β-naphthol in glycerol: A versatile pair for efficient and convenient synthesis of aminonaphthols, naphtho-1,3-oxazines, and benzoxanthenes

Article abstract of DOI:10.1055/s-0033-1338430

Three-component Betti reaction was carried out in the environmentally benign, inexpensive, non-toxic solvent glycerol. Even in the absence of a catalyst, the reaction went completion with an unprecedented high rate and the expected Betti bases were obtained in up to 91% yield. The reaction works well for representative cyclic, acyclic, aliphatic, and aromatic amines and aldehydes. A benzoxanthene was also prepared in 93% yield following the same methodology with 20 mol% methanesulfonic acid catalyst. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338430

1564▌
PAPER
pβa-peNr aphthol in Glycerol: A Versatile Pair for Efficient and Convenient
Synthesis of Aminonaphthols, Naphtho-1,3-oxazines, and Benzoxanthenes
Synthesis of Aminonaphthols, Naphtho-1,3-oxazines, and Benzoxanthenes
Subramaniapillai Selva Ganesan,*a Narendran Rajendran,b Sankahr Ilathur Sundarakumar,a Asaithampi Ganesan,a
Brindha Pemiahb
a
School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu, India
Fax +91(4362)264120; E-mail: selva@biotech.sastra.edu
b
CARISM, SASTRA University, Thanjavur 613401, Tamil Nadu, India
Received: 18.02.2013; Accepted after revision: 28.03.2013
R
Abstract: Three-component Betti reaction was carried out in the
environmentally benign, inexpensive, non-toxic solvent glycerol.
Even in the absence of a catalyst, the reaction went completion with
an unprecedented high rate and the expected Betti bases were ob-
R1
O
tained in up to 91% yield. The reaction works well for representa-
N
N
NMe2
OH
tive cyclic, acyclic, aliphatic, and aromatic amines and aldehydes.
A benzoxanthene was also prepared in 93% yield following the
same methodology with 20 mol% methanesulfonic acid catalyst.
OH
O
R
R2
Key words: glycerol, Betti reaction, one-pot synthesis, naphtho-
1,3-oxazine, benzoxanthenes
1 (ref. 2)
2 (ref. 2)
(antipain agent)
3 (ref. 3)
(antibacterial)
(antipain agent)
Me
O
OH
The Betti reaction,1 discovered by Mario Betti is useful in
the synthesis of substituted aminonaphthols. Aminonaph-
thols have several interesting biological applications, for
example as antipain agents 1 and 2,2 antibacterial activity
3,3 and enhancing drug cytotoxicity to multidrug resistant
cell lines 4,4 etc. (Figure 1). Betti base derivatives have
been employed in the total synthesis of tropane alkaloids5
and they have also been used as a chiral auxiliary in natu-
ral product synthesis.6 Recently, heterogeneous copper(II)
triflate–silica gel,7 copper nanoparticle,8 nanocrystalline
magnesium oxide,9 and non-ionic surfactant10 catalyzed
Betti reactions have been reported in literature. Novel
methodologies in Betti reaction are required to avoid the
use of catalysts and to reduce reaction times. Multicompo-
nent reactions carried out in unconventional/non-organic
solvents have attracted much attention to date.11 Its inex-
pensive, nontoxic, biocompatible, polar nature, and easy
availability makes glycerol a suitable and viable alterna-
tive to solvents such as ionic liquids and supercritical car-
bon dioxide. Recent review article on glycerol by
Cardierno and co-workers12 and Jérôme and co-workers13a
provide good insight into organic transformations carried
out in glycerol solvent. To the best of our knowledge, the
Betti reaction in glycerol has not been reported.
HO
N
Me
O
O
O
OR
O
O
OH
NH
OH
HO
O
O
Br
R =
HO
OMe
4 (ref. 4)
OMe
N-tylosil-1-α-amino-(3-bromophenyl)-methyl-2-naphthol (4)
(enhances cytotoxicity of drugs)
Figure 1 Bioactive Betti base derivatives
of β-naphthol into the corresponding product 6 was ob-
served. Encouraged by this result, we decided to further
investigate the role of temperature and co-solvent on the
Betti reaction in glycerol (Scheme 1, Table 1).
O
N
glycerol
We were interested in investigating the Betti reaction in
glycerol solvent. Initially, a trial reaction was carried out
with β-naphthol (5, 1 mmol), formaldehyde (2 mmol), and
morpholine (2 mmol). At room temperature, β-naphthol
(5) was sparingly soluble in glycerol. However, after stir-
ring for one hour at room temperature, partial conversion
O
OH
OH
1 min
+
CH2O
+
40 °C
N
(37% soln)
H
5
6
91% yield (with 1 mmol of 5)
84% yield (with 10 mmol of 5)
Scheme 1 Aminonaphthol synthesis in glycerol
SYNTHESIS 2013, 45, 1564–1568
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338430; Art ID: SS-2013-Z0059-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Aminonaphthols, Naphtho-1,3-oxazines, and Benzoxanthenes
1565
The formation of product 6 can be easily observed with
the naked eye [Figure 2 (e)]. After one minute, the reac-
tion was quenched with water (2 mL) and the product was
filtered off.
Table 1 Effect of Temperature and Co-solvent on the Yield of the
Betti Reaction Product 6
Entry Methoda Solvent
Temp Time
Yield
(%)
(°C)
(min)
1
2
3
4
5
6
7
A
B
B
C
C
C
D
glycerol
r.t.
40
80
r.t.
1
87
91
86
87
89
69
81
glycerol
1
glycerol
1
glycerol–EtOH (1:1)
3
glycerol–MeOH (1:1) r.t.
3
glycerol–H2O (1:1)
glycerol
r.t.
80
10
10
Figure 2 Sequence: (a) β-Naphthol in glycerol at r.t. (b) After heated
in a water bath at 90 °C for 5 min. (c) After the addition of morpho-
line. (d) Immediately, after the addition of 37% formaldehyde solu-
tion. (e) Reaction mixture after 1 min. (f) Reaction mixture after
quenching with H2O.
a Method A: 1. β-naphthol (1 mmol), glycerol (2 mL), 90 °C (water
bath), 5 min (dissolution); 2. cooled to r.t.; 3. successive addition of
morpholine (2 mmol) and 37% CH2O (2 mmol), r.t., stirring. Method
B: 1. β-naphthol (1 mmol), glycerol (2 mL), indicated temperature,
stirring, 10 min (homogeneous soln); 2. successive addition of mor-
pholine (2 mmol) and 37% CH2O (2 mmol), indicated temperature,
stirring, indicated time. Method C: β-naphthol (1 mmol), glycerol–
alcohol or H2O (1:1, 2 mL) (homogeneous soln, entries 4 and 5); sus-
pension, entry 6), successive addition of morpholine (2 mmol) and
37% CH2O (2 mmol), r.t., stirring. Method D: β-naphthol (1 mmol),
paraformaldehyde (1.5 mmol), morpholine (1.5 mmol), glycerol (2
mL), stirring, 80 °C, 10 min.
A stock solution of β-naphthol (5) in glycerol solvent
could be prepared by heating β-naphthol (10 mmol) in
glycerol (20 mL) in a water bath at 90 °C for approximate-
ly 30 minutes. The homogeneous solution thus obtained
was kept undisturbed at room temperature. However, after
eight hours, β-naphthol (5) began to crystallize from the
solution. Hence, it is essential use a freshly prepared solu-
tion of β-naphthol (5) in glycerol in this reaction. In order
to investigate the scope of reaction during the scale-up
process, the following reaction was performed. To a ho-
mogeneous solution of β-naphthol (5, 10 mmol) in glycer-
ol (20 mL) at 40 °C, morpholine (20 mmol) and 37%
formaldehyde (20 mmol) were added successively in each
in one portion and the reaction mixture was further vigor-
ously stirred at 40 °C for a further 10 minutes. TLC anal-
ysis of reaction mixture revealed the clean and complete
conversion of β-naphthol (5) to the corresponding Betti
base product 6 in 84% yield. This observation shows that
the reaction can be scaled up without difficulty. After
standardizing the reaction conditions in glycerol, the reac-
tion was screened with different amines and aldehyde
(Schemes 2 and 3, Table 2). Acyclic aliphatic amines gave
comparable yields to that of morpholine. However, after
quenching, dimethylamine, diethylamine, and diethanol-
amine products 7–9 could not be isolated by simple filtra-
tion. The products were extracted with ethyl acetate (2 × 2
mL) using a cyclomixer.
Under homogeneous conditions (Table 1, Method A), the
reaction is complete within one minute and the amino-
naphthol product 6 was obtained in 87% yield (entry 1). It
was previously reported in the literature that as the tem-
perature increases, the viscosity of glycerol decreases sub-
stantially and this facilitates the solubility of substrates
and increases the product yield.13 A slight increase in the
reaction temperature to 40 °C only gave a marginal im-
provement in the yield (entry 2) while a further increase in
the temperature above 40 °C reduced the product yield
(entry 3). The use of methanol or ethanol as a co-solvent
enabled the reaction to be performed at room temperature
(entries 4 and 5). In both cases, aminonaphthol product 6
was obtained in good yields. Addition of water as a co-
solvent reduced the solubility of β-naphthol (5) in glycerol
and thus reduced the product yield (entry 6). The replace-
ment of formaldehyde (37%) solution with paraformalde-
hyde did not affect the course of the reaction (entry 7).
Paraformaldehyde is insoluble in glycerol at room tem-
perature and, hence, the reaction must be carried out at a
higher temperature. The use of β-naphthol (1 mmol) in
glycerol (2 mL) was necessary to obtain the optimum
yield.
R2
R1
N
R2
glycerol
3–10 min
OH
+
OH
R22NH
R1CHO
+
40 or 90 °C
The sequence of Betti reaction in glycerol (Method A) is
presented in Figure 2. After the addition of formaldehyde
(37%) solution to the reaction mixture (d), an instanta-
neous exothermic reaction took place with immediate for-
mation of the Betti base product 6.
(37% soln)
5
7–10
up to 87% yield
R22NH = Me2NH, Et2NH, [HO(CH2)2]2NH, morpholine
R1CHO = CH2O, PhCHO
Scheme 2 Betti reaction in glycerol
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1564–1568

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S. S. Ganesan et al.
PAPER
Table 2 Betti Reaction of β-Naphthol (5), Amine, and Aldehyde in Glycerol Mediuma
Entry
Aldehyde
CH2O
Amine
Et2NH
Product
Temp (°C)
Time (min)
Yield (%)
Et
N
Et
1b
40
5
85 (80)c
OH
7
8
Me
N
Me
OH
2b
CH2O
Me2NH
40
5
87 (76)c
OH
OH
N
OH
3b
CH2O
[HO(CH2)2]2NH
40
3
85 (81)c
9
O
Ph
N
4d
PhCHO
morpholine
90
10
71
OH
10
O
N
5b,e
CH2O
CH2O
4-BrC6H4NH2
90
40
10
68
Br
11
O
N
6b,f
BnNH2
8
76 (63)c
12
a Conditions: β-naphthol (5, 1 mmol), glycerol (2 mL), amine (2 mmol), CH2O (2 mmol), stirring.
b After quenching with H2O, the mixture was extracted with EtOAc.
c Reaction carried using Method A (Table 1).
d After quenching with H2O, the mixture was filtered and the product was recrystallized (EtOAc).
e Conditions: β-naphthol (5, 1 mmol), glycerol (2 mL), amine (1.1 mmol), 37% CH2O (3 mmol); the crude product 11 was recrystallized (EtOAc).
f Conditions: β-naphthol (5, 1 mmol), glycerol (2 mL), amine (1.5 mmol), 37% CH2O (3 mmol). The crude product 12 was recrystallized (EtOAc)
and further confirmed by single crystal XRD.14
The Betti reaction in glycerol solvent was also screened ic amine (4-bromoaniline) and aliphatic primary amine
with a representative aromatic aldehyde. With benzalde- (benzylamine) were carried out in glycerol solvent. With
hyde, at room temperature only partial conversion of the excess formaldehyde, 4-bromoaniline and benzylamine
β-naphthol to the corresponding product 10 was observed. gave the corresponding naphtho-1,3-oxazine derivatives
Hence, reaction mixture was stirred in an oil bath at 90 °C 11 and 12, respectively (Scheme 3). It has been previously
for 10 minutes and the product 10 was formed in 71% reported in the literature that with excess formaldehyde,
yield (Table 2, entry 4). The Betti reaction of both aromat- primary amine Betti bases will be converted into the cor-
Synthesis 2013, 45, 1564–1568
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Aminonaphthols, Naphtho-1,3-oxazines, and Benzoxanthenes
1567
anes–EtOAc, 95:5) and products 8, 11, and 12 were recrystallized
(EtOAc).
R
N
glycerol
1-(Morpholinomethyl)naphthalen-2-ol (6)
White solid; yield: 221 mg (91%); mp 107–109 °C (Lit.16 113–
115 °C).
IR (KBr): 3431, 2946, 2845, 1656, 1120, 780 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.68 (br s, 4 H), 3.80 (s, 4 H), 4.15
(s, 2 H), 7.09 (d, J = 8.7 Hz, 1 H), 7.25–7.32 (m, 1 H), 7.43–7.48
(m, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.83
(d, J = 8.4 Hz, 1 H).
OH
+
O
8–10 min
+
RNH2
CH2O
40 or 90 °C
(37% soln)
5
R = 4-BrC6H4 (11), 68% yield
R = Bn (12), 76% yield
Scheme 3 Synthesis of naphthoxazine in glycerol
13C NMR (75 MHz, CDCl3): δ = 53.2, 56.8, 66.8, 110.4, 119.1,
responding naphthoxazine derivatives.3 The rate of the 121.0, 122.6, 126.5, 128.6, 129.0, 129.5, 132.8, 156.2.
Betti reaction in glycerol is unusually very high. The high
reaction rate could be attributed to the high polarity and
strong hydrogen-bonding network of glycerol solvent.
MS (ESI): m/z = 244 (M + 1).
1-[(Diethylamino)methyl]naphthalen-2-ol (7)
Gummy solid; yield: 195 mg (85%).
We were interested in extending this methodology further
to the synthesis of xanthenes. Xanthenes are interesting
class of heterocyclic molecules with good antiprolifera-
tion properties.15 In the presence of methanesulfonic acid
(0.4 mmol), β-naphthol (5, 2 mmol), and 4-fluorobenzal-
dehyde (1.1 mmol) in glycerol (1 mL) at 90 °C for 20 min-
utes gave the expected xanthene 13 in 93% yield (Scheme
4).
1H NMR (300 MHz, CDCl3): δ = 1.07 (t, J = 6.9 Hz, 6 H), 2.59 (q,
J = 6.6 Hz, 4 H), 4.09 (s, 2 H), 7.07 (d, J = 8.7 Hz, 1 H), 7.18–7.23
(m, 1 H), 7.33–7.38 (m, 1 H), 7.60 (d, J = 8.7 Hz, 1 H), 7.66–7.69
(m, 2 H), 12.18 (br s, 1 H).
MS (ESI): m/z = 230 (M + 1).
1-[(Dimethylamino)methyl]naphthalen-2-ol (8)
Light brown solid; yield: 175 mg (87%); mp 57–59 °C.
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 6 H), 4.10 (s, 2 H), 7.10
(d, J = 8.7 Hz, 1 H), 7.28–7.31 (m, 1 H), 7.41–7.46 (m, 1 H), 7.69
(d, J = 9.0 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 1
H).
F
CHO
MeSO3H
(0.4 mmol)
MS (ESI): m/z = 202 (M + 1).
OH
2
+
1-{[Bis(2-hydroxyethyl)amino]methyl}naphthalen-2-ol (9)
glycerol
90 °C, 20 min
Gummy solid; yield: 222 mg (85%).
5
F
1H NMR (300 MHz, CDCl3): δ = 2.75 (t, J = 5.1 Hz, 4 H), 3.72 (t,
J = 5.1 Hz, 4 H), 4.19 (s, 2 H), 5.84 (br s, 3 H), 7.04 (d, J = 9 Hz, 1
H), 7.24–7.28 (m, 1 H), 7.37–7.42 (m, 1 H), 7.61 (d, J = 8.7 Hz, 1
H), 7.69–7.76 (m, 2 H).
O
13
93% yield
Scheme 4 Xanthene synthesis in glycerol solvent
MS (ESI): m/z = 262 (M + 1).
1-[Morpholino(phenyl)methyl]naphthalen-2-ol (10)
Off-white solid; yield: 227 mg (71%); mp 175–177 °C (Lit.17a 177–
179 °C).
1H NMR (300 MHz, CDCl3): δ = 2.45 (br s, 4 H), 3.83 (br s, 4 H),
In conclusion, glycerol was found to be a versatile and en-
vironmentally benign solvent for the rapid, catalyst-free,
efficient, one-pot synthesis of Betti bases. A representa-
tive xanthene derivative was also prepared in good yield
in glycerol. This method offers several advantages such as
exploiting an environmentally benign solvent, shorter re-
action times, easy product isolation etc.
5.14 (s, 1 H), 7.16–7.86 (m, 11 H), 13.18 (br s, 1 H).
MS (ESI): m/z = 320 (M + 1).
2-(4-Bromophenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxa-
zine (11)
White crystals; yield: 230 mg (68%); mp 118–120 °C (Lit.17b 118–
120 °C).
All the reactions were carried out in 98% glycerol (Merck). All the
solvents and reagents were used without further purification.
1H NMR (300 MHz, CDCl3): δ = 4.93 (s, 2 H), 5.39 (s, 2 H), 7.02–
7.07 (m, 3 H), 7.34–7.43 (m, 3 H), 7.53–7.54 (m, 1 H), 7.65–7.70
(m, 2 H), 7.80 (d, J = 8.1 Hz, 1 H).
1-(Morpholinomethyl)naphthalen-2-ol (6); Typical Procedure
(Method B)
13C NMR (75 MHz, CDCl3): δ = 48.4, 79.4, 112.3, 114.2, 118.8,
120.4, 120.9, 123.9, 126.9, 128.6, 128.9, 129.2, 131.2, 132.3, 147.9,
152.3.
A dispersion of β-naphthol (5, 144 mg, 1 mmol) in glycerol (2 mL)
was stirred in an oil bath at 40 °C for 10 min. After complete disso-
lution, morpholine (174 μL, 2 mmol) and 37% CH2O soln (160 μL,
2 mmol) were added successively and the mixture was stirred at this
temperature for 1 min. The mixture was quenched with cold H2O (3
mL). For products 6 and 10, the precipitate was filtered, dried, and
recrystallized (EtOAc). For products 7–9, 11, and 12, after comple-
tion of the reaction, the mixture was quenched with H2O (3 mL) and
extracted with EtOAc (2 × 2 mL) using a cyclomixer. The organic
extract was separated, washed with brine, dried (anhyd Na2SO4),
and solvents were evaporated under reduced pressure. Products 7
and 9 were purified by column chromatography (silica gel, hex-
MS (ESI): m/z = 340 (M+).
2-Benzyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine (12)
White crystals; yield: 209 mg (76%); mp 123–125 °C.
1H NMR (300 MHz, CDCl3): δ = 4.00 (s, 2 H), 4.33 (s, 2 H), 4.97
(s, 2 H), 7.10 (d, J = 9.0 Hz, 1 H), 7.26–7.46 (m, 7 H), 7.55 (d, J =
8.4 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1564–1568

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S. S. Ganesan et al.
PAPER
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J. Org. Chem. 2011, 76, 2694.
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Chem. 2005, 70, 1897.
13C NMR (75 MHz, CDCl3): δ = 47.4, 56.2, 82.1, 111.8, 118.7,
121.2, 123.6, 126.6, 127.5, 128.1, 128.6, 128.7, 129.1, 132.0, 138.3,
151.9.
MS (ESI): m/z = 276 (M + 1).
(7) Dindulkar, S. D.; Puranik, V. G.; Jeong, Y. T. Tetrahedron
Lett. 2012, 53, 4376.
14-(4-Fluorophenyl)-14H-dibenzo[a,j]xanthene (13)
A dispersion of β-naphthol (288 mg, 2 mmol) in glycerol (1 mL)
was stirred in an oil bath at 90 °C for 5 min. After complete disso-
lution, 4-fluorobenzaldehyde (116 μL, 1.1 mmol) and MsOH (26
μL, 0.4 mmol) were added successively and the mixture was stirred
at 90 °C for 20 min. After completion of the reaction, the mixture
was quenched with cold H2O (3 mL) and the product was extracted
with EtOAc (3 × 5 mL). The solvents were evaporated, and the
product was recrystallized (EtOH) to give white crystals; yield: 350
mg (93%); mp 240–242 °C (Lit.18 239–240 °C).
(8) Kumar, A.; Saxena, A.; Dewan, M.; De, A.; Mozumdar, S.
Tetrahedron Lett. 2011, 52, 4835.
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(10) Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett.
2010, 51, 1582.
(11) Gu, Y. Green Chem. 2012, 14, 2091.
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Crochet, P.; Cadierno, V. Chem. Commun. 2011, 47, 6208.
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Savegnago, L.; Alves, D.; Jacob, R. G.; Lenardão, E. J.
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B.; Perin, G.; Lenardão, E. J.; Jacob, R. G.; Alves, D.
Tetrahedron Lett. 2011, 52, 4132.
IR (KBr): 3072, 3005, 2882, 1593, 1502, 1240, 834 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.43 (s, 1 H), 6.74–6.82 (m, 2 H),
7.36–7.46 (m, 6 H), 7.50–7.58 (m, 2 H), 7.72–7.82 (m, 4 H), 8.26–
8.31 (m, 2 H).
(14) Crystal data: For compound 12: Molecular formula:
C19H17NO, MW = 275.34, monoclinic, space group: P21/n,
a = 9.8559(6), b = 5.2439(3), c = 27.8100(16), α = 90.00, β =
98.750(3), γ = 90.00 (CCDC Deposition Number: 903651).
The crystal structure of the compound 12 has already been
reported: Yang, X.-H.; Chen, X.-L.; Diao, X.-J.; Wu, M.-H.
Acta Crystallogr., Sect. E: Struct. Rep. Online 2007, 63,
o3312.
Acknowledgment
Dr. S. Selva Ganesan thanks DST for DST-Fast Track grant (No:
SR/FT/CS-09/2011). All the authors thank the Director, Centre of
Advanced Study in Crystallography and Biophysics, University of
Madras for single crystal XRD facility and the Director, IICT for
LC-MS facility and SASTRA University for providing lab space
and NMR facilities.
(15) Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.;
Hiasa, H.; Ferguson, D. M. Bioorg. Med. Chem. 2010, 18,
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Synthesis 2013, 45, 1564–1568
© Georg Thieme Verlag Stuttgart · New York