lewis, and
Brønsted acid catalysts were used for optimization of reaction con-
ditions in water. Benzaldehyde, pyrrolidine, and 2-naphthol were
taken as a model substrate.
a
The reaction was conducted with aromatic aldehyde (5 mmol), b-naphthol
(3.8 mmol), and secondary amine (3.8 mmol) in a mixture of Triton X-100 (5 mol %)
and water (2 ml) at room temperature for 2–4.5 h.
b
Among the catalysts tested, surfactant catalyzed the reaction
most efficiently. p-Toluenesulfonic acid (TsOH) and boric acid did
not afford the desired product in good yields. TsOH formed two
immiscible layers while the surfactant formed a white turbid reac-
tion mixture indicating that the long alkyl chain of the surfactant is
necessary for the formation of the colloidal dispersion. However, it
was found that the type of surfactant used influenced both the
yield and the reaction time. Non-ionic surfactants (Triton X-100,
Tween-20, and Triton CF-10) were effective, and required a shorter
reaction time, an acidic surfactant DBSA (dodecylbenzenesulfonic
acid) reduced the yield, and anionic surfactants SDS and SDBS(4-
dodecylbenzenesulfonic acid) were slightly less effective than a
cationic surfactant CTAB (cetyltrimethylammonium bromide). In
fact, a combination of TsOH and sodium dodecyl sulfate (SDS)
which formed a colloidal dispersion adduct gave the desired prod-
All products were characterized by 1H and 13C NMR, and mass spectroscopy.
c
Isolated yield.
uct in a modest yield. From these observations, it was concluded
that Triton X-100 is the most efficient surfactant for this reaction
(Table 1). These reactions when performed in water without any
surfactant, starting materials were recovered.
The reaction might proceed through the imine formation of the
aldehyde and the 2° amine, followed by the attack of the b-naph-
thol. This dehydrative imine formation is a characteristic feature
of colloidal dispersion system of our reactions of imines in water.
Dehydration in water is really unusual and exciting because in
water usually hydrolysis occurs. The equilibrium position shifts to-
ward the imine side, because water molecules would be expelled

1584
A. Kumar et al. / Tetrahedron Letters 51 (2010) 1582–1584
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out of the droplets due to hydrophobic nature of their interior
(Fig. 2).
The high solubilizing capacity of non-ionic Triton X-100 is re-
lated to its hydrophobic character, as can be evaluated from its
critical micelle concentration (2.5 Â 10À4 M)28 and hydrophile–
lipophile balance (13.5)29 values. Triton X-100 solubilizes the
nucleophilic reagent, as well as enhances the nucleophilicity of
the counterions. Besides, the surfactant properties of Triton
X-100 improve the reaction kinetics by increasing interfacial area.
The optimization reveals that Triton X-100 gives the best results
hence the generality of this procedure has been examined. A series
of aldehyde and amines with 2-naphthol was carried out using Tri-
ton X-100 as surfactant catalyst in water.30,31 The results are
shown in (Table 2). All the aromatic aldehydes reacted almost
equally well to afford Betti base (4a–n) in excellent yields.
In conclusion, we have developed an efficient non-ionic surfac-
tant, Triton X-100 catalyzed multicomponent Mannich-type reac-
tions for the synthesis of Betti base from aldehydes, secondary
amines, and 2-naphthol in water. Triton X-100 forms stable colloi-
dal medium which plays an essential role in acceleration of the
reactions in water.
17. (a) Yong, L.; Butenschoen, H. Chem. Commun. 2002, 2852; (b) Kusama, H.;
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Lett. 2002, 4, 2569.
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1941, I, 381; (c) Ghandi, M.; Olyaei, A.; Raoufmoghaddam, S. Synth. Commun.
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20. Gerlach, et al. U.S. Patent 7,202,242 B2, 2007.
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22. Sharifi, A.; Mirzaei, M.; Naimi-Jamal, M. R. Montash. Chem. 2001, 132, 875.
23. Katritzky et al J. Org. Chem. 1999, 64, 6071–6075.
24. (a) Kumar, A.; Maurya, R. A. Tetrahedron 2008, 64, 3471–3482; (b) Kumar, A.;
Maurya, R. A. Tetrahedron Lett. 2008, 49, 5471–5474; (c) Kumar, A.; Sharma, S.;
Maurya, R. A. Tetrahedron Lett. 2009, 43, 5937–5940; (d) Kumar, A.; Kumar, M.;
Gupta, M. K. Tetrahedron Lett. 2009, 50, 7024–7027.
25. Bhattacharya, A.; Purohit, V.; Rinaldi, F. Org. Process Res. Dev. 2003, 7, 254.
26. (a) Hinze, W. L.; Pramauro, E. Crit. Rev. Anal. Chem. 1993, 24, 133–177; (b) Jones,
M. N. Int. J. Pharm. 1999, 177, 137–159.
27. Zeng, X.; Osseo-Asare, K. J. Colloid Interface Sci. 2004, 272, 298–307.
28. Griffin, W. C. J. Soc. Cosmet. Chem. 1949, 1, 311–326.
The process is high yielding, eco-friendly, and demonstrates the
value of the non-ionic surfactant-mediated organic solvent-free
methodology in organic synthesis.
29. Neugebauer, J. A Guide to the Properties and Uses of Detergents in Biology and
Biochemistry; Calbiochem-Novabiochem Int: La Jolla, 1994.
30. General procedure for the synthesis of compound (4). In a typical experiment, the
aldehyde (5 mmol), b-naphthol (3.8 mmol) and pyrolidine (3.8 mmol) were
taken in a mixture of Triton X-100 (5 mol %) and water (2 ml) to a round-
bottomed flask. The reaction mixture was vigorously stirred at room
temperature. After the reaction was completed (monitored by TLC) the
reaction mixture was extracted with ethylacetate, the aqueous-phase was
back extracted with ethylacetate (3 Â 15 ml). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to leave the crude product as a white solid which was purified by
silica gel column chromatography (EtoAc/hexane mixtures).
Acknowledgments
M.K.G. and M.K. are thankful to CSIR-UGC New Delhi, for the
award of a SRF. The authors also acknowledge SAIF-CDRI for pro-
viding spectral and analytical data.
31. Analytical data for few representative compounds. 1-(Phenyl(pyrrolidin-1-
yl)methyl)naphthalen-2-ol (4a) white solid; mp 178–179 °C. 1H NMR (CDCl3,
300 MHz): d = 1.85 (br s, 4H), 2.43 (br s, 4H), 5.12 (s, 1H), 7.13–7.38 (m, 6H,
ArH), 7.58–7.70 (m, 4H), 7.86 (d, J = 9 Hz,1H), 13.82 (br s, 1H), 13C NMR
(50 MHz, CDCl3) d = 23.81, 54.20, 71.25, 120.20, 120.31, 121.54, 122.80, 126.81,
127.25, 128.01, 128.26, 128.91, 129.0, 129.1, 129.91, 129.30, 132.32, 141.71,
156.00. IR (KBr): 3120, 3058, 2972, 2843, 1621, 1453, 1239, 750 cmÀ1. ESIMS:
m/z 304 (M+H)+. 1-((3-Bromophenyl)(diethylamino)methyl)naphthalen-2-ol (4e)
white solid; mp 157 °C. 1H NMR (CDCl3, 300 MHz) d = 1.02 (t, J = 7.05 Hz, 6H,
CH3), 2.74 (br, d, J = 6.42 Hz, 4H, –NCH2), 5.39 (s, 1H, CH), 7.09–7.14 (m, 2H,
ArH), 7.20–7.24 (m, 1H, ArH), 7.30–7.33 (m, 1H, ArH), 7.36–7.42 (m, 1H, ArH),
7.58–7.60 (d, J = 7.62 Hz, 1H, ArH), 7.67–7.77 (m, 2H, ArH), 7.81 (d, J = 8.58 Hz,
2H, ArH), 14.01 (s, 1H, OH). 13C NMR (CDCl3, 300 MHz) d = 9.91, 42.86, 66.97,
115.89, 120.19, 120.58, 122.44, 122.65, 126.60, 127.64, 128.62, 129.05, 129.68,
130.38, 131.07, 131.87, 132.03, 142.41, 156.02. IR (KBr): 3140, 3061, 2965,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.056.
References and notes
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Savage, P. E. Green Chem. 2004, 6, 227.
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Kanan, M. W.; Liu, D. R. Angew. Chem., Int. Ed. 2002, 41, 1796.
.
2839, 1617, 1450, 1235, 749 cmÀ1 ESIMS: m/z 384 (M+H)+. 1-((4-
Chlorophenyl)(dimethylamino)methyl)naphthalen-2-ol (4h) white solid; mp
128–130 °C. 1H NMR (CDCl3, 300 MHZ) d = 2.34 (s, 6H, NCH3), 4.95 (s, 1H,
CH), 7.08–7.45 (m, 4H, ArH), 7.50–7.53 (m, 3H, ArH), 7.65–7.83 (m, 3H, ArH),
9.98 (s, 1H, ArH). 13C NMR (CDCl3, 75 MHz) d = 41.54, 72.76, 116.32, 119.85,
121.14, 122.38, 126.42, 127.70, 128.48, 128.67, 128.83, 128.89, 129.75, 131.21,
142.37, 155.20. IR (KBr): 3129, 3061, 2976, 2848, 1629, 1462, 1240, 758 cmÀ1
.
ESIMS: m/z 312 (M+H)+. 1-((2-Methoxyphenyl)(piperidin-1-yl)methyl)naph-
thalen-2-ol (4k) mp 181 °C, white solid; 1H NMR (CDCl3, 300 MHz) d = 1.42–
1.73 (m, 6H, -CH2), 2.07–2.25 (m, 2H, –NCH2), 2.25 (d, J = 4.35 Hz, 1H, –(NCH),
3.27 (d, J = 11.7 Hz, 1H, –(NCH), 3.99 (s, 3H -OCH3), 5.81 (s, 1H, CH), 6.81 (t,
J = 7.56 Hz, 1H, ArH), 6.85 (d, J = 8.16 Hz, 1H, ArH), 7.11–7.21 (m, 3H, ArH),
7.26–7.32 (m, 1H, ArH), 7.46–7.51 (m, 1H, ArH), 7.61–7.66 (m, 2H, ArH), 7.75
(d, J = 8.58 Hz, 1H, ArH). 13C NMR (CDCl3, 75 MHz) d = 24.14, 25.93, 26.31,
49.37, 54.76, 55.55, 62.15, 110.33, 116.67, 119.93, 121.43, 121.48, 122.15,
126.19, 127.61, 128.42, 128.49 128.53, 128.87, 128.92, 130.00, 132.89, 156.45,
´
11. (a) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35, 7947; (b) Luo, S.;
Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555; (c) Basavaiah, D.;
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Schmidt, M.; Nuyken, O.; Weberskirch, R. Macromolecules 2005, 38, 254.
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156.77 ppm. IR (KBr): 3131, 3054, 2961, 2854, 1652, 1449, 1238, 747 cmÀ1
.
ESIMS: m/z 348 (M+H)+. 1-((4-(Dimethylamino)phenyl)(piperidin-1-yl)methyl)-
naphthalen-2-ol (4n) Oil, 1H NMR (CDCl3, 200 MHz) d = 1.25 (br s, 6H, CH2), 1.66
(br s, 4H, –NCH2), 2.85 (s, 6H, NCH3), 4.98 (s, 1H, CH), 6.65 (d, J = 8.00 Hz, 2H,
ArH), 7.11–7.68 (m, 8H, ArH), 7.80 (d, J = 8.46 Hz, 1H, ArH), 14.18 (s, 1H, OH).
13C NMR (CDCl3, 50 MHz) d = 4.24, 26.11, 29.68, 40.04, 40.34, 71.46, 110.98,
112.34, 116.72, 119.90, 121.22, 122.10, 126.16, 127.09, 128.61, 128.74, 128.92,
129.90, 131.97, 132.43, 149.96, 155.44. IR (neat): 3119, 3052, 2969, 2848,
1628, 1461, 1232, 745 cmÀ1. ESIMS: m/z 361 (M+H)+.