Catalyst-free, one-pot, expeditious synthesis of aminoalkylnaphthols at room temperature

Article abstract of DOI:10.1080/00397911.2011.575524

Aminoalkylnaphthols possess several biological and catalytic activities. A methodology has been developed for the multicomponent one-pot synthesis of aminoalkylnaphthols in dichloromethane under catalyst-free conditions at room temperature. The present ap

Full text of DOI:10.1080/00397911.2011.575524

This article was downloaded by: [University of Illinois Chicago]
On: 15 July 2012, At: 03:39
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Catalyst-Free, One-Pot, Expeditious
Synthesis of Aminoalkylnaphthols at
Room Temperature
Chhanda Mukhopadhyay a , Sunil Rana a & Ray J. Butcher b
a Department of Chemistry, University of Calcutta, Kolkata, India
b Department of Chemistry, Howard University, Washington, DC, USA
Accepted author version posted online: 10 Jan 2012. Version of
record first published: 21 Jun 2012
To cite this article: Chhanda Mukhopadhyay, Sunil Rana & Ray J. Butcher (2012): Catalyst-Free, One-
Pot, Expeditious Synthesis of Aminoalkylnaphthols at Room Temperature, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:20, 3077-3088
To link to this article: http://dx.doi.org/10.1080/00397911.2011.575524
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 3077–3088, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.575524
CATALYST-FREE, ONE-POT, EXPEDITIOUS SYNTHESIS
OF AMINOALKYLNAPHTHOLS AT ROOM
TEMPERATURE
Chhanda Mukhopadhyay,1 Sunil Rana,1 and Ray J. Butcher2
1Department of Chemistry, University of Calcutta, Kolkata, India
2Department of Chemistry, Howard University, Washington, DC, USA
GRAPHICAL ABSTRACT
Abstract Aminoalkylnaphthols possess several biological and catalytic activities. A method-
ology has been developed for the multicomponent one-pot synthesis of aminoalkylnaphthols
in dichloromethane under catalyst-free conditions at room temperature. The present
approach possesses several advantages such as excellent yields, quick reaction time, mild
reaction conditions, and very easy purification processes. Thirteen new compounds in
addition to six known compounds have been synthesized by this methodology.
Keywords Aminoalkylnaphthols; catalyst-free; dichloromethane; one-pot synthesis;
room temperature
INTRODUCTION
Recently, the synthesis of aminoalkylnaphthols has received special attention
from the scientific community because of their significant biological[1] and catalytic[2]
properties. These compounds, possessing multiple chelating centers, are potent inhi-
bitors of metalloenzymes containing Fe, Cu, Zn, and Co ions as cofactors.[3–6] In
addition, these compounds have the ability to act as scavengers of heavy metals
(Hg, Cd, Pb, As, Sb).[7,8] They also show potent oxytocic activity.[9] A number of
Received February 12, 2011.
Address correspondence to Chhanda Mukhopadhyay, Department of Chemistry, University of
Calcutta, 92 APC Road, Kolkata 700009, India. E-mail: cmukhop@yahoo.co.in
3077

3078
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
Scheme 1. Synthesis of aminoalkylnaphthols.
aminomethylphenols have been reported in the literature[10] as chelating agents in
metal-catalyzed asymmetric induction in many reactions. Chiral Mannich bases
are frequently used as ligands in a variety of metal-mediated enantioselective car-
bon–carbon bond formation reactions.[11–17] Such importance of the aminoalkyl-
naphthols has caused us to pursue a simple and easy method for their synthesis.
Since 1900, aminoalkylnaphthols have been synthesized by the
three-component condensation of secondary amines, aromatic aldehydes, and
naphthols (Scheme 1). In 1900, Mario Betti synthesized aminoalkylnaphthols
(so-called Betti bases) for the first time.[18] After a long gap, Katritzky et al. in
1999 reported the synthesis of aminoalkylphenols by benzotriazole methodology
using phase-transfer catalysis.[19a] Saidi et al. synthesized the compounds with lith-
ium perchlorate.[19b] Recently, Jha et al have developed the methodology of
p-toluene sulfonic acid–catalyzed microwave irradiation.[20] Kumar et al. explored
the synthesis by nonionic surfactant-catalysed methodology.[21] In addition to these,
a few other methodologies are also available in the literature.[22]
RESULTS AND DISCUSSION
Most of the earlier procedures for aminoalkylnaphthol synthesis[18–22] suffer
from harsh reaction conditions, catalyst nonrecyclability, or a need for column chro-
matography for further purification. Our main aim was to synthesize aminoalkyl-
naphthols while avoiding expensive catalysts, using mild reaction conditions, and
avoiding time-consuming column chromatography. After a thorough search for
proper catalysts and reaction medium for the standard reaction of pyrrolidine,
2-naphthol, and 4-bromobenzaldehyde, we found that dichloromethane at room
temperature (25–30 ꢀC) proved to be the best reaction medium (Table 1, entry 3),
and the product conversion was so high that no additional catalyst was required.
This is the most important aspect of our methodology. The workup procedure is also
very simple. After the completion of the reaction, checked by thin-layer chromato-
graphy (TLC), dichloromethane was pumped out by rotary evaporation. The pro-
duct was purified by direct crystallization from ethylacetate and petroleum ether
(60–80 ꢀC), thus avoiding time-consuming column chromatography. This is the
second important aspect of our methodology.
Once the optimum condition was reached for the model reaction, various aro-
matic aldehydes and secondary amines were tried for this reaction. Aromatic alde-
hydes with slightly electron-withdrawing groups yielded the best results, while
electron-donating groups slightly decreased the yield. Aromatic aldehydes with

SYNTHESIS OF AMINOALKYLNAPHTHOLS
3079
Table 1. Choice of reaction medium for the synthesis of the aminoalkylnaphthols at room temperature
taking the standard reaction of 2-naphthol, 4-bromobenzaldehyde, and pyrrolidine
Entry
Solvents (5 ml)
Time (h)
Yield (%) (isolated)
1
2
Methanol
Ethanol
2
2
2
2
2
2
2
2
2
2
55
60
92
67
45
55
58
40
35
53
3
Dichloromethane
Dichloroethane
Acetonitrile
DMF
4
5
6
7
Water
DMSO
8
9
10
1,4-Dioxane
THF
Figure 1. X-ray structural analysis of a single crystal of 2-[(4-chlorophenyl)-piperidine-1-yl-methyl]-
naphthalen-1-ol (4q) (Table 2, entry 17) showing the crystallographic numbering (CCDC 800110). (Figure
is provided in color online.)

3080
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
ortho-substitution also decrease the yield slightly. This may be due to the steric
effect. Of the secondary amines, piperidine, pyrrolidine, morpholine, N-methyl pip-
erazine, and dimethylamine were used. In all cases, the yields of the desired products
were moderate to excellent. We further extended the scope of the reaction by using
4-hydroxycoumarin and 1-naphthol as nucleophiles in place of 2-naphthol, with
good yields. With 1-naphthol, the substitution occurs specifically at the 2-position
(and not at 4) because of the stability of the product by intramolecular six-membered
hydrogen-bond formation (further evidence in Fig. 1).
1
All the products are well characterized by melting points, infrared (IR), H
1
NMR, 13C NMR, and CHN analysis. In H NMR, the -NCH2 protons and in 13C
NMR, the -NCH2 carbons appear as broad peaks. This is due to electrical quadruple
moment of nitrogen. The crystal structure of 1-[(4-bromophenyl)-pyrrolidin-
1-yl-methyl]-naphthalen-2-ol (Table 2, entry 7) is given in Fig. 2. which shows a
strong hydrogen bonding between OH of 2-naphthol and N of the pyrrolidine moiety.
The crystal structure of 2-[(4-chlorophenyl)-piperidine-1-yl-ethyl]-naphthalen-
1-ol (Table 2, entry 17) is given in Fig. 1, which conclusively proves that 1-naphthol
reacts through its 2 position.
Probably, the mechanism goes through the iminium ion formation followed by
the attack of 2-naphthol at the 1-position for the specific reaction shown in Scheme 2.
Figure 2. X-ray structural analysis of a single crystal of 1-[(4-bromo-phenyl)-pyrrolidin-1-yl-methyl]-
naphthalen-2-ol (4g) (Table 2, entry 7) showing the crystallographic numbering (CCDC 791677). (Figure
is provided in color online.)

SYNTHESIS OF AMINOALKYLNAPHTHOLS
3081
Table 2. Synthesis of the aminoalkylnaphthols at room temperature (25–30 ꢀC)
Starting materials
Products[ref.] Time
Yield (%),
isolated
Entry
Amines
Piperidine
Piperidine
Aldehydes
Naphthols
2-Naphthol
(4a–4s)
(h)
1
2
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Chlorobenzaldehyde
4a[20]
4b
2
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
95
92
96
84
75
90
92
74
90
83
76
85
78
81
76
78
74
83
82
2-Naphthol
2-Naphthol
3
Dimethylamine
Piperidine
Piperidine
4c[21]
4
3,4-dimethoxybenzaldehyde 2-Naphthol
4d
5
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
2-Methoxybenzaldehyde
4-Chlorobenzaldehyde
2-Naphthol
2-Naphthol
2-Naphthol
2-Naphthol
2-Naphthol
4e
6
Pyrrolidine
Pyrrolidine
Piperidine
4f
7
4g
8
4h[21]
4i[20]
4j
9
Morpholine
Morpholine
Piperidine
10
11
12
13
14
15
16
17
18
19
3,4-Dimethoxybenzaldehyde 2-Naphthol
Benzene-1,4-Dialdehyde
4-Chlorobenzaldehyde
3-Nitrobenzaldehyde
4-Chlorobenzaldehyde
2-Naphthol
4k
Piperidine
Piperidine
Dimethylamine
4-Hydroxycoumarin
4-Hydroxycoumarin
4-Hydroxycoumarin
2-Naphthol
4l
4m
4n
4o[20]
4p[20]
4q
N-methylpiperazine Benzaldehyde
Piperidine
Piperidine
Morpholine
Pyridine-4-aldehyde
4-Chlorobenzaldehyde
Benzaldehyde
2-Naphthol
1-Naphthol
1-Naphthol
1-Naphthol
4r
N-methylpiperazine 4-Bromobenzaldehyde
4s
Scheme 2. Probable mechanism for the formation of aminoalkylnaphthols.

3082
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
CONCLUSION
We have developed a very simple, catalyst-free protocol for the synthesis of
aminoalkylnaphthols by a one-pot, three-component methodology. The advantages
of the methodology include (a) mild catalyst-free reaction condition, (b) shorter reac-
tion time, (c) very easy purification procedure that avoids column chromatography,
and (d) applicability to large-scale preparation.
EXPERIMENTAL
Ethyl acetate, petroleum ether (boiling range 60–80 ꢀC), dichloromethane were
distilled before use. All the chemicals were purchased from Aldrich Chemical Com-
pany and Spectrochem, Pvt. Ltd. (Mumbai, India). Silica gel G with binder from
Spectrochem, Pvt. Ltd., Mumbai, India, was used for TLC. 1H and 13C NMR spec-
tra were obtained on a Bruker 300-MHz instrument at 300 and 75 MHz respectively.
CDCl3 and dimethylsulfoxied (DMSO-d6) were purchased from Aldrich Chemical
Company. Melting points were determined on an electrical melting-point apparatus
with an open capillary. IR spectra were recorded on a Perkin-Elmer spectrophot-
ometer RX=FT-IR system. The C-H-N-analyses were carried out on a 2400 series
II CHNS analyzer, (Perkin-Elmer, USA).
General Experimental Procedure for Aminoalkylnaphthol Formation
Aromatic aldehydes (1 mmol), secondary amine (1.1 mmol), (naphthol=
4-OH-coumarin) (1 mmol), and dichloromethane (5 ml) were added in a 25-ml,
round-bottomed flask. The resulting mixture was stirred vigorously with a magnetic
bar on a magnetic stirrer for 2h at room temperature (25–30 ꢀC). The progress of the
reaction was monitored by TLC. After the completion of the reaction as checked by
TLC, dichloromethane was pumped out by rotary evaporation. The crude product
was purified directly by crystallization from ethyl acetate and petroleum ether
(60–80 ꢀC).
Spectral and Analytical Data of the Compounds (4a–4q)
In 13C spectra, most of the compounds show one extra peak in the completely
saturated carbon region. The nonequivalence of the similar type of carbons may
occur because of the restricted rotation of the C-N bond.
1-[(4-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4a) (Table 2,
Entry 1). White solid. Mp 164–166 ꢀC (EtOAc), lit.[20] Mp 165–166 ꢀC; IR (KBr):
3050, 2939, 2854, 1590, 1475, 1408, 1352, 1262, 1233, 1152, 1091, 942 and 823 cmꢁ1
;
1H NMR (300 MHz; CDCl3): dH 13.80 (s, 1H, OH), 7.76 (d, J ¼ 8.4 Hz, 1H,
ArH), 7.69–7.58 (m, 2H, ArH), 7.48–7.45 (m, 2H, ArH), 7.38–7.32 (m, 1H,
ArH), 7.23–7.17 (m, 3H, ArH), 7.14 (d, J ¼ 9.0 Hz, 1H, ArH), 5.03 (s, 1H, CH),
3.28 (br, 1H, -NCH), 2.62 (br, 1H, -NCH), 2.06–1.50 (m, 8H, -NCH, -CH2);
13C NMR (CDCl3, 75 MHz): dc 155.4, 138.2, 133.6, 132.1, 130.3, 129.5, 128.9,
128.6, 126.4, 122.4, 120.7, 119.9, 115.7, 71.2, 54.6, 51.9, 26.0 and 24.0.

SYNTHESIS OF AMINOALKYLNAPHTHOLS
3083
1-[(4-Bromophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4b) (Table 2,
Entry 2). White solid. Found: C, 66.79; H, 5.52; N, 3.45%. C22H22BrNO requires C,
66.67; H, 5.60; N, 3.53%. Mp 158–160 ꢀC (EtOAc); IR (KBr): 3056, 2937, 2852,
2592, 1589, 1515, 1475, 1449, 1408, 1352, 1261, 1233, 1152, 1079, 1009, 943, 822
and 740 cmꢁ1 1H NMR (300 MHz; CDCl3): dH 13.79 (s, 1H, OH), 7.90 (d,
;
J ¼ 8.7 Hz, 1H, ArH), 7.69–7.61 (m, 2H, ArH), 7.45–7.30 (m, 5H, ArH), 7.23–1.12
(m, 2H, ArH), 4.99 (s, 1H, CH), 3.25 (br, 1H, -NCH), 2.61 ((br, 1H, -NCH),
2.02–1.20 (m, 8H, -NCH, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.3, 138.7,
132.1, 131.8, 130.6, 129.5, 128.9, 128.6, 126.4, 122.4, 121.7, 120.7, 119.9, 115.6,
71.2, 54.4, 51.9, 25.9 and 23.9.
1-[(4-Chlorophenyl)-dimethylamino-methyl]naphthalen-2-ol(4c)(Table2,
Entry 3). White solid. Mp 128–130 ꢀC (EtOAc), lit.[21] Mp 129–131 ꢀC; IR (KBr):
;
3129, 3061, 2976, 2848, 1629, 1462, 1240 and 758 cmꢁ1 1H NMR (CDCl3,
300 MHZ): dH 10.01 (s, 1H, OH), 7.65–7.83 (m, 3H, ArH), 7.50–7.53 (m, 3H,
ArH), 7.08–7.45 (m, 4H, ArH), 4.95 (s, 1H, CH), 2.34 (s, 6H, NCH3); 13C NMR
(CDCl3, 75 MHz): dC 155.2, 142.4, 131.2, 129.7, 128.9, 128.8, 128.7, 128.5, 127.7,
126.4, 122.4, 121.1, 119.8, 116.3, 72.8 and 41.5.
1-[(3,4-Dimethoxyphenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4d)
(Table 2, Entry 4). White solid. Found: C, 76.59; H, 7.13; N, 3.62%. C24H27NO3
requires C, 76.36; H: 7.21; N; 3.71%. Mp 120–122 ꢀC (EtOAc); IR (KBr): 3056,
1
2934, 2841, 1595, 1513, 1455, 1418, 1355, 1264, 1145, 1027, 942 and 816 cmꢁ1; H
NMR (300 MHz; CDCl3): dH 14.0 (s, 1H, OH), 7.83 (d, J ¼ 8.4 Hz, 1H, ArH),
7.69–7.61 (m, 2H, ArH), 7.35 (t, J ¼ 8.4 Hz, 1H, ArH), 7.24–7.11 (m, 3H, ArH),
7.06 (d, J ¼ 8.1 Hz, 1H, ArH), 6.73 (d, J ¼ 8.1 Hz, 1H, ArH), 5.01 (s, 1H, CH),
3.79 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.30 (br, 1H, NCH), 2.65 (br, 1H, NCH),
2.20–1.50 (m, 8H, NCH, -CH2); 13C NMR (CDCl3, 75 MHz): dc 155.4, 148.6,
132.3, 132.1, 129.2, 128.8, 128.6, 126.2, 122.2, 121.7, 121.0, 119.8, 116.2, 110.8,
71.7, 54.6, 51.7, 26.0, 24.1.
1-[(2-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-2-ol (4e) (Table 2,
Entry 5). White solid. Found: C, 75.24; H, 6.21; N, 3.88%. C22H22ClNO requires C,
75.09; H, 6.30; N, 3.98%. Mp 136–138 ꢀC (EtOAc); IR (KBr): 3060, 2933, 2821,
2607, 1590, 1516, 1447, 1352, 1265, 1239, 1151, 1093, 1033, 978, 821 and 745 cmꢁ1
;
1H NMR (300 MHz; CDCl3): dH 14.28 (s, 1H, OH), 7.84 (d, 3J ¼ 8.4 Hz, 1H,
ArH), 7.72–7.64 (m, 3H, ArH), 7.42–7.37 (m, 2H, ArH), 7.26–7.09 (m, 4H,
ArH), 5.88 (s, 1H, CH), 3.35 (d, J ¼ 11.4 Hz, 1H, NCH), 2.66 (d, J ¼ 10.8 Hz,
1H, NCH), 2.41–2.27 (m, 2H, NCH), 1.78–1.25 (m, 6H, -CH2), 13C NMR (CDCl3,
75 MHz): dc 156.5, 136.9, 134.2, 132.8, 130.9, 129.5, 129.3, 129.1, 128.7, 128.5,
127.9, 126.6, 122.4, 121.2, 120.0, 115.8, 66.2, 54.7, 49.3, 26.3, 25.9 and 24.0.
1-[(4-Chlorophenyl)-pyrrolidin-1-yl-methyl]naphthalen-2-ol (4f) (Table 2,
Entry 6). White solid. Found: C: 74.94; H, 5.86; N, 4.06%. C21H20ClNO requires C,
74.66; H, 5.97; N, 4.15%. Mp 118–120 ꢀC (EtOAc); IR (KBr): 3059, 2963, 2829,
1592, 1451, 1400, 1347, 1228, 1100, 949, 889, 820 and 741 cmꢁ1 1H NMR
;
(300 MHz; CDCl3): dH 13.69 (s, 1H, OH), 7.92 (d, 3J ¼ 9.0 Hz, 1H, ArH),
3
3
7.74–7.63 (m, 2H, ArH), 7.53 (d, J ¼ 8.4 Hz, 2H, ArH), 7.37 (dt, J ¼ 8.4 Hz and
4J ¼ 1.5 Hz, 1H, ArH), 7.28–7.20 (m, 3H, ArH), 7.14 (d, J ¼ 8.7 Hz, 1H, ArH),
3

3084
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
5.07 (s, 1H, CH), 3.50–3.10 (br, 1H, NCH), 2.80–2.10 (m, 3H, NCH), 1.91 (br, 4H, -
CH2); 13C NMR (CDCl3, 75 MHz): dc 155.4, 139.7, 133.5, 131.6, 129.8, 129.6, 128.9,
128.8, 128.6, 126.4, 122.4, 120.8, 119.9, 116.2, 69.9, 53.3 and 23.3.
1-[(4-Bromophenyl)-pyrrolidin-1-yl-methyl]naphthalen-2-ol (4g) (Table 2,
Entry 7). White solid. Found: C, 66.19; H, 5.16; N, 3.76%. C21H20BrNO requires
C, 65.98; H, 5.27, N, 3.66%. Mp 140–142 ꢀC (EtOAc); IR (KBr): 3068, 2967,
2818, 2568, 1589, 1451, 1407, 1236, 1107, 1010, 951 and 820 cmꢁ1 1H NMR
;
(300 MHz; CDCl3): dH 13.68 (s, 1H, OH), 7.79 (d, 3J ¼ 8.7 Hz, 1H, ArH),
3
7.70–7.62 (m, 2H, ArH), 7.44 (d, J ¼ 8.4 Hz, 2H, ArH), 7.36–7.31 (m, 3H, ArH),
3
3
7.20 (t, J ¼ 7.5 Hz, 1H, ArH), 7.15 (d, J ¼ 8.7 Hz, 1H, ArH), 5.03 (s, 1H, CH),
3.17 (br, 1H, -NCH), 2.70–2.10 (m, 3H, -NCH, -NCH2), 1.77 (s, 4H, -CH2); 13C
NMR (CDCl3, 75 MHz): dc 155.4, 140.2, 132.1, 131.7, 130.0, 129.6, 128.8,128.5,
126.4, 122.4, 121.6, 120.7, 119.8, 116.1, 69.9, 53.4 and 23.3.
1-[(2-Methoxyphenyl)-Piperidin-1-yl-methyl]naphthalen-2-ol (4h) (Table2,
Entry 8). White solid. Mp 160–162 ꢀC, lit.[21] Mp 160–161 ꢀC; IR (KBr): 3135, 3050,
2959, 2849, 1659, 1442, 1242, 742 cmꢁ1. 1H NMR (CDCl3, 300 MHz): dH 13.4 (s, 1H,
OH), 7.82 (d, J ¼ 8.55 Hz, 1H, ArH), 7.57–7.67 (m, 3H, ArH), 7.28–7.34 (m, 1H,
ArH), 7.12–7.22 (m, 3H, ArH), 6.77–6.89 (m, 2H, ArH), 5.89 (s, 1H, CH), 3.99 (s,
3H -OCH3), 3.23–3.30 (m, 1H, -NCH), 2.64–2.71 (m, 1H, -NCH), 2.29–2.40 (m,
2H, -NCH2), 1.71–1.92 (m, 6H, -CH2), 13C NMR (CDCl3, 75 MHz) dc: 23.19,
23.57, 50.13, 54.61, 55.53, 60.74, 110.47, 117.19, 119.95, 121.46, 121,54, 122.20,
126.19, 128.36, 128.52, 128.80, 129.07, 129.29, 129.67, 132.36, 156.19, 156.40.
1-[(4-Chlorophenyl)-morpholin-4-yl-methyl]naphthalen-2-ol(4i)(Table2,
Entry 9). White solid. Mp 130–132 ꢀC, lit.[20] Mp 130–131 ꢀC; IR (KBr): 3437, 3061,
1621, 1596, 1451, 1383, 1237 and 1118 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 13.17
(s, 1H, OH), 7.78–7.70 (m, 3H, ArH), 7.57–7.52 (m, 2H, ArH), 7.45–7.40 (m, 1H,
ArH), 7.32–7.18 (m, 4H, ArH), 5.14 (s, 1H, CH), 3.72–3.51 (s, 4H, O-CH2),
3.19–3.14 (m, 1H, NCH), 2.55-2.33 (m, 3H, NCH2); 13C NMR (CDCl3, 75 MHz):
dc 154.9, 137.4, 134.5, 132.4, 131.1, 130.5, 129.9, 129.5, 129.2, 127.2, 123.3, 121.2,
120.3, 115.0, 71.6, 67.3, 67.1, 54.3 and 51.9.
1-[(3,4-Dimethoxyphenyl)-morpholin-4-yl-Methyl]naphthalen-2-ol (4j)
(Table 2, Entry 10). White solid. Found: C, 72.99; H, 6.54; N, 3.66%.
C23H25NO4 requires C, 72.80; H, 6.64; N, 3.69%. Mp 68–70 ꢀC (EtOAc); IR
(KBr): 3058, 2957, 2841, 1595, 1514, 1456, 1413, 1354, 1263, 1143, 1119, 1023,
1
941, 870, 817 and 749 cmꢁ1; H NMR (300 MHz; CDCl3): dH 13.16 (s, 1H, OH),
3
3
7.84 (d, J ¼ 8.7 Hz, 1H, ArH), 7.74–7.64 (m, 2H, ArH), 7.37 (t, J ¼ 7.2 Hz, 1H,
3
ArH), 7.24–7.07 (m, 4H, ArH), 6.73 (d, J ¼ 8.4 Hz, 1H, ArH), 5.05 (s, 1H, CH),
3.79 (s, 4H, O-CH2), 3.76 (s, 6H, OCH3), 3.05 (br, 1H, NCH), 2.43 (brs, 3H,
NCH2); 13C NMR (CDCl3, 75 MHz): dc 154.6, 149.3, 148.8, 132.2, 131.0, 129.3,
128.8, 126.4, 122.5, 121.8, 120.9, 119.6, 115.2, 111.5, 110.9, 71.6, 66.8, 55.7, 55.6
and 51.1.
1,4-Bis[1-f(Piperidin-1-yl)methylg-2-hydroxynaphthyl]benzene
(4k)
(Table 2, Entry 11). White solid. Found: C, 82.16; H, 7.13; N, 5.10%.
C38H40N2O2 requires C, 81.98; H, 7.24; N, 5.03%. Mp 190–192 ꢀC (EtOAc); IR

SYNTHESIS OF AMINOALKYLNAPHTHOLS
3085
(KBr): 3055, 2930, 2852, 1617, 1514, 1449, 1412, 1357, 1268, 1234, 1152, 1098, 945,
1
814 and 743 cmꢁ1; H NMR (300 MHz; CDCl3): dH 13.76 (s, 2H, OH), 7.52 (t,
3J ¼ 10.2 Hz, 2H, ArH), 7.68–7.59 (m, 4H, ArH), 7.44 (s, 4H, ArH), 7.36–7.24 (m,
3
2H, ArH), 7.17 (d, J ¼ 7.8 Hz, 2H, ArH), 7.11 (d,3J ¼ 9.0 Hz, 2H, ArH), 4.99 (s,
2H, CH), 3.20 (br, 2H, NCH), 2.50–1.30 (m, 18H, NCH, -CH2); 13C NMR (CDCl3,
75 MHz): dc 155.5, 139.2, 132.4, 129.3, 128.8, 128.5, 126.3, 121.1, 119.9, 116.1, 116.1,
71.4, 52.3, 26.0 and 24.1.
3-[(4-Chlorophenyl)-piperidin-1-yl-methyl]-4-hydroxy-Chromen-2-one (4l)
(Table 2, Entry 12). White solid. Found: C, 68.41; H, 5.36; N, 3.67%. C21H20ClNO3
requires C, 68.20; H, 5.45; N%. Mp 176–178 ꢀC (EtOAc); IR (KBr): 3069, 2950, 2861,
1
1650, 1605, 1539, 1460, 1414, 1367, 1331, 1275, 1232, 1066, 951 and 758 cmꢁ1; H
3
NMR (300 MHz; CDCl3): dH 11.14 (s, 1H, OH), 7.84 (d, J ¼ 7.5 Hz, 1H, ArH),
3
7.62 (d, J ¼ 8.4 Hz, 2H, ArH), 7.45–7.37 (m, 3H, ArH), 7.22–7.05 (m, 2H, ArH),
5.13 (s, 1H, CH), 3.76 (d, J ¼ 11.7 Hz, 1H, NCH), 2.93 (d, J ¼ 11.4 Hz, 1H,
NCH), 2.78–2.69 (m, 1H, NCH), 2.42–2.33 (m, 1H, NCH), 1.90–1.40 (m, 6H,
-CH2); 13C NMR (CDCl3, 75 MHz): dc 173.6, 164.0, 154.0, 135.0, 134.7, 131.3,
130.3, 129.2, 124.1, 123.0, 120.6, 116.4, 94.6, 70.3, 53.6, 50.4, 24.3 and 22.4.
4-Hydroxy-3-[(3-nitrophenyl)-piperidin-1-yl-methyl]chromen-2-one (4m)
(Table 2, Entry 13). White solid. Found: C, 66.56; H, 5.36; N, 7.27%.
C21H20N2O5 requires C, 66.31; H, 5.30; N, 7.36%. Mp 184–186 ꢀC (EtOAc); IR
(KBr): 3076, 2948, 2863, 1642, 1604, 1535, 1461, 1402, 1348, 1284, 1237, 1072, 953
1
and 762 cmꢁ1; H NMR (300 MHz; CDCl3): dH 11.15 (s, 1H, OH), 8.42 (s, 1H,
3
ArH), 8.16 (d, J ¼ 8.1 Hz, 1H, ArH), 8.01–7.95 (m, 2H, ArH), 7.53–7.43 (m, 2H,
ArH), 7.24–7.18 (m, 2H, ArH), 5.24 (s, 1H, CH), 3.79 (d, J ¼ 10.5 Hz, 1H, NCH),
2.91 (d, J ¼ 9.9 Hz, 1H, NCH), 2.80–2.72 (m, 1H, NCH), 2.46ꢁ2.38 (m, 1H,
NCH), 2.00–1.41 (m, 6H, -CH2); 13C NMR (CDCl3, 75 MHz): dc 173.1, 163.8,
154.0, 148.5, 138.6, 134.9, 131.7, 130.3, 124.2, 124.0, 123.3, 116.6, 95.0, 70.2, 54.2,
24.5 and 22.6.
3-[(4-Chlorophenyl)-dimethylamino-methyl]-4-hydroxy-chromen-2-one
(4n) (Table 2, Entry 14). White solid. Found: C, 65.79; H, 4.82; N, 4.18%.
C18H16ClNO3 requires C, 65.56, H, 4.89; N, 4.25%. Mp 168–170 ꢀC (EtOAc); IR
(KBr): 3074, 2856, 1647, 1603, 1543, 1467, 1413, 1358, 1319, 1287, 1219, 1139,
1
1046, 949, 826 and 756 cmꢁ1; H NMR (300 MHz; DMSO-d6): dH 10.55 (s, 1H,
3
3
OH), 7.84 (d, J ¼ 7.8 Hz, 1H, ArH), 7.66 (d, J ¼ 8.4 Hz, 2H, ArH), 7.45–7.35 (m,
3H, ArH), 7.20–7.08 (m, 2H, ArH), 5.26 (s, 1H, CH), 2.67 (s, 6H, NMe2); 13C
NMR (DMSO-d6, 75 MHz): dc 173.9, 163.0, 153.7, 152.6, 137.3, 133.0, 130.0,
128.6, 124.4, 124.2, 123.0, 120.0, 115.9, 93.1, 68.9 and 42.0.
1-[(4-Methyl-Piperazin-1-yl)-phenyl-methyl]naphthalen-2-ol(4o)(Table2,
Entry 15). White solid. Mp 140–142 ꢀC (EtOAc), lit.[20] Mp 141–142 ꢀC; IR (KBr):
3048, 2944, 2840, 2791, 2686, 1593, 1513, 1454, 1415, 1356, 1277, 1238, 1144, 1084
and 1002 cmꢁ1 1H NMR (300 MHz; CDCl3): dH 13.42 (s, 1H, OH), 7.97
;
(d,3J ¼ 8.7 Hz, 1H, ArH), 7.96–7.77 (m, 2H, ArH), 7.69 (d,3J ¼ 7.2 Hz, 2H, ArH),
3
7.50 (t, J ¼ 7.2 Hz, 1H, ArH), 7.42–7.32 (m, 4H, ArH), 7.27 (d,3J ¼ 8.7 Hz, 1H,
ArH), 5.25 (s, 1H, CH), 3.34–2.60 (m, 8H, N-CH2); 2.43 (s, 3H, N-CH3),

3086
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
13C NMR (CDCl3, 75 MHz): dc 155.3, 139.5, 132.6, 130.1, 129.3, 129.1, 128.8, 128.6,
128.1, 127.0, 123.0, 121.5, 120.3, 116.0, 71.9, 55.6, 55.3, 53.7, 51.2 and 46.2.
1-(Piperidin-1-yl-pyridin-4-yl-methyl)naphthalen-2-ol (4p) (Table 2, Entry
16). Off-white solid, Mp 184–186 ꢀC (EtOAc), lit.[20] Mp 185–186 ꢀC; IR (KBr):
3047, 2943, 2825, 2670, 1593, 1513, 1449, 1416, 1356, 1317, 1270, 1230, 1152,
1
1094, 1032, 945, 869, 815 and 739 cmꢁ1; H NMR (300 MHz; CDCl3): dH 13.51 (s,
1H, OH), 8.53 (d,3J ¼ 4.5 Hz, 2H, ArH), 7.83 (d,3J ¼ 8.4 Hz, 1H, ArH), 7.75–7.69
3
4
(m, 2H, ArH), 7.54 (d,3J ¼ 4.5 Hz, 2H, ArH), 7.43 (dt, J ¼ 7.7 Hz and J ¼ 1.3 Hz,
1H, ArH), 7.27 (dt, 3J ¼ 6.2 Hz and 4J ¼ 1.6 Hz, 1H, ArH), 7.19 (d,3J ¼ 9.0 Hz,
1H, ArH), 5.09 (s, 1H, CH), 3.28 (brs, 1H, NCH), 2.61–1.69 (m, 3H, NCH),
1.69–1.25 (m, 6H, NCH2CH2 and NCH2CH2CH2),13C NMR (CDCl3, 75 MHz): dc
155.4, 150.1, 148.5, 132.0, 129.9, 129.0, 128.6, 126.6, 123.6, 122.5, 120.4, 119.8,
114.6, 70.7, 53.6, 25.8 and 23.8.
2-[(4-Chlorophenyl)-piperidin-1-yl-methyl]naphthalen-1-ol (4q) (Table 2,
Entry 17). White solid. Found: C, 75.35; H, 6.22; N, 3.91%. C22H22ClNO requires
C, 75.09, H; 6.30; N, 3.98%. Mp 152–154 ꢀC (EtOAc); IR (KBr): 3050, 2930, 2826,
2659, 1628, 1576, 1450, 1380, 1311, 1216, 1150, 1091, 1015, 934, 871, 836, 800 and
1
753 cmꢁ1; H NMR (300 MHz; CDCl3): dH 13.27 (s, 1H, OH), 8.33 (d,3J ¼ 7.5 Hz,
1H, ArH), 7.71 (d,3J ¼ 7.5 Hz, 1H, ArH), 7.56–7.05 (m, 7H, ArH), 6.95
(d,3J ¼ 8.4 Hz, 1H, ArH), 4.51 (s, 1H, CH), 2.43 (brs, 3H, NCH), 1.50 (brs, 5H,
NCH2-CH2), 1.26 (brs, 2H, NCH2-CH2-CH2).
2-(Morpholin-4-yl-phenyl-methyl)naphthalen-1-ol (4r) (Table 2, Entry
18). Yellow solid. Found: C, 78.75; H, 6.52; N, 4.48%. C21H21NO2 requires C,
78.97; H, 6.63; N, 4.39%. Mp 116–118 ꢀC (EtOAc); IR (KBr): 3421, 3052, 2938,
1
2798, 1631, 1577, 1456, 1387, 1297, 1145, 1007, 854, 804 and 761 cmꢁ1; H NMR
(300 MHz; CDCl3): dH 12.60 (s, 1H, OH), 8.35 (d, 3J ¼ 7.5 Hz, 1H, ArH), 7.73
4
(dd,3J ¼ 8.1 Hz and J ¼ 1.8 Hz, 1H, ArH), 7.53–7.44 (m, 4H, ArH), 7.38–7.24 (m,
3
4H, ArH), 7.05 (d, J ¼ 8.4 Hz, 1H, ArH), 4.52 (s, 1H, CH), 3.88–3.80 (m, 4H,
O-CH2), 2.85–2.45 (m, 4H, NCH2), 13C NMR (CDCl3, 75 MHz): dc 151.5, 139.4,
133.7, 128.9, 128.6, 128.1, 127.2, 127.0, 126.2, 125.3, 124.9, 122.3, 119.0, 117.5,
77.0, 66.9 and 52.4.
2-[(4-Bromo-phenyl)-(4-methyl-piperazin-1-yl)-methyl]-naphthalen-1-ol
(4s) (Table 2, Entry 19). Yellow solid. Found: C, 64.47; H, 5.55; N, 6.88%.
C22H23BrN2O requires C, 64.24; H, 5.64, N: 6.81%. Mp 74–76 ꢀC (EtOAc); IR
(KBr): 3421, 3052, 2938, 2798, 1631, 1577, 1456, 1387, 1297, 1145, 1085, 1007,
1
854, 804 and 761 cmꢁ1; H NMR (300 MHz; CDCl3): dH 12.38 (s, 1H, OH), 8.20
3
4
3
4
(dd, J ¼ 8.1 Hz and J ¼ 2.1 Hz, 1H, ArH), 7.62 (dd, J ¼ 6.6 Hz and J ¼ 2.4 Hz,
1H, ArH), 7.39–7.34 (m, 2H, ArH), 7.31 (d, 3J ¼ 8.7 Hz, 2H, ArH), 7.21 (d,
3J ¼ 8.7 Hz, 2H, ArH), 7.14 (d, J ¼ 8.4 Hz, 1H, ArH), 6.88 (d, J ¼ 8.7 Hz, 1H,
ArH), 4.35 (s, 1H, CH), 2.41 (brs, 8H, NCH2), 2.23 (s, 3H, NCH3) ; 13C NMR
(CDCl3, 75 MHz): dc 151.7, 138.8, 133.8, 132.1, 131.6, 131.5, 130.3, 127.3, 126.7,
126.3, 125.4, 125.1, 122.4, 122.1, 119.1, 117.4, 75.7, 68.3, 55.0 and 45.5.
3
3

SYNTHESIS OF AMINOALKYLNAPHTHOLS
3087
ACKNOWLEDGMENTS
One of the authors (S. R.) thanks the Council of Scientific and Industrial
Research, New Delhi, for his fellowship SRF. We thank the CAS Instrumentation
Facility, Department of Chemistry, University of Calcutta, for spectral data. We
also acknowledge a grant received from the University Grants Commission for
Major Project F. No. 37-398=2009 (SR).
REFERENCES
1. Gerlach et al. Substituted 1 and 2-naphthol Mannich bases. U.S. Patent 7,202,242 B2, 2007.
2. Lu, J.; Xu, X.; Wang, C.; He, J.; Hu, Y.; Hu, H. Synthesis of chiral ligands derived from
the Betti base and their use in the enantioselective addition of diethylzinc to aromatic
aldehydes. Tetrahedron Lett. 2002, 43, 8367–8369.
3. Brown, P. D. Matrix metalloproteinase inhibitors in the treatment of cancer. Med. Oncol.
1997, 14, 1–10.
4. Johnson, K. W.; Lofland, D.; Moser, H. E. PDF inhibitors: An emerging class of antibac-
terial drugs. Curr. Drug Targets: Infect. Disord. 2005, 5, 39–52.
5. Lowther, W. T.; Matthews, B. W. Structure and function of the methionine aminopepti-
dases. Biochim. Biophys. Acta 2000, 1477, 157–167.
6. Waller, A. S.; Clements, J. M. Novel approaches to antimicrobial therapy: Peptide defor-
mylase. Curr. Opin. Drug Discov. Dev. 2002, 5, 785–792.
7. Chappell, L. T. Applications of EDTA chelation therapy. Altern. Med. Rev. 1997, 2,
426–432.
8. Ford, M. D. Heavy Metals, 4th ed.; McGraw Hill: New York, 1996.
9. Cohen, A.; Hall, R. A.; Heath-Brown, B.; Parkes, M. W.; Rees, A. H. Oxytocic activity of
basic (aminomethyl) derivatives of phenols and related compounds. J. Pharmacol.
Chemother. 1957, 12, 194–208.
10. (a) Smrcina, M.; Vyskocil, S.; Maca, B.; Polasek, M.; Claxton, T. A.; Abbott, A. P.;
Kocovsky, P. Selective cross-coupling of b-naphthoal and 2-naphthylamine derivatives:
A facile synthesis of 2,20, 3-trisubstituted and 2,20,3,30-tet rasubstituted 1,l0-binaphthyls.
J. Org. Chem. 1994, 59, 2156–2163; (b) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera,
P.; Kocovsky, P. Synthesis of enantiomerically pure 2,20-dihydroxy-1,l0-binaphthyl,
2,20-diamino-l,l0-binaphthyl and 2-amino-20-hydroxy-l,l0-binaphthyl: Comparison of
processes operating as diastereoselective crystallization and as second-order asymmetric
transformation. J. Org. Chem. 1992, 57, 1917–1920; (c) Vyskocil, S.; Jaracz, S.; Smrcina,
M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. Synthesis of N-alkylated
and N-arylated derivatives of 2-amino-20-hydroxy-1,10-binaphthyl (NOBIN) and
2,20-diamino-1,10-binaphthyl and their application in the enantioselective addition of
diethylzinc to aromatic aldehydes. J. Org. Chem. 1998, 63, 7727–7737; (d) Yuan, Y.; Li,
X.; Sun, I.; Ding, K. L. To probe the origin of activation effect of carboxylic acid and
(þ)-NLE in tridentated titanium catalyst systems. J. Am. Chem. Soc. 2002, 124, 14866–
14867; (e) Kim, Y.; Singer, R. A.; Carreira, E. R. Total synthesis of macrolactin a with
versatile catalytic, enantioselective dienolate aldol addition reactions. Angew. Chem. Int.
Ed. 1998, 37, 1261–1263.
11. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortorella, P. Use of readily avail-
able chiral compounds related to the Betti base in the enantioselective addition of diethyl-
zinc to aryl aldehydes. Tetrahedron 1999, 55, 14685–14692.
12. Cardellicchio, C.; Ciccarella, G.; Naso, G.F.; Schingaro, E.; Scordari, F. The Betti base:
Absolute configuration and routes to a family of related chiral nonracemic bases. Tetra-
hedron: Asymmetry 1998, 9, 3667–3675.

3088
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
13. Palmieri, G. A practical o-hydroxybenzylamines-promoted enantioselective addition of
dialkylzincs to aldehydes with asymmetric amplification. Tetrahedron: Asymmetry 2000,
11, 3361–3373
14. Liu, D. X.; Zhang, L. C.; Wang, Q.; Da, C. S.; Xin, Z. Q.; Wang, R.; Choi, M. C. K.;
Chan, A. S. C. The application of chiral aminonaphthols in the enantioselective addition
of diethylzinc to aryl aldehydes. Org. Lett. 2001, 3, 2733.
15. Cimarelli, C.; Palmieri, G.; Volpini, E. A practical stereoselective synthesis of secondary
and tertiary aminonaphthols: Chiral ligands for enantioselective catalysts in the addition
of diethylzinc to benzaldehyde. Tetrahedron: Asymmetry 2002, 13, 2417–2426
16. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. Solvent-free asymmetric aminoalk-
ylation of electron-rich aromatic compounds: stereoselective synthesis of aminoalkyl-
naphthols by crystallization-induced asymmetric transformation. J. Org. Chem. 2001,
66, 4759–4765.
17. Ji, J. X.; Qiu, L. Q.; Yip, C. W.; Chan, A. S. C. A convenient, one-step synthesis of opti-
cally active tertiary aminonaphthol and its applications in the highly enantioselective alke-
nylations of aldehydes. J. Org. Chem. 2002, 68, 1589–1590.
18. Betti, M. Condensation between b-naphthol, aldehydes, and amines. Gazz. Chim. Ital.
1900, 30, 310–316.
19. (a) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Belyakov, S. A.;
Ghiviriga, I.; Steel, P. J. Amino(hetero)arylmethylation of phenols with N-[a -amino(he-
tero)arylmethyl]benzotriazoles. J. Org. Chem. 1999, 64, 6071–6075; (b) Saidi, M. R.; Azizi,
N.; Naimi-Jamal, M. R. Lithium perchlorate–assisted, one-pot, three-component ami-
noalkylation of electron-rich aromatic compounds. Tetrahedron Lett. 2001, 42, 8111–
8113.
20. Jha, A.; Paul, N. K.; Trikha, S.; Cameron, T. S. Novel synthesis of 2-naphthol Mannich
bases and their NMR behavior. Can. J. Chem. 2006, 84, 843–853.
21. Kumar, A.; Gupta, M. K.; Kumar, M. Non-ionic surfactant–catalyzed synthesis of Betti
base in water. Tetrahedron Lett. 2010, 51, 1582–1584.
22. (a) Cardelliccho, C.; Capozzi, M. A. M.; Naso, F. The Betti base: The awakening of a
sleeping beauty. Tetrahedron: Asymmetry 2010, 21, 507–517; (b) Betti, M. b-Naphthol
phenylaminomethane. Org. Synth. Coll. Vol. 1, 1941, 381; (c) Ghandi, M.; Olyaei, A.;
Raoufmoghaddam, S. One-pot, three-component uncatalyzed quantitative synthesis of
new aminonaphthols (Betti bases) in water. Synth. Commun. 2008, 38, 4125–4138.