Revisiting the Betti Synthesis: Using a Cheap, Readily Available, Recyclable Clay Catalyst under Solventless Conditions

Article abstract of DOI:10.1002/ejoc.201800826

One-pot multicomponent reactions have gained significant importance in recent years because they are usually more selective, simple, efficient, atom-economic and green than their multistep counterparts. The Betti synthesis involves the combination of aldehydes, amines and 2-naphthol to form compounds which can serve as catalysts or as biologically active compounds. In this study, Montmorillonite K30 was used as a heterogeneous catalyst for the Betti reaction at 60 °C in relatively short reaction times. Positively, it is cheap, readily and commercially available and requires no preparation, it can be used in neat conditions whilst minimizing excess reagent amounts. Most importantly, it is fully recoverable and can be recycled up to 5 times. In reactions involving secondary aliphatic amines, very good to excellent results were obtained whilst primary ones including benzylamine gave appreciable yields. In addition, the heteroaromatic aldehyde 4-pyridinecarboxaldehyde and the polyaromatic aldehyde 1-naphthaldehyde also gave encouraging results.

Full text of DOI:10.1002/ejoc.201800826

A Journal of
Accepted Article
Title: Revisiting the Betti synthesis: using a cheap, readily-available,
recyclable clay catalyst in solventless conditions
Authors: Giovanna Bosica, Roderick Abdilla, and Kaylie Demanuele
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800826
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Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
Revisiting the Betti synthesis: using a cheap, readily-available,
recyclable clay catalyst in solventless conditions
[
a]
[a]
[a]
Giovanna Bosica* , Roderick Abdilla, and Kaylie Demanuele
3
Abstract: One-pot multicomponent reactions have gained significant
importance in recent years because they are usually more selective,
simple, efficient, atom-economic and green than their multistep
counterparts. The Betti synthesis involves the combination of
aldehydes, amines and 2-naphthol to form compounds which can
serve as catalysts or as biologically active compounds. In this study,
Montmorillonite K30 was used as a heterogeneous catalyst for the
by an alkyne in the A -coupling, by a nitro compound in the nitro-
Mannich reaction, by an indole in the aza-Friedel-Crafts reaction
or by a naphthol in the case of the Betti synthesis.[3-6]
Originally, the Betti reaction involved
condensation of two equivalents of benzaldehyde (1a), one
equivalent of ethanolic ammonia (2a) and one equivalent of 2-
naphthol (3) to give 4 which is identified as 1,3-diphenyl-2,3-
dihydro-1H-naphth[1,2-e][1,3]oxazine.[
hydrochloric acid followed by potassium hydroxide yielded 1-(α-
aminobenzyl)-2-naphthol which is also called the Betti base (5)
(Scheme 1). With time this reaction was modified by replacing
ammonia with alkyl or aryl amines and various catalysts were
developed in order to improve the yield of theses reactions.[7]
a three component
0
Betti reaction at 60 C in relatively short reaction times. Positively, it is
6]
cheap, readily and commercially available and requires no
preparation, it can be used in neat conditions whilst minimizing excess
reagent amounts. Most importantly, it is fully recoverable and can be
recycled up to 5 times. In reactions involving secondary aliphatic
amines, very good to excellent results were obtained whilst primary
ones including benzylamine gave appreciable yields. In addition, the
heteroaromatic aldehyde 4-pyridinecarboxaldehyde and the
polyaromatic aldehyde 1-naphthaldehyde also gave encouraging
results.
Treatment of
4
by
Betti bases have several uses including catalytic and biological
ones. With regards to the former use, the condensation of 2-
naphthol, benzaldehyde and (S)-methylbenzylamine followed by
N-methylation was discovered to catalyze the enantioselective
ethylation of aryl aldehydes to secondary alcohols.[8]
Introduction
Over the past few years most of our studies have focused on one-
pot multicomponent reactions (MCRs) because of the significant
advantages they offer over conventional multistep synthesis
including: selectivity, atom-economy, simplicity, shorter reaction
times and environmental benignity.[1] The earliest MCR which was
discovered was the Strecker (1850) synthesis and along with it
there are several other tried and tested classical ones including:
the Biginelli (1891), Hantzsch (1882), Mannich (1912), Passerini
(
1921) and the Ugi (1959) reactions.[1] However, organic chemists
have used various rational methods in order to develop new
MCRs to build novel chemical libraries. Amongst such methods,
the single reactant replacement (SRR) technique involves
replacing one of the reactants by a related one which can have a
similar role in the overall mechanism of the reaction.[2] For
Scheme 1. The original Betti reaction between benzaldehyde (1a), ammonia
(2a) and 2-naphthol (3) to yield 4 before treating with HCl and KOH to ultimately
form the Betti base (5).
example, whereas the Mannich reaction is classically
a
combination of an aldehyde, an amine and a carbonyl compound
which acts as a nucleophile for the imine formed between the
aldehyde and the amine, the carbonyl compound can be replaced
Meanwhile, various products synthesized using morpholine or
N,N-dimethylamine instead of ammonia were tested as analgesic
agents because of their affinity towards α-adrenergic and opioid
receptors.[ More importantly, the hydroxyl group in Betti bases
can be exploited to form compounds which have several
9]
[
a]
G., Bosica (Corresponding Author)
Department of Chemistry
biological applications such as antibacterial, hypotensive and
bradycardiac activities[
10,11]
in fact one of the most important
University of Malta
Msida, MSD 2080 Malta
E-mail: giovanna.bosica@um.edu.mt
https://www.um.edu.mt/profile/giovannabosica
areas of application of these aminonaphtol derivatives is the
[12]
synthesis of new heterocycles.
Focusing on the reaction between aldehydes, amines and 2-
naphthol, both homogeneous and heterogeneous catalysts were
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
employed to varying success. In earlier studies, the former type
of catalysts were used including lithium perchlorate in diethyl
ether solvent, p-toluenesulfonic acid (TSA) under microwave
radiation, DMEA organocatalyst in neat conditions, Triton X-100
surfactant in water etc.[13-16] Furthermore, in two separate studies,
an ionic liquid and polyethylene glycol (PEG) were utilized
better results. In conclusion, activated Montmorillonite K30 was
chosen because it gave the best result of 81% (entry 14).
Table 1. Catalyst screening for the model reaction involving benzaldehyde
(1a), pyrrolidine (2b) and 2-naphthol (3a).
because
they
serve
as
catalysts
and
solvents
simultaneously.[
17,18]
However, all of these catalysts cannot be
Entry[a]
Catalyst
Amount of catalyst
Yield[b] (%)
reused or recycled easily and suffer from one or more of the
following disadvantages: they need to be used in a solvent, are
expensive and have short-term stability.
(mol% or g)
Methanesulfonic acid –
alumina (0.5 mmol/g)[
1
2
10 mol%
42
26
c]
Conversely, heterogeneous catalysts can be usually reused and
recycled and studies involving nano-magnesium oxide, nano-
magnetite, nano-titania-perchloric acid and nano-silica-boric acid
were greener because they gave excellent yields in short reaction
times usually in neat conditions.[19-22] Yet, nano-catalysts are more
difficult and expensive to prepare, more problematic to separate
from the crude reaction mixture (centrifugation) whilst the latter
catalysts involve the use of the highly corrosive and non-
environmentally benign perchloric acid and boric acid respectively.
Henceforth, in continuation of our research on new synthetic
methods in organic synthesis using heterogeneous catalysts, we
developed a multicomponent Betti synthesis employing a metal-
free, clay catalyst, Montmorillonite K30, which is specifically a
phyllosilicate, and has the following advantages amongst others
Amberlyst 15
0.3 g
0.3 g
Silicotungstic acid /
Amberlyst 15 (30% w/w)[
3
4
5
41
63
66
d]
Silicotungstic acid /
Montmorillonite K10 (20%
0.3 g
[e]
w/w)
Perchloric acid – cellulose
5 mol%
(
0.5 mmol/g)[
f]
acidic alumina[g]
6
7
0.3 g
0.3 g
0.3 g
66
77
22
Activated acidic alumina[h]
Neutral activated
alumina[
(
as will be discussed later on):
8
9
h]




Cheap and readily and commercially available
Requires no preparation
Easily recyclable and reusable
Metal free (no leaching is possible)
Silica[g]
0.3 g
0.3 g
39
55
10
Zirconium (IV) oxide[g]
1
1
Montmorillonite K10[g]
0.3 g
0.3 g
0.3 g
0.3 g
73
78
75
81
Results and Discussion
Activated Montmorillonite
K10[
1
2
3
h]
Catalyst screening and condition optimization
Montmorillonite K30[g]
1
Prior to identifying MK30 as the ideal catalyst for substrate
screening, various other catalysts were tested for the model
reaction shown in Scheme 2.
Activated Montmorillonite
K30[
14
h]
1
5
6
4A Molecular sieves[g]
0.3 g
33
62
Copper(I) iodide –
alumina[
1
10 mol%
i]
Copper(I) iodide –
Amberlyst A21[
17
10 mol%
0
j]
Copper(II)-Montmorillonite
K10[
18
19
20
21
0.3 g
0.3 g
0.3 g
0.3 g
68
63
69
36
k]
Iron(III)-Montmorillonite
K10[
k]
Scheme 2. Model reaction between benzaldehyde (1a), pyrrolidine (2b) and 2-
naphthol (3) to form 6a.
Aluminium(III) –
Montmorillonite K10[
k]
Zinc (II) – Montmorillonite
K10[
k]
When heterogeneous Brønsted acids were initially tested (Table
1, entries 1 – 5) the yields were not very interesting whilst when
[
a] All reactions were performed at room temperature for 24 hours in neat
metal/non-metal oxides were used results were no better except
for the case of acidic alumina (entries 6 and 7). The use of
phyllosilicate catalysts Montmorillonite K10 and Montmorillonite
K30 (entries 11 – 14) caused an upshift in yields especially on
using them after drying for 24 hours in an oven set at 130 0C.
Lewis acid exchanged Montmorillonite K10 catalysts did not give
conditions with the reactants (benzaldehyde (1a) / pyrrolidine (2b) / 2-
naphthol (3)) in the molar ratio of 1.2 : 1 : 1 at a scale of 2.5 mmol. [b] Pure
isolated yield after column chromatography and recrystallization from
ethanol. [c] Catalyst was prepared according to method reported in [23]. [d]
Catalyst was prepared according to method reported in [24]. [e] Catalyst was
prepared according to method reported in [25]. [f] Catalyst was prepared
according to method reported in [26]. [g] Catalyst was used as bought and
was not dried. [h] Catalyst was dried at 130 0C for 24 hours before use. [i]
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European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
Catalyst was prepared according to method reported in [27]. [j] Catalyst was
prepared according to method reported in [28]. [k] Catalyst was prepared
according to method reported in [29].
Substrate screening: using pyrrolidine
In the initial stages of substrate screening (Table 3), a wide range
of aldehydes were reacted with pyrrolidine (2b) and 2-naphthol
(
3). Furthermore, in order to highlight further the difference the
increase in temperature made, most reactions were performed
under both the ideal conditions established at room temperature
and at 60 C. At the latter conditions, very good to excellent yields
Subsequently, condition optimization was performed by initially
varying the amount of catalyst (Table 2). Decreasing the amount
proved detrimental whilst increasing it caused the reaction to dry
out completely and a significant amount of diethyl ether would
have had to be added to ensure stirring, something which is not
environmentally benign (entries 2, 3). Conversely, using the
original amount of catalyst whilst increasing the amine excess,
caused a positive change in the yield (entry 4).
0
(
79 – 92%) were usually obtained in a maximum of 6 hours for
several different aldehydes with the exception of 4-
fluorobenzaldehyde (50%), probably owing to its photo and
thermal instability, and 2-methoxybenzaldehyde (60%) probably
due to steric hindrance. Understandably, the electron rich
methoxybenzaldehydes (entries 3 – 5) gave lower results than
the electron poor cyano- and nitrobenzaldehydes (entries 7 – 8).
Regrettably, aliphatic aldehydes gave several products each of
which was very small in amount and could not be identified
The last few trials (entries 5 – 8) involved carrying out the reaction
0
at a higher temperature of 60 C and impressively reaction times
decreased to 3 hours. More importantly, when the reactant ratio
between benzaldehyde (1a), pyrrolidine (2b) and 2-naphthol (3)
was 1.2 : 1.5 : 1, both activated and unactivated MK30 yielded
identical results (entries 7 – 8). Finally, when the ratio was
changed to 1.1 : 1.2 : 1 and unactivated MK30 was used (entry
(
entries 15 – 17). Positively, the polyaromatic aldehyde 1-
naphthaldehyde gave a very good result (entry 9) as did the
heteroaromatic aldehyde 4-pyridinecarboxaldehyde (entry 10)
the latter of which, to the best of our knowledge, has never been
employed.
9), a yield of 91% was obtained meaning that the latter conditions
had to be chosen because they would result in a more energy-
efficient and green procedure.
Table 3. Yields and reaction times for the reactions involving aldehydes (1a
0
-
q), pyrrolidine (2b) and 2-naphthol (3) at room temperature and at 60 C.
Table 2. Condition optimization for model Betti reaction using
Montmorillonite K30 as the catalyst of choice.
Yield[c]
Catalyst
Amount
Reactant
ratio[
(%)
[Time]
Entry[a]
Catalyst
b]
0
T ( C)
(hours)
Activated
MK30
1
0.3 g
1.2 : 1 : 1
RT
81 [24]
d
[a]
[a]
Yield (%) at
Yield (%) at
60 C
2
3
0.2 g
0.4 g
1.2 : 1 : 1
1.2 : 1 : 1
RT
RT
56 [24]
/[e]
1
[b]
0
[c]
Entry
R or 1
RT
[
Time (hrs)]
[Time (hrs)]
91 [3]
(6a)
6 5
C H
4
0.3 g
1.2 : 1.5 : 1
RT
86 [24]
1* (model
reaction)
86 [7]
(1a)
Unactivated
5
6
7
8
9
[f]
0.3 g
0.3 g
0.3 g
0.3 g
0.3 g
1.2 : 1.1 : 1
1.2 : 1.1 : 1
1.2 : 1.5 : 1
1.2 : 1.5 : 1
1.1 : 1.2 : 1
60
60
60
60
60
78 [3]
84 [3]
90 [3]
90 [3]
91 [3]
MK30
4-CH
(1b)
-OCH -C
(1c)
3
-C
6
H
4
90 [3]
(6b)
2
3
4
5
6
7
8
83 [7]
51 [24]
72 [24]
48 [12]
0 [24]
90 [4]
91[4]
Activated
MK30[d]
2
3
4
3
6
6
6
H
H
H
4
4
4
60 [6]
(6c)
Unactivated
[f]
MK30
-OCH
3
-C
81 [3]
(6d)
Activated
[d]
MK30
(1d)
Unactivated
MK30[f]
-OCH
3
-C
83 [2]
(6e)
(1e)
[
a] All reactions were performed on a 2.5 mmol scale using activated or
unactivated MK30. [b] Molar ratio of benzaldehyde (1a), pyrrolidine (2b) and
-naphthol (3). [c] Pure isolated yield following column chromatography and
recrystallization from ethanol. [d] Montmorillonite K30 was dried at 130
for 24 hours. [e] Reaction dried out immediately and a lot of solvent would
have had to be required to ensure stirring, something which is not
environmentally-benign. [f] Montmorillonite K30 was used directly as
bought.
2-NO
1f)
4-NO -C
1g)
2
-C
6
H
H
4
4
0 [6]
(
(6f)
2
0
C
2
6
92 [2]
(6g)
(
4
-CN-C
6
H
4
92 [2]
(6h)
(1h)
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European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
O
7
9 [6]
9
70 [24]
(
6i)
(1i)
O
7
4 [6]
1
0
70 [24]
Yield (%)[b] at 60 0
C
N
(6j)
Entry[a]
R1
Amine
[
Time (hrs)]
(
1j)
H
N
4
-F-C
6
H
4
-
50 [6]
(6k)
4
-CH
3
-C
6
H
4
87 [10]
11
37 [24]
75 [24]
79 [24]
59 [12]
(1k)
1
(
1b)
(6r)
4
-Cl-C
1l)
-Br-C
1m)
,4-Cl -C
6
H
4
-
83 [2]
(6l)
12
13
14
(2c)
(
4
-NO
2
-C
6
H
4
76 [12]
(6s)
2
3
2
c
c
4
6
H
4
-
84 [2]
(6m)
86 [5]
(6n)
(
1g)
(
4
-CN-C
(1h)
6
H
4
90 [4]
(6t)
2
3
2
6
H
3
H
N
(1n)
86 [12]
O
0
[3]
4
1b
O
15
0 [24]
(6u)
(6o)
(2d)
(
1o)
1p)
7
8 [12]
(6v)
O
5
6
1g
1h
2d
2d
0
[6]
1
6
7
0 [24]
0 [24]
84 [12]
(6p)
(
6w)
(
CH
3
(CH
)
2 3
CHO
0 [4]
[
a] Reactions were performed on a 2.5 mmol scale using a molar ratio of
aldehyde (1b/g/h), piperidine/morpholine (2c/d) and 2-naphthol (3) of 1.1 :
.2 : 1 at 60 C in neat conditions in the presence of 0.3 g inactivated MK30.
1
(1q)
(6q)
0
1
[
b] Pure isolated yield following column chromatography and
recrystallization from ethanolTable Footnote.
[
a] Pure isolated yield following column chromatography and
recrystallization from ethanol. [b] Reactions were performed on a 2.5 mmol
scale using a molar ratio of aldehyde (1a-q), pyrrolidine (2b) and 2-naphthol
(
0
3) of 1.2 : 1.5 : 1 at room temperature in neat conditions in the presence of
.3g activated MK30. [c] Reactions were performed on a 2.5 mmol scale
Turning onto the aliphatic primary amines (Table 5), products
were obtained in varying yields (37 – 80%) with the lower ones
being obtained by cyclopentylamine and isopentylamine and the
highest obtained using the linear n-butylamine (entries 1 - 3).
Interestingly, benzylamine gave appreciable results (entries 4, 5)
which, to the best of our knowledge, have never been obtained
under neat heterogeneous conditions. On the other hand aniline
did not give any product owing to its relative lack of reactivity.
using a molar ratio of aldehyde (1a-q), pyrrolidine (2b) and 2-naphthol (3)
of 1.1 : 1.2 : 1 at 60 C in neat conditions in the presence of 0.3 g
unactivated MK30.
0
Substrate screening: using other secondary aliphatic amines and
primary amines
The use of either piperidine (2c) or morpholine (2d) instead of
pyrrolidine (2b) yielded excellent results (Table 4) although it
must be noted that the reaction times increased to a significant
extent (up to 12 hours) when compared to those involving
pyrrolidine.
Table 5. Yields and reaction times for the reactions involving aldehydes
(1a,h), primary amines (2e – i) and 2-naphthol (3a) at 60 0C.
Table 4. Yields and reaction times for the reactions involving aldehydes (1b,
0
g, h), piperidine/morpholine (2c-d) and 2-naphthol (3) at 60 C.
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European Journal of Organic Chemistry
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FULL PAPER
Yield (%)[
b]
Recycling test
Amine
0
at 60 C
Time (hrs)]
80 [12]
Entry [a]
1
When the model reaction involving the synthesis of 6a from 1a,
2b and 3 was repeated after filtering and reusing the catalyst, it
was found out that the latter could be reused for up to five times
with the yield decreasing from 91% to 80% (Figure 2).
Considering that all reactions were allowed to take place for the
same amount of time (i.e. 7 hours), the results show only a slight
loss of activity of the catalyst, according to the small decrease of
the yields obtained. Between each trial, the catalyst was left to dry
R or 1
(2e-i)
[
C
6
H
5
-
CH
3
(CH
2 3
) NH
2
1
(1a)
(2e)
NH2
(6x)
38 [12]
1a
2
(6y)
0
in an oven at 130 C overnight in order to remove any solvent and
(2f)
moisture adsorbed onto it during the reaction.
H C
3
NH 2
38 [12]
1
a
a
3
4
CH3
(
6z)
66 [12]
6aa)
37 [12]
6bb)
0 [30]
6cc)
Recycling tests
(
2g)
9
5
NH2
91
91
90
1
90
85
(
85
(2h)
80
4-CN-C
6 4
H -
8
0
2h
5
6
(
1h)
(
75
NH 2
7
0
1
b
1
st cycle 2nd cycle 3rd cycle 4th cycle 5th cycle
(
(2i)
Figure 2. Yields of recycling trials.
[
a] Reactions were performed on a 2.5 mmol scale using a molar ratio of
0
aldehyde (1a/h), amine (2e-i) and 2-naphthol (3) of 1.1 : 1.2 : 1 at 60 C in
neat conditions in the presence of 0.3g inactivated MK30. [b] Pure isolated
yield following column chromatography and recrystallization from ethanol.
Green metrics
The “greenness” of a reaction can be approximately quantified by
calculating both the E-factor and the atom economy amongst
other factors. For the model reaction, involving 1a, 2b and 3, the
atom economy is equal to:
Interestingly during 13C-NMR spectroscopy characterization we
found that all products having heterocyclic amines had a similar
trend for the amine ring portion, showing two broad peaks for the
푅푀푀푝푟ꢀ푑푢ꢁꢂ
퐴푡표푚 푒푐표푛표푚푦 =
∗ 100%
∑
푅푀푀푠ꢂ푎푟ꢂ푖ꢃ푔 ꢄ푎ꢂꢅ푟푖푎푙푠
2 2
NCH
- carbons and so one carbon more in count.[12b]
-
CH
Performing a temperature study on sample 6w we observed that
these two broad peaks become single one at higher
3
03.40
=
∗ 100% = 94%
1
44.16 + 106.12 + 71.12
a
temperatures (Figure 1), indicating a restricted rotation at room
Meanwhile, the E-factor for the same reaction is equal to:
temperature.
푡표푡ꢆꢈ 푚ꢆꢉꢉ 표푓 ꢊꢇ표ꢋꢌ푐푡
퐸 − 푓ꢆ푐푡표ꢇ =
푡표푡ꢆꢈ 푚ꢆꢉꢉ 표푓 푤ꢆꢉ푡푒
9
1% ∗ 0.00250 ∗ 303.40
0.00250 ∗ 144.16) + (0.00275 ∗ 106.12) + (0.003 ∗ 71.12) − 91% ∗ 0.00250 ∗ 303.40
3.92
=
=
(
The one-pot multicomponent approach, using commercially
available non-hazardous starting materials, displays a ‘green’
protocol with a high atom economy and low E-factor.
Conclusions
The one-pot multicomponent Betti synthesis was performed
under green heterogeneous and neat conditions in the presence
of Montmorillonite K30 catalyst which is safe, cheap, readily
available and does not require any preparations. It is fully
recoverable and recyclable for up to 5 runs. Furthermore, it could
catalyse reactions involving both secondary and primary aliphatic
Figure 1. Temperature study on 13C-NMR spectroscopy for compound (6w).
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European Journal of Organic Chemistry
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FULL PAPER
(6a) 1-(phenyl(pyrrolidin-1-yl)methyl)naphthalen-2-ol.[30]
crystals. M.P.: 166 0C. IR (NaCl): 3062, 3018, 2974, 2877, 2827, 1622,
White
amines to give products usually in good to excellent yields. In
addition, to the best of our knowledge this is the first time that
benzylamine could be used in neat heterogeneous conditions
whose products have immense potential. The developed protocol
displays both a very high Atom Economy as well as a low E-Factor.
1
600, 1585, 1519, 1506, 1467, 1452, 1415, 1381, 1350, 1313, 1265, 1238,
-
1
1
215, 1157, 1141, 1124, 1107, 1080, 1028, 950, 837, 815, 767, 630 cm .
1
H NMR (500 MHz, CDCl
3
) δ 13.85 (br s, 1H), 7.87 (d, J = 8.54 Hz, 1H),
7
2
7
.69 (d, J = 8.13 Hz, 1H), 7.66 (d, J = 8.85 Hz, 1H), 7.60 (d, J = 8.19 Hz,
H), 7.36 (ddd, J = 1.37, 6.87, 8.54 Hz, 1H), 7.26 - 7.29 (m, 1H), 7.22 -
.25 (m, 1H), 7.18 - 7.22 (m, 2H), 7.15 (d, J = 8.85 Hz, 1H), 5.13 (s, 1H),
Experimental Section
Methodology
3.10 – 3.50 (br s, 1H), 2.00 – 2.75 (br s, 3H), 1.86 (br s, 4H).
(6b)
Yellow crystals. M.P.: 120 0C. IR (NaCl): 3049, 3014, 2974, 2924, 2877,
1-(4-methylphenyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol.[31]
2
823, 1622, 1600, 1581, 1514, 1467, 1452, 1413, 1381, 1350, 1311, 1267,
General
-
1 1
1
236, 1215, 1157, 1126, 1112, 952, 817, 756, 667, 628 cm . H NMR (500
) δ 13.89 (br s, 1H), 7.86 (d, J = 8.54 Hz, 1H), 7.68 (d, J =
.32 Hz, 1H), 7.65 (d, J = 8.85 Hz, 1H), 7.48 (d, J = 8.19 Hz, 2H), 7.35
ddd, J = 1.37, 6.94, 8.47 Hz, 1H), 7.18 - 7.23 (m, 1H), 7.14 (d, J = 8.85
Hz, 1H), 7.06 (d, J = 8.19 Hz, 2H), 5.10 (s, 1H), 3.09 – 3.47 (br s, 1H), 2.81
2.41 (br s, 2H) 2.30 - 2.40 (m, 1H), 2.25 (s, 3H), 1.85 (br s, 4H).
MHz, CDCl
7
3
All commercially available chemicals were purchased from Aldrich and
used without further purification. IR spectra were recorded on a Shimadzu
IR Affinity-1 FTIR spectrometer calibrated against a 1602 cm-1 polystyrene
absorbance spectra. Samples were analysed as thin films in between
sodium chloride discs. The 1H and 13C NMR spectra were recorded on a
(
–
Bruker Avance III HD® NMR spectrometer, equipped with an Ascend 500
1
(6d)
1-(3-methoxyphenyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol.
1
1
1.75 Tesla superconducting magnet, operating at 500.13 MHz for H and
Yellow crystals. M.P.: 110 0C. IR (NaCl): 3049, 305, 2970, 2875, 2833,
25.76 MHz for 13C, and a multinuclear 5 mm PABBO probe. Samples
1622, 1600, 1585, 1521, 1489, 1452, 1436, 1413, 1381, 1350, 1303, 1269,
were dissolved in deuterated chloroform (with TMS). Mass spectra were
performed using a Waters® ACQUITY® TQD UPLC/MS/MS system
equipped with the Atmospheric Solids Analysis Probe (ASAP). Melting
points of products were measured using a Stuart® SMP11 melting point
determination apparatus fitted with a mercury thermometer. Reactions
were monitored using TLC plates composed of silica on PET with
fluorescent indicator. Plates were observed under a UV lamp at a
wavelength of 254 nm before staining in an iodine-saturated chamber.
-
1 1
1
238, 1157, 1124, 1049, 952, 894, 819, 752, 702, 667, 640 cm . H NMR
) δ 13.80 (br s, 1 H), 7.88 (d, J=8.70 Hz, 1 H), 7.69 (d,
J=8.04 Hz, 1 H), 7.65 (d, J=8.85 Hz, 1 H), 7.37 (t, J=7.74 Hz, 1 H), 7.13 -
.23 (m, 5 H), 6.73 (d, J=7.68 Hz, 1 H), 5.09 (s, 1 H), 3.74 (s, 3 H), 3.27
br s, 1 H), 2.68 (br s, 1 H), 2.35 (br s, 1 H), 2.25 (br s, 1 H), 1.85 (br s, 4
H). 13C NMR (126 MHz, CDCl
) δ 159.71, 155.58, 142.80, 131.89, 129.60,
28.82, 128.57, 126.34, 122.32, 121.14, 120.88, 119.92, 116.50, 114.35,
(500 MHz, CDCl
3
7
(
3
1
1
3
+
12.80, 70.74, 55.14, 54.54, 52.41, 23.39. MS (ES+): m/z = 334.25 [M+H] ,
04.20, 257.33, 219.19, 145.06, 55.18, 54.87.
Overall method
(
6e) 1-(4-methoxyphenyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol.[32]
Yellow crystals. M.P.: 92 0C. IR (NaCl): 3062, 3005, 2970, 2875, 2835,
The general procedure for the Betti reaction involved stirring the aldehyde
(2.75 mmol), the amine (3.00 mmol) and the 2-naphthol (2.50 mmol) until
1
622, 1618, 1581, 1512, 1467, 1456, 1413, 1381, 1350, 1311, 1267, 1238,
the latter dissolved. Then, Montmorillonite K30 catalyst (0.30 g) was
carefully added via a plastic funnel before the reaction mixture was allowed
to stir under neat conditions in a nitrogen-dried 10 mL two-necked round-
bottomed flask fitted with a reflux condenser and heated in an oil bath set
at 60 0C. Often times, reaction mixture thickened completely after 1-2
hours of mixing and hence about 4 – 6 drops of ethanol had to be added
to continue stirring. TLCs were carried out at 30 min or 1 h intervals. Once
the 2-naphthol spot no longer appeared on TLC or once its intensity did
not appear to change, stirring was stopped and acetone (5 - 10 mL) was
added to the mixture to dissolve all constituents. Stirring ensued for 30
more minutes before the catalyst was filtered using a sintered funnel. After
concentrating the filtrate by rotary evaporation, the crude reaction mixture
was loaded onto a silica-gel filled column solvated by a mixture of 9 : 1 n-
hexane / ethyl acetate. The final product could be eluted after increasing
the polarity of the solvent mixture by increasing the relative amount of ethyl
acetate. After concentrating in the rotary evaporator and drying under
vacuum created by an oil pump, a white/yellow solid was obtained. This
was dissolved and recrystallized from boiling-hot ethanol before recording
the yield. IR, NMR and MS analysis were ultimately performed to
characterise the final product.
-
1 1
1
178, 1110, 1031, 952, 887, 829, 815, 748, 667, 628 cm . H NMR (500
) δ 13.90 (br s, 1H), 7.84 (d, J = 8.54 Hz, 1H), 7.69 (d, J = 7.98
Hz, 1H), 7.65 (d, J = 8.85 Hz, 1H), 7.50 (d, J = 8.85 Hz, 2H), 7.36 (ddd, J
1.37, 6.94, 8.54 Hz, 1H), 7.21 (ddd, J = 1.07, 6.87, 7.93 Hz, 1H), 7.14 (d,
J = 8.85 Hz, 1H), 6.78 (d, J = 8.85 Hz, 2H), 5.09 (s, 1H), 3.72 (s, 3H), 3.10
MHz, CDCl
3
=
-
4
3.44 (br s, 1H), 2.49 - 2.81 (m, 1H), 2.11 - 2.43 (m, 2H), 1.72 - 1.99 (br s,
H).
(
6j) 1-(4-pyridinyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol. White
crystals. M.P.: 150 0C. IR (NaCl): 3055, 3022, 2972, 2877, 2833, 1622,
1
8
597, 1521, 1506, 1465, 1413, 1344, 1315, 1267, 1238, 1157, 1120, 950,
-
1 1
3
91, 817, 748, 667, 632, 617 cm . H NMR (500 MHz, CDCl ) δ 13.37 (br
s, 1H), 8.51 (d, J = 6.10 Hz, 2H), 7.84 (d, J = 8.54 Hz, 1H), 7.72 (d, J =
.24 Hz, 1H), 7.69 (d, J = 8.85 Hz, 1H), 7.54 (d, J = 6.10 Hz, 2H), 7.41
ddd, J = 1.37, 6.94, 8.47 Hz, 1H), 7.24 - 7.26 (m, 1H), 7.15 (d, J = 8.85
Hz, 1H), 5.12 (s, 1H), 2.60 (br s, 1H), 2.31 - 2.55 (m, 3H), 1.77 - 1.97 (m,
8
(
4
1
5
H). 13C NMR (126 MHz, CDCl
) δ 155.60, 150.36, 149.64, 131.59, 130.09,
3
29.07, 128.64, 126.69, 123.16, 122.67, 120.59, 119.90, 115.29, 69.65,
+
3.46 23.43. MS (ES+): m/z = 305.21 [M+H] ,188.26, 162.07, 64.73, 51.01.
(
6k)
1-(4-fluorophenyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol.[33]
In order to test the recyclability of the catalyst, the same procedure above
was repeated with the difference being that the catalyst was left to dry
overnight in an oven set at 130 C before reusing it in the subsequent trial
Yellow crystals. M.P.: 146 0C. IR (NaCl): 3064, 3010, 2970, 2875, 2833,
1620, 1600, 1508, 1467, 1456, 1415, 1350, 1307, 1267, 1234, 1159, 1124,
0
-
1 1
1
097, 952, 835, 817, 771, 744, 667, 626 cm . H NMR (500 MHz, CDCl
δ 13.75 (br s, 1H), 7.82 (d, J = 8.54 Hz, 1H), 7.71 (d, J = 8.01 Hz, 1H), 7.67
d, J = 8.85 Hz, 1H), 7.55 - 7.60 (m, 2H), 7.37 (ddd, J = 1.37, 6.87, 8.54
Hz, 1H), 7.23 (ddd, J = 0.92, 6.94, 8.01 Hz, 1H), 7.15 (d, J = 8.85 Hz, 1H),
3
)
run.
(
Analytical information for selected compounds
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
1097, 943, 816, 744, 700 cm . 1H NMR (500 MHz, CDCl
-1
6
1
.92 - 6.98 (m, 2H), 5.12 (s, 1H), 3.01 – 3.52 (br s, 1H), 2.45 – 2.83 (br s,
H), 2.05 – 2.46 (br s, 1H), 1.87 (br s, 4H).
3
) δ 7.73 (br s,
1H), 7.69 - 7.74 (m, 3H), 7.40 - 7.45 (m, 2H), 7.27 - 7.36 (m, 3H), 7.20 -
7.25 (m, 2H), 7.15 (d, J = 8.85 Hz, 1H), 5.76 (s, 1H), 3.31 (br s, 1H), 2.02
-
2.10 (m, 1H), 1.89 - 1.97 (m, 1H), 1.62 - 1.75 (m, 2H), 1.55 - 1.61 (m, 2H),
(
6n) 1-(3,4-dichlorophenyl(pyrrolidine-1-yl)methyl)naphthalen-2-ol.
13C NMR (126 MHz, CDCl
) δ157.32, 141.97, 132.56,
3
Yellow crystals. M.P.: 64 0C. IR (NaCl): 3061, 3014, 2972, 2877, 2833,
1.39 - 1.53 (m, 2H).
29.60, 129.15, 128.85, 127.99, 127.74, 126.44, 122.32, 121.12, 120.29,
113.63, 62.51, 58.92, 32.79, 32.34, 23.54, 23.58. MS (ES+): m/z = 319.32
1
1
1
622, 1600, 1519, 1469, 1454, 1413, 1350, 1319, 1269, 1236, 1215, 1157,
-
1 1
3
122, 1031, 950, 896, 817, 748, 667, 636 cm . H NMR (500 MHz, CDCl )
+
+
[M+2] , 318.31 [M+H] , 304.01, 273.14, 233.04, 145.00, 86.17, 54.99.
δ 13.50 (br s, 1H), 7.78 (d, J = 8.54 Hz, 1H), 7.72 (d, J = 7.93 Hz, 1H), 7.67
-
7.70 (m, 2H), 7.47 (dd, J = 1.98, 8.39 Hz, 1H), 7.40 (ddd, J = 1.22, 7.02,
.54 Hz, 1H), 7.33 (d, J = 8.24 Hz, 1H), 7.23 - 7.25 (m, 1H), 7.15 (d, J =
.85 Hz, 1H), 5.08 (s, 1H), 3.02 – 3.49 (br s, 1H), 2.09 – 2.80 (br s, 3H),
8
8
1
1
1
3
2
(6z) 1-((isopentylamino)(phenyl)methyl)naphthalen-2-ol. White
crystals. M.P.:122 0C. IR (NaCl): 3313, 3061, 3024, 2955, 2924, 2866,
1622, 1601, 1558, 1520, 1468, 1456, 1414, 1317, 1269, 1238, 1092, 941,
.79 - 2.01 (br s, 4H). 13C NMR (126 MHz, CDCl
3
) δ 141.48, 132.63, 131.93,
-
1 1
31.55, 130.73, 130.28, 129.95, 129.03, 128.63, 127.79, 126.66, 122.63,
20.61, 119.98, 115.62, 69.60, 54.46, 52.43, 23.38. MS (ES+): m/z =
3
813, 745, 698 cm . H NMR (500 MHz, CDCl ) δ 7.68 – 7.78 (m, 3H), 7.43
- 7.47 (m, 2H), 7.27 - 7.36 (m, 3H), 7.20 - 7.25 (m, 2H), 7.15 (d, J = 8.85
Hz, 1H), 5.67 (s, 1H), 2.84 (dd, J = 6.56, 8.09 Hz, 2H), 1.63 (td, J = 6.60,
13.35 Hz, 1H), 1.52 - 1.60 (m, 3H), 1.41 - 1.51 (m, 1H), 0.89 (d, J = 6.41
+
+
74.16 [M+2] , 372.07 [M] , 328.24, 304.07, 264.03, 229.25, 216.91,
14.95, 144.93, 90.92, 54.87.
Hz, 6H). 13C NMR (126 MHz, CDCl
3
) δ 156.92, 141.74, 132.63, 129.64,
1-(4-methylphenyl(piperidine-1-yl)methyl)naphthalen-2-ol.[34]
129.10, 128.84, 128.48, 128.07, 127.74, 126.41, 122.36, 121.16, 120.17,
(
6r)
White crystals. M.P.: 145 0C. IR (NaCl): 3049, 3008, 2937, 2856, 2814,
113.41, 64.55, 47.48, 38.62, 26.07, 22.57, 22.51.MS (ES+): m/z = 320.27
+
[
M+H] , 273.27, 249.04, 233.04, 176.18, 144.93, 88.07.
1
1
622, 1601, 1519, 1454, 1417, 1361, 1315, 1269, 1236, 1217, 1157, 1107,
-
1 1
087, 1037, 945, 875, 839, 819, 756, 667, 611 cm . H NMR (500 MHz,
) δ 14.00 (br s, 1H), 7.82 (d, J = 8.54 Hz, 1H), 7.67 (d, J = 7.70 Hz,
H), 7.64 (d, J = 8.85 Hz, 1H), 7.42 (br s., 2H), 7.34 (ddd, J = 1.22, 6.94,
CDCl
3
(6aa) 1-((benzylamino)(phenyl)methyl)naphthalen-2-ol.[36]
White
1
8
1
2
crystals. M.P.: 132 0C. IR (NaCl): 3310, 3061, 3028, 2853, 1620, 1600,
1583, 1520, 1494, 1467, 1452, 1414, 1317, 1269, 1238, 1157, 1072, 1028,
.62 Hz, 1H), 7.19 (ddd, J = 1.22, 6.94, 8.01 Hz, 1H), 7.13 (d, J = 8.85 Hz,
H), 7.05 (d, J = 8.24 Hz, 2H), 5.04 (s, 1H), 3.30 (br s, 1H), 2.67 (br s, 1H),
.24 (s, 3H), 2.11 (br s, 1H), 1.91 (br s, 1H), 1.68 (br s, 4H), 1.56 (br s, 2H).
939, 818, 742, 698 cm . 1H NMR (500 MHz, CDCl
7.72 - 7.77 (m, 2H), 7.69 (d, J = 8.54 Hz, 1H), 7.26 - 7.40 (m, 9H), 7.19 -
.26 (m, 4H), 5.76 (s, 1H), 4.06 (d, J = 13.12 Hz, 1H), 3.83 (d, J = 13.12
-1
) δ 13.55 (br s, 1H),
3
7
Hz, 1H).
(
6u) 1-((morpholino(4-methylphenyl)methyl)naphthalen-2-ol. White
0
crystals. M.P.: 54 C. IR (NaCl): 3055, 3012, 2963, 2920, 2853, 1622, 1506,
1
7
8
456, 1414, 1362, 1314, 1271, 1234, 1119, 1072, 1003, 949, 878, 814,
(6bb) 1-((benzylamino)(4-cyanophenyl)methyl)naphthalen-2-ol. White
crystals. M.P.: 54 C. IR (NaCl): 3302, 3061, 3028, 2853, 2228, 1622, 1601,
-
1
1
0
68, 667 cm . H NMR (500 MHz, CDCl
3
) δ 13.14 (br s, 1H), 7.83 (d, J =
.54 Hz, 1H), 7.69 (d, J = 7.93 Hz, 1H), 7.66 (d, J = 8.85 Hz, 1H), 7.44 (d,
1558, 1520, 1468, 1454, 1414, 1269, 1238, 1159, 1076, 1018, 939, 820,
-
1 1
J = 8.24 Hz, 2H), 7.37 (ddd, J = 1.53, 7.02, 8.54 Hz, 1H), 7.23 (ddd, J =
3
748, 698 cm . H NMR (500 MHz, CDCl ) δ 13.12 (br s, 1H), 7.75 - 7.79
1
.07, 6.87, 7.93 Hz, 1H), 7.13 (d, J = 8.85 Hz, 1H), 7.08 (d, J = 8.24 Hz,
(m, 2H), 7.61 (d, J = 8.54 Hz, 1H), 7.56 (d, J = 8.54 Hz, 2H), 7.51 (d, J =
8.54 Hz, 2H), 7.32 - 7.40 (m, 4H), 7.26 - 7.31 (m, 3H), 7.20 (d, J = 8.85 Hz,
1H), 5.80 (s, 1H), 4.03 - 4.10 (m, 1H), 3.82 (d, J = 12.82 Hz, 1H). 13C NMR
2
H), 5.09 (s, 1H), 3.81 (br s, 4H), 3.11 (br s, 1H), 2.35 - 2.62 (m, 3H), 2.25
(
s, 3H). 13C NMR (126 MHz, CDCl
) δ 154.71, 137.99, 135.61, 132.35,
3
1
7
2
29.72, 129.66, 129.59, 128.90, 126.53, 122.58, 121.05, 119.76, 115.27,
1.72, 66.93, 53.96, 51.52, 21.05. MS (ES+): m/z = 334.25 [M+H] , 320.27,
78.20, 277.19, 259.23, 247.15, 233.17, 201.16, 161.82, 142.97, 105.02.
3
(126 MHz, CDCl ,) δ 156.74, 146.23, 137.47, 132.89, 132.39, 130.47,
+
129.12, 128.94, 128.64, 128.56, 128.05, 126.88, 122.84, 120.60, 120.15,
+
118.40, 112.01, 111.92, 61.82, 52.59. MS (ES+): m/z = 365.11 [M+H] ,
221.02, 196.04, 186.99, 144.68, 143.98, 107.93, 90.92, 88.89.
(
6w) 1-((morpholino(4-cyanophenyl)methyl)naphthalen-2-ol. White
0
crystals. M.P.: 94 C. IR (NaCl): 3019, 2965, 2857, 2228, 1622, 1520, 1472,
1
-
1
456, 1417, 1361, 1314, 1267, 1234, 1117, 949, 880, 818, 752, 667 cm .
Acknowledgements
1
H NMR (500 MHz, CDCl
7.75 (m, 4H), 7.58 (d, J = 8.54 Hz, 2H), 7.41 (ddd, J = 1.37, 6.94, 8.47
Hz, 1H), 7.25 – 7.30 (m, 1H), 7.14 (d, J = 8.85 Hz, 1H), 5.18 (s, 1H), 3.82
br s, 4H), 2.15 – 2.65 (m, 4H). 13C NMR (126 MHz, CDCl
) δ 154.74,
54.48, 144.11, 140.59, 138.80, 132.71, 132.01, 130.44, 129.16, 128.89,
26.94, 122.97, 120.44, 119.84, 118.29, 113.97, 112.20, 71.38, 66.71,
3
) δ 12.80 (s, 1H), 7.77 (d, J = 8.54 Hz, 1H), 7.68
–
The authors thank the University of Malta for financial and
technical support. The authors would also like to thank Prof.
Robert M. Borg for assistance with the acquisition of the NMR
spectra and Mr. Godwin Sammut for MS analyses. The
contribution of COST (European Cooperation in Science and
Technology) Action CA15106 (C–H Activation in Organic
Synthesis – CHAOS) is acknowledged.
(
3
1
1
5
1
+
+
+
3.61, 51.91. MS (ES+): m/z = 345.25 [M+H] , 344.24 [M] , 343.23 [M-1] ,
95.09, 172.95, 172.00.
(
6x) 1-((butylamino)(phenyl)methyl)naphthalen-2-ol.[35]
crystals.M.P.: 146 0C. IR (NaCl): 3300, 3061, 3028, 2959, 2926, 2856,
White
1
1
7
7
622, 1600, 1519, 1471, 1456, 1418, 1373, 1319, 1269, 1238, 1159, 1141,
092, 939, 815, 765, 748, 698 cm . H NMR (500 MHz, CDCl ) δ 7.68 –
3
.76 (m, 3H), 7.43 - 7.48 (m, 2H), 7.27 - 7.36 (m, 3H), 7.20 - 7.25 (m, 2H),
.15 (d, J = 8.85 Hz, 1H), 5.67 (s, 1H), 2.83 (t, J = 7.17 Hz, 2H), 1.50 - 1.67
Keywords: Multi-component reactions • Solventless • Green
chemistry • Heterogeneous catalysis • One-pot • Clay catalyst
-
1 1
[
[
[
1]
2]
3]
a) B. Ganem, Acc. Chem. Res. 2009, 17, 463 – 472; b) R. C. Cioc, E.
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V. A. Chebanov, S. M. Desenko, Diversity Oriented Synth. 2014, 1, 43 –
(
6y) 1-((cyclopentylamino)(phenyl)methyl)naphthalen-2-ol. White
63.
crystals. M.P.: 128 0C. IR (NaCl): 3300, 3061, 3022, 2954, 2866, 1622,
a) H. B. Chen, Y. Zhao, Y. Liao, RSC Adv. 2015, 5, 37737 – 37741; b)
G. Bosica, J. Gabarretta, RSC Adv., 2015, 5, 46074-46087.
1601, 1585, 1558, 1520, 1468, 1456, 1414, 1379, 1315, 1269, 1236, 1155,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800826
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Multi-component reactions • Green
chemistry • One-pot • Heterogeneous
catalysis
Giovanna Bosica*, Roderick Abdilla and
Kaylie Demanuele
Page No.1 – Page No.9
The one-pot multicomponent Betti synthesis was performed under green
heterogeneous and neat conditions in the presence of Montmorillonite K30 catalyst,
which is safe, cheap, and commercially available and does not require any
preparations. It is fully recoverable and recyclable for up to 5 runs. Both secondary
and primary aliphatic amines give products in good to excellent yields. The
developed protocol displays a very high Atom Economy and a low E-Factor.
Revisiting the Betti synthesis: using a
cheap, readily-available, recyclable
clay catalyst in solventless
conditions
This article is protected by copyright. All rights reserved.