Sulfanilic acid: A versatile and efficient catalyst among various organoacids screened for the synthesis of 1-amidoalkyl-2-naphthols under solvent-free condition

Article abstract of DOI:10.1007/s11164-013-1513-5

A series 1-amidoalkyl-2-naphthols were synthesized by one-pot three-component condensation reaction of β-naphthol with various aromatic aldehydes and amides under thermal (hot plate and oil bath) and microwave techniques. and the effect of various organoa

Full text of DOI:10.1007/s11164-013-1513-5

Res Chem Intermed
DOI 10.1007/s11164-013-1513-5
Sulfanilic acid: a versatile and efficient catalyst
among various organoacids screened for the synthesis
of 1-amidoalkyl-2-naphthols under solvent-free
condition
•
•
•
Rajesh K. Singh Balpreet Singh Robita Duvedi
Sahil Kumar
Received: 20 July 2013 / Accepted: 13 December 2013
Ó Springer Science+Business Media Dordrecht 2014
Abstract A series 1-amidoalkyl-2-naphthols were synthesized by one-pot three-
component condensation reaction of b-naphthol with various aromatic aldehydes
and amides under thermal (hot plate and oil bath) and microwave techniques. and
the effect of various organoacids used as catalyst was studied. Among the various
acids screened, p-aminobezene sulphonic acid (sulfanilic acid) came out to be a
versatile catalyst and the corresponding products were obtained in good to excellent
yield (84–94 %) under solvent-free condition.
Keywords Sulfanilic acid ꢀ 1-Amidoalkyl-2-naphthol ꢀ Organoacid
catalyst ꢀ One-pot reaction ꢀ Microwave irradiation ꢀ Solvent-free
Introduction
Nowadays, the 1-amidoalkyl-2-naphthols derivatives were paid much attention in
synthetic organic chemistry for their various biological activities. It has been reported
that 1-amidoalkyl-2-naphthols can be converted to biologically active 1-aminoalkyl-
2-naphthols derivatives by an amide hydrolysis reaction exhibiting depressor and
bradycardic activities in humans [1, 2]. In addition, 1-amidoalkyl-2-naphthols can also
be converted to 1, 3-oxazine derivatives [3, 4] which have widespread areas of useful
biological activities like antibiotic [5], antitumor [6], antipsychotic [7], antimalarial
[8], antianginal [9], antihypertensive [10], and antibacterial [11]. Recently, the 1,3-
R. K. Singh (&) ꢀ B. Singh ꢀ R. Duvedi
Pharmaceutical Chemistry Division, Shivalik College of Pharmacy, (Under Local Govt. Dept.,
Punjab) Nangal, Distt-Rupnagar, Nangal 140126, Punjab, India
e-mail: rksingh244@gmail.com
S. Kumar
Department of Pharmaceutical Chemistry, Indo-Soviet Friendship (I.S.F.) College of Pharmacy,
Ferozepur G.T. Road, Moga 142001, Punjab, India
123

R. K. Singh et al.
oxazine nucleus has attracted considerable interest because it is a good synthon for the
production of potent drugs including nucleoside antibiotics and HIV protease
inhibitors, such as ritonavir and lipinavir [12, 13].
Because of this unique position in synthetic as well as medicinal chemistry, there
have been intensive searches for theses compounds’ efficient and facile synthesis. A
literature survey reveals the established method for the synthesis of these
compounds by condensation reaction of aromatic aldehydes, 2-naphthol, and
amides or urea in the presence of a variety of catalysts such as chlorosulphonic acid
[14], p-toluene sulphonic acid [15], NaHSO4ꢀH2O [16], Fe(HSO4)3 [17], Sr(OTf)2
[18], iodine [19], boric acid [20], hetropoly acid catalysts like cation-exchange
resins [21], silica-supported perchloric acid [22, 23], FeCl3.SiO2 [24], montmoril-
lonite K10 clay [25], silica sulfuric acid [26], sulfamic acid [27, 28], N,N,N0,N0-
tetrabromobenzene-1,3-disulfonamide [29], and ionic liquids [30–34]. However, the
majority of them suffer from several limitations such as high temperature, long
reaction time, the use of expensive reagents, low yields of products, high catalyst
loading, corrosive reagents, strongly acidic conditions, and further purification of
products. Therefore, the development and introduction of convenient and efficient
methods for the preparation of 1-amidoalkyl-2-naphthols is of practical importance
and is still demanded. According to the principle of safe chemistry, synthetic
methods should be designed to use substances that exhibit little or no toxicity to
human health and the environment [35, 36].
In recent years, a lot of attention has been paid to green synthesis by organocatalysts
owing to their eco-friendliness and ability to proceed under aerobic atmosphere, while
other notable advantages are: usually less expensive and commercial available [37]. In
continuation with our research for the exploration of various catalysts and
development of green procedure for the synthesis of various heterocyclic and
synthetic intermediates [38–46], in this study, we have screened various readily
available organoacids for their catalytic activity in the synthesis of 1-amidoalkyl-2-
naphthols by thermal and microwave techniques. Various acids like sulfanilic acid,
citric acid, chloroacetic acid, anthranilic acid, malic acid, and nicotinic acid have been
used to catalyze the synthesis of 1-amidoalkyl-2-naphthols, out of which sulfanilic
acid came out to be the most effective catalyst under solvent-free condition by three
methods (A, B, and C). The synthetic approach is outlined in Scheme 1.
Sulfanilic acid
(0.2 mmol,
catalyst)
OH
O
+
+
X-CHO
NH
R
X
H2N
R
OH
Method (A, B, C)
O
X=Substituted aryl/heteroarylaldehydes
R1=Various amides
Method A: Microwave irradiation
Method B: Oil bath
Method C: Hot plate
Scheme 1 Synthesis of 1-amidoalkyl-2-naphthols
123

Sulfanilic acid
O
O
O
S
OH
H
H2N
S O
O
H2N
S OH
O
H3N
OH
O
Sulfanilic acid
Fig. 1 Amphiprotic property of sulfanilic acid
Sulfanilic acid is useful, inexpensive, and environmentally benign, and exists as
grayish-white crystals or powder, which is stable and incompatible with strong
oxidizing agents. It has earlier been used as catalyst for the synthesis of a wide
variety of heterocyclic compounds [47–49]. The solid exists as zwitterion. The
amine and sulphonic acid functional groups found in sulfanilic acid allow them to
have amphiprotic properties (Fig. 1). Sulfonic acid groups (–SO3H) can be
deprotonated to become negative sulfonate (–SO3-), and amino groups which can
be protonated to become positive ammonium groups (–NH3?). The zwitter ionic
property of sulfanilic acid may be responsible for the excellent catalytic property for
the synthesis of amidoalkyl naphthols, where strong bronsted acid is found
detrimental. It offers milder conditions relative to other strong acids such as
sulphonic acid, p-TSA, chloroacetic acid, etc. Moreover, sulfanilic acid is
commercially available, cheap, non-corrosive and hence easy to handle, non-
inflammable, and a stable catalyst compared to other organoacid catalysts which are
corrosive, expensive, and provide strongly acidic conditions. The removal of
organic solvents and their disposal are the most important goal in green chemical
synthesis. The remarkable catalytic activities of sulfanilic acid in solvent-free
condition provide operational simplicity and make it the most suitable catalyst
among various catalysts screened, having none of the above-mentioned drawbacks.
Experimental
All the chemicals were purchased from commercial suppliers. The melting points
were determined on a Veego-programmable melting point apparatus (microproces-
sor based) and are uncorrected. 1H NMR spectra were obtained using a Brucker AC-
400 F, 400 MHZ spectrometer. IR spectra were obtained with Perkin Elmer 882
Spectrum and RXI and FT-IR. Elemental analyses for C, H, and N were performed
on a Thermo-flash EA-1112 CHNS-O Analyzer. Reactions were monitored and the
homogeneity of the products was checked by TLC. All chemicals were dried and
freshly prepared prior to use according to standard procedure.
General procedure for the preparation of 1-amidoalkyl-2-naphthols
Method A
A mixture of substituted aromatic aldehydes (1 mmol), 2-naphthol (1 mmol), and
substituted amides (1.2 mmol) in the presence of effective amount of sulfanilic acid
(20 mol%, 0.2 mmol) were taken in a 20-ml conical flask and was subjected to
123

R. K. Singh et al.
microwave irradiation in microwave oven (LG model MS1927C) at 450 W and
each pulse was of 30 s with intermittent time to avoid overheating for the
appropriate time to avoid overheating. The reaction mass was cooled to room
temperature, washed with water, and filtered. Then, the solid residue was
recrystallized from ethanol to get the purified product.
Method B
A mixture of substituted aromatic aldehydes (1 mmol), 2-naphthol (1 mmol),
substituted amides (1.2 mmol), and effective amounts of sulfanilic acid (20 mol%,
0.2 mmol) were taken in a 100-ml conical flask and heated in an oil bath at
110–120 °C for the appropriate time with occasionally stirring. The progress of the
reaction was monitored by TLC. After completion of the reaction, the mass was
cooled to room temperature, washed with water, and filtered. The solid residue was
purified by recrystallization from EtOH to get the purified product.
Method C
A mixture of substituted aromatic aldehydes (1 mmol), 2-naphthol (1 mmol),
substituted amides (1.2 mmol), and sulfanilic acid (20 mol%, 0.2 mmol) were
crushed in a mortar and pestle to a fine powder, transferred into a china dish, and
heated on hot plate at 110–115 °C for an appropriate time with occasional stirring.
After completion of the reaction followed by TLC, water (10 ml) was added, and
the solution filtered and then recrystallized from ethyl alcohol to get the pure
product.
All the products were identified by their 1H NMR, IR, and CHN data and
compared with literature reports.
Spectral data for the 1-amidoalkyl-2-naphthols
N-[(2-Hydroxynaphthalen-1-yl)-phenyl-methyl)]-acetamide (Entry 1)
IR(KBr, mmax/cm-1): 3,441 (O–H, Ar, str), 3,177 (N–H 2°amide, str), 3,057 (C–H,
Ar, str), 1,694 ([C=O, amide, str), 1,555–1,462 (C=C, Ar, str), 1,243–1,095 (C–N/
C–O, str), 770 (C–H, Ar, out of plane, bend), 746 (N–H, out of plane, bend); H
1
NMR (400 MHz, DMSO-d6): d 9.85 (s, 1H, –CONH), 8.27 (d, J = 12 Hz, Ar–OH)
7.97 (t, J = 8 Hz, 1H, Ar–H), 7.75 (d, J = 8 Hz, 1H, Ar–H), 7.69 (d, J = 8 Hz,
1H, Ar–H), 7.40–7.12 (m, 9H, Ar–H), 2.04 (s, 3H, –COCH3); Anal. Calcd. for
C19H17NO2: C 78.33, H 5.87, N 4.81; Found: C 77.47, H 5.79, N 4.76 %.
N-[(2-Hydroxynaphthalen-1-yl)-phenyl-methyl)]-urea (Entry 2)
IR (KBr, mmax/cm-1):3,319 (O–H, Ar, str), 3,272 (N–H 2°amide, str), 3,067–3,025 (C–
H, Ar, str), 1,694 ([C=O, amide, str), 1,594–1,401 (C=C, Ar, str), 1,221–1,106 (C–N/
C–O, str), 830 (C–H, Ar, out of plane, bend), 745 (N–H, out of plane, bend); 1H NMR
(400 MHz,DMSO-d6): d 8.76 (s, 1H, -CONH), 7.83–7.68 (m, 4H, Ar–H), 7.65 (d,
123

Sulfanilic acid
J = 8 Hz, Ar–OH), 7.55–7.18 (m, 8H, Ar–H), 6.09 (s, 2H, -NH2); Anal. Calcd. for
C18H16N2O2: C 73.95, H 5.52, N 9.58; Found: C 73.90, H 5.49, N 9.59 %.
N-[(2-Hydroxynaphthalen-1-yl)-phenyl-methyl)]-benzamide (Entry 3)
IR (KBr, mmax/cm-1): 3,420 (O–H, Ar, str), 3,217 (N–H 2°amide, str), 3,021 (C–H,
Ar, str), 1,629 ([C=O, amide, str), 1,515–1,435 (C=C, Ar, str), 1,270–1,076 (C–N/
C–O, str), 822 (C–H, Ar, out of plane, bend), 750 (N–H, out of plane, bend); H
1
NMR (400 MHz, DMSO-d6): d 10.09 (bs, 1H, -CONH), 8.92 (d, J = 8 Hz, Ar–
OH), 8.15 (d, J = 8 Hz, 1H, Ar–H), 7.91–7.78 (m, 6H, Ar–H), 7.73–7.12 (m, 9H,
Ar–H), 6.55 (s, 1H, -CHNH); Anal. Calcd. for C24H19NO2: C 81.56, H 5.42, N 3.96;
Found: C 81.65, H 5.69, N 3.87 %.
N-[(4-Chlorophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-urea (Entry 4)
IR (KBr, mmax/cm-1): 3,320 (O–H, Ar, str), 3,179 (N–H 2°amide, str), 3,022 (C–H,
Ar, str), 1,694 ([C=O, amide, str), 1,592–1,431 (C=C, Ar, str), 1,402–1,107 (C–N/
C–O, str), 803 (C–H, Ar, out of plane, bend), 830 (C–Cl, str), 744 (N–H, out of
plane, bend); 1H NMR (400 MHz,DMSO-d6): d 8.75 (s,1H, -CONH), 7.88–7.83 (m,
4H, Ar–H), 7.40–7.27 (m, 7H, Ar–H), 7.59 (d, J = 8 Hz, Ar–OH), 6.09 (bs, 2H,
–NH2); Anal. Calcd. for C18H15ClN2O2: C 66.16, H 4.63, N 8.57; Found: C 66.20,
H 4.57, N 8.63 %.
N-[(4-Chlorophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-acetamide (Entry 5)
IR (KBr, mmax/cm-1): 3,391 (N–H 2°amide, str), 3,218 (O–H, Ar, str), 3,056 (C–H,
Ar, str), 1,624 ([C=O, amide, str), 1,515–1,437 (C=C, Ar, str), 1,277–1,091 (C–N/
C–O, str), 847 (C–H, Ar, out of plane, bend), 817 (C–Cl, str), 746 (N–H, out of
1
plane, bend); H NMR (400 MHz,DMSO-d6): d 9.86 (s, 1H, –CONH), 8.25 (d,
J = 12 Hz, Ar–OH), 7.97–7.66 (m, 4H, Ar–H), 7.41–7.11 (m, 7H, Ar–H), 2.04 (s,
3H, –COCH3); Anal. Calcd. for C19H16ClNO2: C 70.03, H 4.95, N 4.30; Found: C
69.97, H 4.91, N 4.38 %.
N-[(4-Chlorophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-benzamide (Entry 6)
IR (KBr, mmax/cm-1): 3,419 (–NH 2°amide, str), 3,279 (–OH, Ar, str), 3,056 (C–H, Ar,
str), 1,629 (C=O, amide, str), 1,513–1,440 (C=C, Ar, str), 1,265–1,048 (C–N/C–O, str),
831 (C–H, Ar, out of plane, bend), 811 (C–Cl, str), 723 (N–H, out of plane, bend); 1H
NMR (400 MHz,DMSO-d6): d 10.14 (s, 1H, –CONH), 8.90 (d, J = 8 Hz, Ar–OH), 8.12
(d, J = 8 Hz, 1H, Ar–H), 7.89–7.71 (m, 4H, Ar–H), 7.52–7.20 (m, 11H, Ar–H); Anal.
Calcd. for C24H18ClNO2: C 74.32, H 4.68, N 3.61; Found: C 73.78, H 4.76, N 3.56 %.
N-[(4-Dimethylamino-phenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-urea (Entry 7)
IR (KBr, mmax/cm-1): 3,424 (N–H, Ar, str), 3,217 (O–H 2°amide, str), 3,150 (C–H,
Ar, str), 2,951–2,917 (C–H, alkane, str), 1,697 ([C=O, amide, str), 1,518–1,386
123

R. K. Singh et al.
(C=C, Ar, str), 1,220–1,112 (C–N/C–O, str), 818 (C–H, Ar, out of plane, bend), 741
(N–H, out of plane, bend); 1H NMR (400 MHz,DMSO-d6): d 9.68 (s, 1H, –CONH),
7.85–7.15 (m, 10H, Ar–H) 6.74 (bs, Ar–OH), 6.01 (s, 1H, –CHNH), 5.79 (bs, 2H,
–NH2), 2.92 (s, 6H, –N(CH3)2); Anal. Calcd. for C20H21N3O2: C 71.62, H 6.31, N
12.53; Found: C 73.76, H 7.94, N 11.18 %.
N-[(4-Dimethylaminophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-acetamide
(Entry 8)
IR (KBr, mmax/cm-1): 3,372 (O–H, Ar, str), 3,248 (N–H 2°amide, str), 3,084 (C–H,
Ar, str), 2,924 (C–H, alkane, str), 1,652 ([C=O, amide, str), 1,581–1,397 (C=C, Ar,
str), 1,372–1,031 (C–N/C–O, str), 827 (C–H, Ar, out of plane, bend), 698 (N–H, out
1
of plane, bend); H NMR (400 MHz, DMSO-d6): d 9.68(s, 1H, –CONH), 7.90 (d,
J = 8 Hz, Ar–OH), 7.89–7.06 (m, 10H, Ar–H), 6.73 (s, 1H, –CHNH), 3.10 (s, 6H,
-N(CH3)2), 2.13 (s, 3H, –COCH3); Anal. Calcd. for C21H22N2O2: C 75.44, H 6.58,
N 8.38; Found: C 75.76, H 6.84, N 8.36 %.
N-[(4-Methyphenyl)-(2-hydroxy-naphthalen-1-yl)-methyl)]-urea (Entry 9)
IR (KBr, mmax/cm-1): 3,274 (O–H, Ar, str), 3,145 (N–H 2°amide, str), 3,069–3,022
(C–H, Ar, str), 2,913 (C–H, alkane, str), 1,624 ([C=O, amide, str), 1,591–1,455
(C=C, Ar, str), 1,394–1,114 (C–N/C–O, str), 807 (C–H, Ar, out of plane, bend), 740
(N–H, out of plane, bend); 1H NMR (400 MHz,DMSO-d6): d 9.51(s, 1H, –CONH),
8.72 (d, Ar–OH), 7.92–7.09 (m, 12H, Ar–H ? –NH2), 2.25(s, 3H, –CH3); Anal.
Calcd. for C19H18N2O2: C 74.49, H 5.92, N 9.14; Found: C 74.38, H 5.96, N 9.21 %.
N-[(4-Methyphenyl)-(2-hydroxy-naphthalen-1-yl)-methyl)]-acetamide (Entry 10)
IR (KBr, mmax/cm-1): 3,395 (N–H 2°amide, str), 3,054 (O–H, Ar, str), 2,972 (C–H,
Ar, str), 2,922–2,874 (C–H, alkane, str), 1,626 ([C=O, amide, str), 1,518–1,436
(C=C, Ar, str), 1,331–1,062 (C–N/C–O, str), 810 (C–H, Ar, out of plane, bend), 744
(N–H, out of plane, bend); 1H NMR (400 MHz, DMSO-d6): d 9.86 (s, 1H,–CONH),
8.31 (d, J = 8 Hz, 1H Ar–OH) 7.88 (d, J = 8 Hz, 1H Ar–H), 7.74 (d, J = 8 Hz, 1H
Ar–H), 7.68 (d, J = 8 Hz, 1H Ar–H),7.34 (t, J = 8 Hz, 1H Ar–H), 7.24–6.98 (m,
7H, Ar–H), 2.22 (s, 3H, –COCH3), 1.98 (s, 3H, –PhCH3); Anal. Calcd. for
C20H19NO2: C 78.66, H 6.27, N 4.95; Found: C 78.50, H 6.32, N 4.51 %.
N-[(4-Methyphenyl)-(2-hydroxy-naphthalen-1-yl)-methyl)]-benzamide (Entry 11)
IR (KBr, mmax/cm-1): 3,414 (N–H 2°amide, str), 3,008 (O–H, Ar, str overlapping
with C–H, Ar, str), 2,824 (C–H, alkane, str), 1,630 (C=O, amide, str), 1,529–1,483
(C=C, Ar, str), 1,346–1,248 (C–N/C–O, str), 817 (C–H, Ar, out of plane, bend), 711
(N–H, out of plane, bend); 1H NMR (400 MHz, DMSO-d6): d 10.20 (s, 1H,
–CONH), 8.93 (br d, J = 8 Hz,1H Ar–OH), 7.84–7.70 (m, 4H, Ar–H), 7.51–7.16
(m, 9H, Ar–H), 7.02 (d, J = 8 Hz, 2H, Ar–H), 2.23 (s, 3H, –CH3); Anal. Calcd. for
C25H21NO2: C 81.72, H 5.76, N 3.81; Found: C 81.63, H 5.68, N 3.88 %.
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Sulfanilic acid
N-[(3-Nitrophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-urea (Entry 12)
IR (KBr, mmax/cm-1): 3,636 (O–H, Ar, str), 3,399–3,316 (N–H 2°amide, str),
3,183–3,076 (C–H, Ar, str), 1,640 ([C=O, amide, str), 1,481–1,436 (C = C, Ar,
str), 1,346–1,068 (C–N/C–O, str), 1,528 (N–O, str), 810 (C–H, Ar, out of plane,
1
bend), 744 (N–H, out of plane, bend); H NMR (400 MHz, DMSO-d6): d 8.93 (s,
1H, –CONH), 8.64 (d, J = 8 Hz, Ar–OH), 8.11–7.60 (m, 7H, Ar–H),7.59–7.23 (m,
3H, Ar–H), 6.88 (s, 2H, –NH2), 6.36 (s, 1H, –CHNH); Anal. Calcd. for
C18H15N3O4: C 64.09, H 4.48, N 12.46; Found: C 64.16, H 4.56, N 12.38 %.
N-[(3-Nitrophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-acetamide (Entry 13)
IR (KBr, mmax/cm-1): 3,372 (N–H 2°amide, str), 3,200 (O–H, Ar, str), 3,084 (C–H,
Ar, str), 1,645 ([C=O, amide, str), 1,435–1,346 (C=C, Ar, str), 1,252–1,065 (C–N/
C–O, str), 1,522 (N–O, str), 807 (C–H, Ar, out of plane, bend), 740–709 (N–H, out
1
of plane, bend); H NMR (400 MHz, DMSO-d6): d 9.94 (s, 1H, –CONH), 8.39 (d,
J = 8 Hz, 1H, Ar–OH), 8.09–8.01 (m, 2H, Ar–H), 7.97–7.22 (m, 8H, Ar–H), 6.83
(d, 1H, –CHNH), 2.08 (s, 3H, –COCH3); Anal. Calcd. for C18H15N3O4: C 67.85, H
4.79, N 8.33; Found: C 67.85, H 4.81, N 8.35 %.
N-[(3-Nitrophenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-benzamide (Entry 14)
IR (KBr, mmax/cm–1): 3,265 (O–H, Ar, str), 3,369 (N–H 2°amide, str), 3,074 (C–H,
Ar, str), 1,632 (C=O, amide, str), 1,438 (C=C, Ar, str), 1,342–1,066 (C–N/C–O, str),
1,524 (N–O, str), 812 (C–H, Ar, out of plane, bend), 733–692 (N–H, out of plane,
1
bend); H NMR (400 MHz, DMSO-d6): d 10.35 (s, 1H, –CONH), 9.03 (br d,
J = 8 Hz, Ar–OH), 8.08–7.68 (m, 9H, Ar–H), 7.61–7.24 (m, 7H, Ar–H); Anal.
Calcd. for C24H18N2O4: C 72.35, H 4.55, N 7.03; Found: C 72.93, H 4.63, N
7.05 %.
N-[(2,5-Dimethoxyphenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-acetamide
(Entry 15)
IR (KBr, mmax/cm-1): 3,367 (O–H, Ar, str overlapping with N–H 2° amide, str),
3,056 (C–H, Ar, str), 2,927–2,832 (C–H, alkane, str), 1,640 ([C=O, amide, str),
1,595–1,408 (C=C, Ar, str), 1,235–1,043 (C–N/C–O, str), 814 (C–H, Ar, out of
1
plane, bend), 748 (N–H, out of plane, bend); H NMR (400 MHz, DMSO-d6): d
9.68 (s, 1H, –CONH), 8.45(d, J = 8 Hz, 1H), 7.88–7.04 (m, 9H, Ar–H), 6.45 (s, 1H,
–CHNH), 3.62 (s, 3H, –OCH3), 3.45 (s, 3H, –OCH3), 1.87 (s, 3H, –COCH3); Anal.
Calcd. for C21H21NO4: C 71.78, H 6.02, N 3.99; Found: C 71.50, H 6.50, N 3.90 %.
N-[(4-Chloro-phenyl)-(2-hydroxynaphthalen-1-yl)-methyl)]-nicotinamide
(Entry 16)
IR (KBr, mmax/cm-1): 3,340 (N–H, 2°amide, str), 3,200 (O–H, Ar, str), 3,057–3,021
(C–H, Ar, str), 1,654 ([C=O, amide, str), 1,596–1,464 (C=C, Ar, str), 1,371–1,032
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R. K. Singh et al.
Table 1 Effective study of different catalysts for the synthesis of 1-amidoalkyl-2-naphthols
Entry
Organoacids
Time (min)a
Yield (%)b
1
2
3
4
5
6
7
a
Sulfanilic acid
20
20
20
20
20
20
20
94
88
54
65
58
47
32
Chloroacetic acid [32a]
Citric acid
Anthranilic acid
Malic acid
Nicotinic acid
In the absence of catalyst
The reaction was carried out under thermal solvent-free conditions in an oil bath at 110–120 °C; molar
ratio 4-chloro benzaldehyde/2-naphthol/acetamide (1:1:1.2 mmol)
b
Isolated yields
(C–N/C–O, str), 883–856 (C–H, Ar, out of plane, bend), 738 (C–Cl, str), 716 (N–H,
out of plane, bend); 1H NMR (400 MHz, DMSO-d6): d 8.55 (d, J = 8 Hz, Ar–OH),
7.89–7.85 (m, 4H, Ar–H), 7.62–7.13 (m, 10H, Ar–H), 6.66 (s, 1H, –CHNH); Anal.
Calcd. for C21H21NO4: C 71.78, H 4.37, N 7.20; Found: C 71.10, H 4.51, N 7.95 %.
N-[(2-Hydroxynaphthalen-1-yl)(thiophen-2-yl) methyl]acetamide (Entry 17)
IR (KBr, mmax/cm–1): 3,380 (N–H, 2oamide, str), 3,230 (O–H, Ar, str), 3,057–3,021
(C–H, Ar, str), 1,640 ([C=O, amide, str), 1,590–1,460 (C=C, Ar, str), 1,030 (C–N/
C–O, str), 858 (C–H, Ar, out of plane, bend), 715 (N–H, out of plane, bend); H
1
NMR (400 MHz,DMSO-d6): 10.2 (s, 1H), 8.6 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 8.0
Hz, 1H), 7.7–7.8 (m, 2H), 7.4 (t, J = 6.5 Hz, 1H), 7.20–7.30 (m, 4H), 6.85–6.90 (m,
1H), 6.70 (d, J = 2.7 Hz, 1H), 1.92 (s, 3H, –COCH3); Anal. Calcd. for C17H15NO2S
%: C: 68.66, H: 5.08, N: 4.71, S: 10.78 %. Found: C: 68.42, H: 5.29, N: 4.7 %
N-[(2-Hydroxynaphthalen-1-yl)(naphthalene-2-yl)methyl)acetamide (Entry 18)
IR (KBr, mmax/cm-1): 3,427 (OH), 3,275 (NH), 1,652 (C=O), 1,546, 1,50 (C=C),
1,102 (C–O); NMR (400 MHz, DMSO-d6): 9.8 (s, 1H), 7.0–7.85 (m, 13H), 1.95 (s,
3H, –COCH3); Calcd. for C23H19NO2%: C: 80.92, H: 5.61, N: 4.10. Found: C:
81.05, H: 5.78, N: 4.22 %.
N-[(2-Hydroxynaphthalen-1-yl)(2-chloro-6-flourophenyl) methyl] acetamide
(Entry 19)
IR (KBr, mmax/cm-1): 3,430 (OH), 3,280 (NH), 1,644 (C=O), 1,517, 1,444 (C=C),
1,102 (C–O), 813, 775; 1H NMR (400 MHz, DMSO-d6): 9.5 (s, 1H), 8.7 (d, J = 8.3
Hz, 1H), 7.9 (d, J = 8.7 Hz, 1H), 7.8 (d, J = 8.0 Hz, 1H), 7.7 (d, J = 8.7 Hz, 1H),
7.5 (t, J = 7.2 Hz, 1H), 7.1–7.30 (m, 6H), 1.9 (s, 3H, –COCH3); Anal. Calcd. for
C19H15ClFNO2%: C: 66.38, H: 4.40, N: 4.07. Found: C: 66.25, H: 4.37, N: 4.12 %.
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Table 2 Optimization study of sulfanilic acid catalyst for the synthesis of 1-amidoalkyl-2-naphthols
Entry
Sulfanilic
acid (mmol)
Method A: time
(min)/yield (%)
Method B: time
(min)/yield (%)
Method C: time
(min)/yield (%)
1
2
3
4
0.05
0.1
0.2
0.3
9/76
9/85
9/91
9/85
12/65
12/84
12/88
12/70
15/57
15/65
15/68
15/58
Results and Discussion
In search of an efficient catalyst among various catalysts and the best experimental
condition, we have studied the efficacy of chosen various organocatalysts (1 eqn. as
standard) by taking 4-chloro benzaldehyde, 2-naphthol, and acetamide
(1:1:1.2 mmol) in an oil-bath as the model reaction. We found that sulfanilic acid
was the most effective catalyst for the synthesis of 1-amidoalkyl-2-naphthols in high
yields (Table 1, Entry 1) compared with other catalysts which furnished the product
in lower yields. It is important to mention that, in the absence of a catalyst, the yield
of the product was found to be very low (Table 1, Entry 7).
In order to optimize the quantity of catalyst, we again carried out the synthesis of
N-[4-Chloro-phenyl-(2-hydroxynapthalene-1-yl)-methyl] acetamide by using
2-naphthol, 4-chloro benzaldehyde, and acetamide in the ratio, 1:1:1.2 mmol, with
different quantities of sulfanilic acid at the same temperature and time under
solvent-free conditions. It was found that the best result was obtained when the
reaction was carried out in the presence of 0.2 mmol (20 mol%) of sulfanilic acid
(Table 2, Entry 3). The smaller amounts gave a low yield even after long reaction
times, and the larger amounts could not cause the obvious increase in the yield of
the product. Therefore, 0.2 mmol was chosen as the optimal quantity of sulfanilic
acid.
A slight excess of amide was found to be advantageous. Hence, the molar ratio of
aromatic aldehyde to amide was kept at 1:1.2 mmol. Encouraged by these results, a
wide variety of aromatic aldehydes and amides were treated with b-naphthol using
sulfanilic acid under the optimized conditions to afford the corresponding
1-amidoalkyl-2-naphthols (Table 3) in good to excellent yields.
As reported in the literature, a mechanism for the synthesis of 1-amidoalkyl-2-
naphthols is shown in Scheme 2. The role of Bronsted acids has been proposed to
activate the aldehyde by binding H? with the oxygen atom which ultimately
enhances the electrophilicity of the aldehyde and leads to a reduction in reaction
time. The condensation of 2-naphthol with the activated aldehyde give ortho-
quinone methides (o-QMs) as a highly reactive and ephemeral intermediate. The
same o-QMs, generated in situ, have been reacted with amide to form 1-amidoalkyl-
2-naphthol derivatives. Thus, the 2-naphthol act as Michael acceptors and
araldehydes as nucleophilic resulting in a Michael adduct under the influence of
Bronsted acid. The electron-withdrawing groups substituted on benzaldehyde in o-
QM intermediate increase the rate of 1,4-nucleophilic addition reaction because
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R. K. Singh et al.
H
O
X C H
X
H
OH2
O
OH
O
H
X C H
X
NH2COCH3
X
X
NHCOCH3
OH
O
O
H
H
o-QMs
Scheme 2 Mechanism of action of acid catalyzed synthesis of 1-amidoalkyl-2-naphthols
alkene LUMO is at a lower energy in the neighboring electron-withdrawing groups
than electron-donating groups. Hence, benzene ring with electron-withdrawing
groups gave better yields compared to the electron-donating groups.
Conclusions
In conclusion, we have found sulfanilic acid as the best catalyst among various acids
screened for the synthesis of 1-amidoalkyl-2-naphthols under solvent-free condi-
tions. Out of three methods used, microwave irradiation and oil bath heating offers
high yield and other advantages like clean, environmentally benign and short
reaction times as compared to the direct hot plate heating method. These advantages
makes this protocol an attractive and environmental friendliness (non-corrosive
catalyst) for the synthesis of 1-amidoalkyl-2-naphthols using sulfanilic acid as
catalyst.
Acknowledgments The authors gratefully acknowledged Dr. D.N. Prasad, Principal, and Management,
Shivalik College of Pharmacy, Nangal, Punjab for constant encouragement and support. Thanks are also
due to SAIF, Panjab University, Chandigarh for cooperation in getting the spectral data.
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