Novel synthesis of 2-naphthol Mannich bases and their NMR behaviour

Article abstract of DOI:10.1139/V06-081

A novel two-step procedure involving the formation of 1-arylidene-2- tetralones from 2-tetralone and subsequent Michael addition of a cyclic secondary amine on the alkenone followed by in situ aerial oxidation was developed to produce 2-naphthol Mannich bases. A simple microwave-assisted one-pot synthesis of 2-naphthol Mannich bases was also carried out under solvent-free conditions from 2-naphthol and corresponding aldehydes and amines in the presence of p-toluenesulfonic acid. The compounds of this series displayed interesting NMR behaviour. Extensive variable-temperature NMR investigations, including HSQC experiments, are herein reported. NMR results on the conformation in solution phase were found to be consistent with the X-ray crystal structure in the solid state.

Full text of DOI:10.1139/V06-081

843
Novel synthesis of 2-naphthol Mannich bases and
their NMR behaviour
Amitabh Jha, Nawal K. Paul, Smriti Trikha, and T. Stanley Cameron
Abstract: A novel two-step procedure involving the formation of 1-arylidene-2-tetralones from 2-tetralone and subse-
quent Michael addition of a cyclic secondary amine on the alkenone followed by in situ aerial oxidation was developed
to produce 2-naphthol Mannich bases. A simple microwave-assisted one-pot synthesis of 2-naphthol Mannich bases was
also carried out under solvent-free conditions from 2-naphthol and corresponding aldehydes and amines in the presence
of p-toluenesulfonic acid. The compounds of this series displayed interesting NMR behaviour. Extensive variable-
temperature NMR investigations, including HSQC experiments, are herein reported. NMR results on the conformation
in solution phase were found to be consistent with the X-ray crystal structure in the solid state.
Key words: Mannich bases, microwave-assisted Mannich reaction, temperature-variable NMR spectroscopy,
NMR dynamics, X-ray crystallography.
Résumé : On a mis au point une nouvelle méthode en deux étapes qui permet de produire des bases de Mannich du 2-
naphtol et qui implique la formation de 1-arylidène-2-tétralones à partir de la 2-tétralone, puis une addition subséquente
de Michael d’une amine secondaire cyclique sur l’alcénone, suivie d’une oxydation in situ par de l’air. On a aussi réa-
lisé une synthèse des bases de Mannich du 2-naphtol par une simple réaction monotope du 2-naphtol, des aldéhydes et
des amines correspondants en présence d’acide p-toluènesulfonique, sous l’effet de micro-ondes, dans des conditions
sans solvant. Les composés de cette série présentent des comportements RMN intéressants. On a effectué de nombreu-
ses études RMN à température variable, y compris des expériences de « HSQC ». On a trouvé que les résultats de la
RMN sur la conformation en solution sont en accord avec la structure cristalline déterminée par diffraction des rayons
X, à l’état solide.
Mots clés : bases de Mannich, réaction de Mannich assistée par les micro-ondes, spectroscopie RMN à température
variable, dynamique RMN, cristallographie par diffraction des rayons X.
[Traduit par la Rédaction] Jha et al. 853
Introduction
In addition, potent oxytocic activity of compounds of this
type is reported in the literature (30). Since these compounds
have multiple centres for chelation with metal ions, they are
likely to be potent inhibitors of metalloenzymes containing
Fe, Cu, Zn, Co, etc., ions as cofactors (31–34). Also, these
compounds have the potential to be used as scavengers in
cases of heavy metal (Pd, Hg, Cd, As, Sb, etc.) poisoning
(35, 36).
We herein report a novel synthetic route to this class of
compounds (1–4, Fig. 1) involving two steps starting from
2-tetralones. Also, additional analogs (5–11, Fig. 1) were
obtained in moderate to excellent yields with improved reac-
tion time by modifying a reported microwave-assisted proce-
dure (26). While characterizing the compounds using the
usual spectroscopic means, we observed anomalous and
interesting NMR behaviour of heterocyclic rings. NMR ex-
periments to study the solution phase dynamics as well as
Numerous chiral aminomethyl phenols have been reported
as excellent chelating agents in metal-catalyzed asymmetric in-
duction in a variety of reactions (1–10). Chiral Mannich bases
of 2-naphthol are particularly popular in metal-mediated and
ligand-accelerated catalysis of enantioselective carbon–carbon
bond formation (11–17). Many of these carbon–carbon bond
formation reactions involve the use of organozinc compounds
as alkylating agents, which are relatively unreactive if uncoor-
dinated (11). These ligands may be used in catalytic amounts.
The first synthesis of racemic Mannich bases of 2-naphthol
was achieved by Betti (18–22) at the turn of the 20th century.
Thereafter, numerous modifications of this reaction surfaced
(23–27) and optically pure Betti base analogs were prepared ei-
ther by resolution or by the induction of chirality by the use of
optically active amines (11–17, 28, 29).
Received 4 October 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 7 June 2006.
A. Jha,1 N.K. Paul, and S. Trikha. Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada.
T.S. Cameron.2 Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada.
1Corresponding author (email: amitabh.jha@acadiau.ca).
2Corresponding author regarding X-ray crystallography (e-mail: cameron@dal.ca).
Can. J. Chem. 84: 843–853 (2006)
doi:10.1139/V06-081
© 2006 NRC Canada

844
Can. J. Chem. Vol. 84, 2006
Fig. 1. Molecular structure of the compounds investigated.
1
R = Phenyl, X = CH2
R = 4-Tolyl, X = CH2
2
X
3
R = 4-Nitrophenyl, X = CH2
R = 2-Nitrophenyl, X = CH2
R = 4-Chlorophenyl ,X = CH2
R = 4-Pyridyl, X = CH2
R = H, X =CH2
R
N
R
4
5
OH
6
O
7
8
R = Phenyl, X=O
9
R = 4-Chlorophenyl, X= O
R= 4-Nitrophenyl, X= O
R= Phenyl, X=NCH3
10
11
A
1-11
Scheme 1. Novel synthethic route to 2-naphthol Mannich bases (1–4).
R
R
N
O
O
+
OH
O
Pd/C, TMSCl
DMF
+
R
H
N
H
A
1-4
Scheme 2. Proposed mechanism for conversion of 1-arylidene-2-tetralone to 2-naphthol Mannich bases following Scheme 1.
R
N
R
R
N
R
N
H
O
H
O
H2O
1/2O2
O
O
HN
C
1-4
A
B
solid-state X-ray crystal structure of representative com-
pounds are also reported here.
Synthesis of substituted 1-arylidene-2-tetralones (A)
Palladium-catalyzed Knoevenagel-type condensation (37)
from 2-tetralone and appropriate aldehydes resulted in
1-arylidene-2-tetralones. To
a
mixture of 2-tetralone
(20 mmol), appropriate aromatic aldehyde (22 mmol), 10%
Pd/C (2 mol %), and DMF (30 mL) was added TMSCl
(22 mmol) in dropwise fashion at room temperature. After
30 min, the reaction was warmed to 75 °C and stirred for
5 h. DMF was rotary evaporated and the residue was
chromatographed with 2% EtOAc in hexanes. The resulting
products were characterized as 1-arylidene-2-tetralones (A)
by comparison of their physical and spectral data with those
reported in the literature (38). The melting points (°C) and
percentage yields of the compounds in this series were as
follows: A (R = phenyl): 116 to 117, 76; A (R = 4-tolyl):
103 to 104, 73; A (R = 4-NO2-phenyl): 153 to 154, 82; A
(R = 2-NO2-phenyl): 122 to 123, 71.
Experimental
General
All chemicals were obtained from the Sigma-Aldrich
Chemical Company, Inc. Column chromatographic purifi-
cations were undertaken using silica gel (230–400 mesh) ob-
tained from Silicycle. H and 13C NMR were recorded on
1
Bruker AV500 and AV300 NMR spectrometers. HSQC spec-
tra were obtained on a Bruker AV500 spectrometer using
256 increments and a sweep width of 20 kHz in the indirect
(carbon) dimension. Coherence selection was achieved using
gradients and phase-sensitive HSQC data were obtained us-
ing the echo-antiecho method. All 180° pulses in the se-
quence were replaced with adiabatic shapes for improved
broadband inversion and refocussing over the entire carbon
frequency range. EI-MS and HR-MS spectra were obtained
on a CEC 21-110B Sector instrument. Melting points were
recorded on an electrothermal apparatus and are uncorrected.
UV–vis and IR spectra were recorded on LKB Biochrom
Ultraspec Plus 4054 and Nicolet Avatar 330 FT-IR spectro-
photometers, respectively. A domestic microwave oven man-
ufactured by Kenmore was used for the microwave-assisted
reactions at highest power (900 W) and 2450 MHz operating
frequency.
Synthesis of 1-(arylpiperidin-1-yl methyl)naphthalen-2-
ols (1–11)
Procedure A (Schemes 1 and 2): Appropriate 1-arylidene-
2-tetralones (A, 10 mmol) reacted with excess piperidine at
room temperature to produce the compounds (1–4) over a
period of 7 days. No reaction progress was observed by TLC
after 24 h. The resulting compounds were purified using sil-
ica gel column chromatography with 3% ethyl acetate in
hexanes as the eluent. Unreacted starting materials (A) were
also recovered.
© 2006 NRC Canada

Jha et al.
845
Scheme 3. Synthethic route for the microwave-assisted reactions of compounds 1–12.
X
R
N
OH
+
OH
O
p-TSA, m.w.
+
HN
X
R
H
1-12
Procedure B (Scheme 3): A mixture of 2-naphthol
(10 mmol), appropriate aromatic aldehyde (12 mmol), p-
TSA (50 mg, cat.), and appropriate secondary amine
(12 mmol) was irradiated using the microwave for 1 min
(30 s × 2, to avoid overheating). The reaction mixture was
cooled and methanol was added to it. Several products, viz.
compounds 1, 3, 5, 6, and 8, were purified by digestion in
methanol as follows. The reaction mixture was stirred in hot
methanol (20 mL) for 1 h and kept at room temperature
overnight for crystallization and precipitation. The solid
product was filtered, washed with cold methanol (2 × 5 mL),
and dried under vacuum. The rest of the derivatives were pu-
rified by column chromatography using silica gel. The de-
sired product eluted with 2% ethyl acetate in hexanes. The
products thus obtained were further purified by crystalliza-
tion.
7.18–7.31 (2H, m, Ar-H), 7.42 (1H, t, J= 7.5 Hz, Ar-H),
7.70–7.81 (5H, m, Ar-H), 8.13–8.16 (2H, m, Ar-H), 13.78
(1H, bs, OH). 13C NMR (75 MHz, 273 K, CDCl3) δ: 24.32,
26.10, 26.40, 52.78, 55.03, 71.45, 115.26, 120.48, 120.83,
123.22, 124.61, 127.26, 129.06, 129.61, 130.21, 130.62,
132.33, 147.61, 147.73, 155.74. EI-MS (70 eV) m/z (% int.):
362 (M+, 14), 279 (9), 260 (61), 231 (39), 230 (100), 85
(54), 58 (14). HR-MS calcd. for C22H22N2O3: 362.1630;
found: 362.1634.
1-(2-Nitrophenyl)piperidin-1-ylmethyl)naphthalen-2-ol (4)
UV–vis (MeOH, nm) λmax: 241, 335. IR (KBr disc, cm–1)
ν: 3439, 3052, 2926, 1621, 1595, 1514, 1316, 1265, 1231,
830. 1H NMR (500 MHz, 273 K, CDCl3) δ: 1.25–1.32
(1H, m, CH), 1.67–1.77 (5H, m, 5 × CH), 2.35–2.38 (2H, m,
2 × NCH), 2.58 (1H, d, J = 9.5 Hz, NCH), 3.30 (1H, d, J =
11.5 Hz, NCH), 6.08 (1H, s, Ar-CH-Ar′), 7.15 (1H, d, J =
9.0 Hz, Ar-H), 7.21–7.26 (1H, m, Ar-H), 7.31–7.45 (3H, m,
Ar-H), 7.65–7.71 (3H, m, Ar-H), 7.81–7.85 (2H, m, Ar-H),
14.54 (1H, bs, OH). 13C NMR (125 MHz, 273 K, CDCl3) δ:
23.90, 25.93, 26.52, 49.92, 54.62, 64.02, 115.07, 120.20,
120.64, 122.69, 124.29, 126.97, 128.58, 128.86, 128.93,
130.09, 131.55, 132.61, 133.65, 133.70, 150.22, 156.94. EI-
MS (70 eV) m/z (% int.): 362 (M+, 2), 231 (100), 232 (47),
85 (3). HR-MS calcd. for C23H23NO3: 362.1630; found:
362.1633.
1-(Phenylpiperidin-1-ylmethyl)naphthalen-2-ol (1)
1H and 13C NMR were identical to those reported in the
literature (27). UV–vis (MeOH, nm) λmax: 244, 280, 336. IR
(KBr disc, cm–1) ν: 3443, 3050, 2971, 1621, 1599, 1455,
1268, 1238, 702. EI-MS (70 eV) m/z (% int.): 317 (M+, 11),
231 (100), 200 (2), 84 (41). HR-MS calcd. for C22H23NO:
317.1780; found: 317.1785.
1-(4-Methylphenyl)piperidin-1-ylmethyl)naphthalen-2-ol
(2)
UV–vis (MeOH, nm) λmax: 244, 291, 336. IR (KBr
1-(4-Chlorophenyl)piperidin-1-ylmethyl)naphthalen-2-ol
(5)
disc, cm–1) ν: 3439, 3060, 2963, 1621, 1595, 1384, 1359,
1
1261, 1231, 821. H NMR (300 MHz, 273 K, CDCl3) δ:
UV–vis (MeOH, nm) λ max: 242, 291, 336. IR (KBr
disc, cm–1) ν: 3440, 3080, 2951, 1620, 1519, 1474, 1384,
1.41 (1H, bs, CH), 1.50–1.91 (5H, m, 5 × CH), 2.27–2.46
(4H, m, Ar-CH3, NCH), 2.92 (1H, bs, NCH), 3.23 (1H, bs,
NCH), 3.53 (1H, bs, NCH), 5.23 (1H, s, Ar-CH-Ar′), 7.01–
7.08 (1H, m, Ar-H), 7.22–7.28 (2H, m, Ar-H), 7.37–7.42
(3H, m, Ar-H), 7.49–7.52 (2H, m, Ar-H), 7.68–7.73 (1H, m,
Ar-H), 7.81–7.84 (1H, m, Ar-H), 13.32 (1H, bs, OH). 13C
NMR (75 MHz, 273 K, CDCl3) δ: 21.63, 24.03, 25.72,
26.00, 52.10, 55.20, 64.90, 109.00, 117.82, 120.33, 121.24,
123.06, 126.22, 127.10, 129.11, 129.47, 130.25, 130.87,
134.88, 155.36. EI-MS (70 eV) m/z (% int.): 331 (M+, 14),
247 (10), 231 (100). HR-MS calcd. for C23H25NO:
331.1936; found: 331.1930.
1
1104, 742, 515. H NMR (300 MHz, 273 K, CDCl3) δ: 1.27
(1H, bs, CH), 1.62–1.70 (5H, bs, 5 × CH), 1.97 (1H, bs,
NCH), 2.03 (1H, bs, NCH), 2.73 (1H, bs, NCH), 3.36 (1H,
bs, NCH), 5.07 (1H, s, Ar-CH-Ar′), 7.19–7.41 (4H, m, Ar-
H), 7.43–7.46 (1H, m, Ar-H), 7.54–7.68 (2H, m, Ar-H),
7.71–7.81 (3H, m, Ar-H), 3.12 (1H, bs, OH). 13C NMR
(75 MHz, 273 K, CDCl3) δ: 24.35, 26.10, 26.30, 52.41,
55.14, 71.49, 117.13, 120.45, 121.20, 123.06, 127.08,
129.51, 129.77, 130.22 130.94, 131.16, 132.50, 134.21,
138.33, 156.12. EI-MS (70 eV) m/z (% int.): 353 (M + 2,
0.7), 350 (M+, 2), 266 (2), 264 (2), 231 (6), 84 (100). HR-
MS calcd. for C22H22ClNO: 351.1390; found: 351.1387.
1-(4-Nitrophenyl)piperidin-1-ylmethyl)naphthalen-2-ol (3)
UV–vis (MeOH, nm) λmax: 244, 295, 335. IR (KBr
disc, cm–1) ν: 3439, 3080, 3060, 2926, 1621, 1514, 1441,
1-(Piperidin-1-yl-pyridin-4-ylmethyl)naphthalen-2-ol (6)
UV–vis (MeOH, nm) λmax: 241, 298. IR (KBr disc, cm–1)
ν: 3442, 3044, 2944, 1621, 1598, 1451, 1384, 1267, 1236,
1
1414, 1346, 1265, 1231, 830. H NMR (300 MHz, 273 K,
1
CDCl3) δ: 1.28 (1H, bs, CH), 1.58–1.73 (5H, m, 5 × CH),
2.02 (1H, bs, -NCH), 2.15 (1H, bs, -NCH), 2.65 (1H, bs,
-NCH), 3.37 (1H, bs, -NCH), 5.23 (1H, s, Ar-CH-Ar′),
816. H NMR (300 MHz, 273 K, CDCl3) δ: 1.61 (1H, bs,
CH), 1.72–1.88 (5H, bs, 5 × CH), 2.10 (1H, bs, -NCH), 2.71
(1H, bs, -NCH), 3.16 (1H, bs, -NCH), 3.35 (1H, bs, -NCH),
© 2006 NRC Canada

846
Can. J. Chem. Vol. 84, 2006
Fig. 2. Energy minimized molecular model of compound 1 in two orientations. Hydrogen atoms are omitted for clarity.
5.07 (1H, s, Ar-CH-Ar′), 7.15–7.82 (8H, m, Ar-H), 8.50–
8.52 (2H, d, J = 8 Hz, Ar-H), 13.75 (1H, bs, OH). 13C NMR
(75 MHz, 273 K, CDCl3) δ: 24.40, 26.42, 26.44, 52.71,
54.94, 71.26, 115.17, 120.41, 120.94, 123.15, 124.12,
127.17, 129.01, 129.55, 130.48, 132.39, 149.11, 150.67,
155.87. EI-MS (70 eV) m/z (% int.): 318 (M+, 5), 235 (4),
233 (100), 232 (51). HR-MS calcd. for C21H22N2O:
318.1732; found: 318.1727.
(M+2, 4) 353 (M+, 12), 268 (12), 265 (38), 231 (100), 202
(23), 86 (15). HR-MS calcd. for C21H20ClNO2: 353.1183;
found: 353.1193.
1-[(4-Nitrophenyl)morpholin-4-ylmethyl]naphthalen-2-ol
(10)
1H and 13C NMR were identical to those reported in liter-
ature (27). UV–vis (MeOH, nm) λ max: 242, 298. IR (KBr
disc, cm–1) ν: 3448, 3051, 2935, 1621, 1599, 1519, 1466,
1384, 1364, 786, 739. EI-MS (70 eV) m/z (% int.): 364 (M+,
1), 231 (2), 221 (100). HR-MS calcd. for C21H20N2O4:
364.1423; found: 364.1429.
1-Piperidin-1-ylmethylnaphthalen-2-ol (7)
UV–vis (MeOH, nm) λmax: 245, 288, 334. IR (KBr
disc, cm–1) ν: 3448, 3051, 2935, 1621, 1599, 1474, 1384,
1
1271, 786. H NMR (300 MHz, 273K, CDCl3) δ: 1.23 (1H,
bs, CH), 1.77 (5H, m, CH2, -NCH2), 2.37 (2H, bs, 2 ×
NCH), 3.36 (2H, bs, 2 × NCH), 4.37 (2H, s, -NCH2Ar),
7.28–7.35 (2H, m, Ar-H), 7.46–7.51 (1H, m, Ar-H), 7.73–
7.84 (3H, m, Ar-H), 13.2 (1H, bs, OH). 13C NMR (75 MHz,
273K, CDCl3) δ: 24.38, 26.25, 54.60, 57.68, 111.39, 119.67,
121.34, 122.68, 126.59, 128.79, 129.26, 129.36, 133.09,
157.17. EI-MS (70 eV) m/z (% int.): 241 (M+, 5), 157 (5),
84 (100). HR-MS calcd. for C16H19NO: 241.1467; found:
241.1474.
1-[(4-Methylpiperazin-1-yl)phenylmethyl)]naphthalen-2-
ol (11)
UV–vis (MeOH, nm) λ max: 241, 293, 320. IR (KBr
disc, cm–1) ν: 3448, 3056, 1621, 1581, 1450, 1310, 1240,
1
1137. H NMR (300 MHz, 273 K, CDCl3) δ: 2.40–2.57
(8H, m, 5 × NCH, NCH3), 2.95 (2H, bs, 2 × NCH), 3.25
(1H, bs, NCH), 5.17 (1H, s, Ar-CH-Ar′), 7.14–7.29 (4H, m,
Ar-H), 7.39–7.44 (1H, m, Ar-H), 7.53–757 (2H, m, Ar-H),
7.68–7.71 (3H, m, Ar-H), 7.83–7.87 (1H, m, Ar-H), 13.37
(1H, bs, OH). 13C NMR (75 MHz, 273 K, CDCl3) δ: 46.16,
51.20, 53.74, 55.31, 55.62, 71.94, 115.98, 120.27, 121.54,
123.03, 127.01, 128.12, 128.60, 128.81, 129.08, 129.34,
130.11, 132.61, 139.51, 155.31. EI-MS (70 eV) m/z (% int.):
332 (M+, 13), 233 (3), 232 (16), 231 (100). HR-MS calcd.
for C23H24NO3: 332.1889; found: 332.1882.
1-(Morpholin-4-ylphenylmethyl)naphthalen-2-ol (8)
1H and 13C NMR were identical to those reported in liter-
ature (27). UV–vis (MeOH, nm) λmax: 242, 291, 325. IR
(KBr disc, cm–1) ν: 3443, 3058, 2971, 2842, 1619, 1598,
1454, 1384, 1236, 1116. EI-MS (70 eV) m/z (% int.): 319
(M+, 7), 233 (4), 231 (100), 86 (1). HR-MS calcd. for
C21H21NO2: 319.1572; found: 319.1566.
Molecular modeling
The molecular modeling on compound 1 was performed
using CaChe WorkSystem Pro Version 5. After having set a
weak bond between the hydroxyl hydrogen and the N of the
piperidine ring, an energy minimization experiment was
performed in two steps. First, the “fastest procedure” (aug-
mented MM3 parameters) was used, followed by the “stan-
dard procedure” (PM3 parameters). The energy-minimized
conformation indicated strong H-bonding in the molecule
(Fig. 2).
1-[(4-Chlorophenyl)morpholin-4-ylmethyl]naphthalen-2-
ol (9)
UV–vis (MeOH, nm) λ max: 242, 293, 319. IR (KBr
disc, cm–1) ν: 3438, 3062, 2958, 1619, 1597, 1450, 1411,
1
1384, 1238, 1117. H NMR (300 MHz, 273 K, CDCl3) δ:
2.32–2.54 (3H, m, 3 × NCH), 3.14–3.18 (1H, m, NCH),
3.51–3.71 (4H, m, 4 × OCH), 5.14 (1H, s, Ar-CH-Ar′),
7.17–7.31 (4H, m, Ar-H), 7.40–7.45 (1H, m, Ar-H), 7.53–
7.56 (2H, m, Ar-H), 7.71–7.76 (3H, m, Ar-H), 13.15 (1H,
bs, OH). 13C NMR (75 MHz, 273 K, CDCl3) δ: 51.95,
54.28, 67.10, 67.30, 71.59, 115.03, 120.27, 121.19, 123.33,
127.23, 129.22, 129.50, 129.91, 130.55, 131.10, 132.44,
134.55, 137.37, 154.95. EI-MS (70 eV) m/z (% int.): 355
X-ray crystallography
Crystals of compound 9 were grown from a saturated
dichloromethane–methanol (1:1) solution, while crystals of
compound 11 were grown from saturated diethyl ether solu-
© 2006 NRC Canada

Jha et al.
847
Table 1. Crystallographic data collection parameters for 9 and 11.
Parameter
Compound 9
Compound 11
Empirical formula
C21H20ClNO2
C22H24N2O
Formula weight
Crystal color, habit
Crystal dimensions (mm3)
F(000)
353.85
332.44
Colorless, needle
0.17 × 0.22 × 0.30
744
Colorless, block
0.24 × 0.27 × 0.38
712
Crystal system
Space group
Z
Monoclinic
Cc (No. 9)a
4
Orthorhombic
Pna21 (No. 33)
4
a (Å)
b (Å)
c (Å)
9.782(5)
10.723(6)
13.483(8)
12.849(8)
18.645(5)
10.240(4)
91.42(3)
1867(1)
1.259
β (°)
V (Å3)
1857(2)
1.189
dcalcd (g cm–3)
Temperature (K)
Radiation
213
213
Mo Kα (λ = 0.710 69 Å)
Mo Kα (λ = 0.710 69 Å)
µ (mm–1)
0.217
2975
2893
231
0.073
3090
2836
227
Total reflections
Observed reflections (Fo > 4σ(Fo))
No. of variables
Rint
0.067
0.000
θ range (°)
0–30
0.950
0.039
0–30
0.942
0.039
S (GoF) on F2
R1 (I > 4σ(I))b
wR2 (all data)c
Largest diff. peak and hole (e Å–3)
0.138
0.202
0.19 and –0.17
0.20 and –0.17
aFlack parameter 0.0 (1).
bR1 = Σ||Fo| – |Fc||/Σ|Fo|.
cwR2 = [Σ(w(Fo – Fc2)2)/Σw(Fo )2]1/2, where w = 1/[σ2(Fo ) + (0.0664P)2 + (0.0000P)] (9) and w = 1/[σ2(Fo ) +
2
2
2
2
(0.1000P)2 + (0.0000P)] (11), where P = (max(Fo , 0) + 2Fc2)/3.
2
tion. Crystals were mounted using a glass fiber. All mea-
surements were made on a Rigaku AFC5R diffractometer
with graphite monochromated Mo Kα radiation.
Results and discussion
One of the interests of this laboratory lies in the use of
2-tetralone–2-naphthol skeletons as versatile building blocks
(48–50). Substituted 1-arylidene-2-tetralones (A) were
prepared from 2-tetralone and appropriate aldehydes by
palladium-catalyzed Knoevenagel-type condensation (37).
Subsequently, 1-arylidene-2-tetralones reacted with piperi-
dine to produce the compounds 1–4 instead of the expected
aza-Michael adducts (B or C). Based on this observation, it
appears highly probable that aza-Michael adducts (B or C)
are unstable and that they collapse back to the starting mate-
rials if they are not trapped by aerial oxidation of the
dihydronaphthalene ring to form stable and aromatic 1-(aryl-
piperidin-1-ylmethyl)naphthalen-2-ols (1–4), as shown in
Scheme 2. This rather unusual conversion, driven by the
aromatization, was found to be slow and the best yield after
a reaction time of 7 days was ~30%. Although the reactions
suffer from rather long reaction times and low yields, this is
a novel conversion.
The data were collected at a temperature of –60 1 °C to
a maximum 2θ value of 60.2°. The structure was solved by
direct methods (39) and expanded using Fourier techniques
(40). The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined using the riding model. The
neutral atom scattering factors were taken from Cromer and
Weber (41). Anomalous dispersion effects were included in
Fcalcd (42); the values for ∆ f ′ and ∆ f ′′ were those of Creagh
and McAuley (43). The values for the mass attenuation
coefficients are those of Creagh and Hubbell (44). All calcu-
lations were performed using the CrystalStructure crystallo-
graphic software package (45, 46) except for refinement,
which was performed using SHELXL-97 (47).
The crystallographic data collection parameters, bond
lengths, and bond angles for 9 and 11 are presented in
Tables 1–3. The full details of the structure have been depos-
ited.3
3 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5046. For
more information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 606518 and 606519 contain the
crystallographic data for this manuscript. These data can be obtained, free of charge, via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(Or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
© 2006 NRC Canada

848
Can. J. Chem. Vol. 84, 2006
Table 3. Bond lengths and angles for 11.
Table 2. Bond lengths and angles for 9.
Bond lengths (Å)
Bond angles (°)
Bond lengths (Å)
Bond angles (°)
Cl(1)—C(5)
O(1)—C(19)
O(1)—C(20)
O(2)—C(9)
N(1)—C(1)
N(1)—C(18)
N(1)—C(21)
C(1)—C(2)
C(1)—C(8)
C(2)—C(3)
C(2)—C(7)
C(3)—C(4)
1.745(4)
1.413(6)
1.414(6)
1.351(5)
1.492(5)
1.470(6)
1.483(6)
1.516(6)
1.530(5)
1.385(6)
1.391(6)
1.365(7)
1.372(7)
1.366(6)
1.362(6)
1.378(6)
1.432(6)
1.425(6)
1.347(7)
1.402(7)
1.409(7)
1.436(6)
1.344(8)
1.408(8)
1.361(7)
1.398(6)
1.508(7)
1.511(7)
Cl(1)-C(5)-C(4)
Cl(1)-C(5)-C(6)
O(1)-C(19)-C(18)
C(20)-O(1)-C(19)
O(1)-C(20)-C(21)
O(2)-C(9)-C(8)
O(2)-C(9)-C(10)
C(18)-N(1)-C(1)
C(21)-N(1)-C(1)
N(1)-C(1)-C(8)
119.5(4)
120.4(3)
112.2(4)
110.5(4)
111.0(4)
123.6(4)
116.1(4)
113.5(3)
108.9(3)
111.1(3)
113.2(3)
109.3(4)
108.5(3)
109.3(4)
122.4(4)
109.6(3)
121.3(3)
121.0(4)
119.5(4)
122.3(5)
116.2(4)
122.2(4)
119.4(5)
120.1(4)
119.6(4)
120.2(4)
119.5(4)
123.9(4)
119.2(4)
120.8(4)
121.6(4)
118.7(4)
122.0(4)
119.3(4)
121.1(5)
116.9(4)
120.6(5)
119.2(5)
122.8(5)
O(1)—C(9)
N(1)—C(1)
N(1)—C(18)
N(1)—C(21)
N(2)—C(19)
N(2)—C(20)
N(2)—C(22)
C(1)—C(2)
C(1)—C(8)
C(2)—C(3)
C(2)—C(7)
C(3)—C(4)
1.361(7)
1.499(6)
1.470(7)
1.452(8)
1.413(9)
1.454(7)
1.481(8)
1.507(7)
1.529(7)
1.389(8)
1.386(8)
1.39(1)
O(1)-C(9)-C(8)
O(1)-C(9)-C(10)
N(1)-C(1)-C(2)
123.1(4)
116.2(5)
113.4(4)
109.0(4)
110.3(4)
114.5(4)
108.4(4)
108.5(4)
111.4(5)
112.3(6)
109.8(4)
111.7(5)
110.1(5)
109.6(5)
122.6(5)
111.3(4)
120.5(5)
121.0(4)
119.3(4)
116.9(5)
121.1(6)
121.1(6)
120.8(6)
118.9(7)
121.2(7)
120.7(5)
119.5(4)
123.5(4)
118.6(5)
121.0(5)
120.9(5)
119.3(5)
122.3(5)
118.3(5)
120.8(6)
117.9(5)
121.3(7)
119.0(7)
122.6(5)
N(1)-C(1)-C(8)
C(21)-N(1)-C(1)
C(18)-N(1)-C(1)
C(21)-N(1)-C(18)
N(1)-C(18)-C(19)
N(1)-C(21)-C(20)
N(2)-C(19)-C(18)
C(20)-N(2)-C(19)
C(22)-N(2)-C(19)
N(2)-C(20)-C(21)
C(22)-N(2)-C(20)
C(1)-C(2)-C(7)
C(8)-C(1)-C(2)
C(1)-C(2)-C(3)
C(1)-C(8)-C(9)
C(1)-C(8)-C(17)
C(7)-C(2)-C(3)
N(1)-C(1)-C(2)
N(1)-C(18)-C(19)
C(21)-N(1)-C(18)
N(1)-C(21)-C(20)
C(1)-C(2)-C(3)
C(8)-C(1)-C(2)
C(1)-C(2)-C(7)
C(1)-C(8)-C(9)
C(1)-C(8)-C(17)
C(2)-C(3)-C(4)
C(7)-C(2)-C(3)
C(2)-C(7)-C(6)
C(4)—C(5)
C(5)—C(6)
C(6)—C(7)
C(8)—C(9)
C(4)—C(5)
C(5)—C(6)
C(6)—C(7)
C(8)—C(9)
1.36(1)
1.36(1)
1.38(1)
1.371(7)
1.428(7)
1.423(7)
1.341(9)
1.406(9)
1.426(9)
1.442(7)
1.34(1)
C(8)—C(17)
C(9)—C(10)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
C(12)—C(17)
C(13)—C(14)
C(14)—C(15)
C(15)—C(16)
C(16)—C(17)
C(18)—C(19)
C(20)—C(21)
C(8)—C(17)
C(9)—C(10)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
C(12)—C(17)
C(13)—C(14)
C(14)—C(15)
C(15)—C(16)
C(16)—C(17)
C(18)—C(19)
C(20)—C(21)
C(2)-C(3)-C(4)
C(2)-C(7)-C(6)
C(3)-C(4)-C(5)
C(4)-C(5)-C(6)
C(3)-C(4)-C(5)
C(4)-C(5)-C(6)
C(5)-C(6)-C(7)
1.41(1)
1.365(9)
1.395(8)
1.514(8)
1.513(9)
C(5)-C(6)-C(7)
C(8)-C(9)-C(10)
C(17)-C(8)-C(9)
C(8)-C(17)-C(16)
C(8)-C(17)-C(12)
C(9)-C(10)-C(11)
C(10)-C(11)-C(12)
C(11)-C(12)-C(17)
C(11)-C(12)-C(13)
C(17)-C(12)-C(13)
C(12)-C(13)-C(14)
C(12)-C(17)-C(16)
C(13)-C(14)-C(15)
C(14)-C(15)-C(16)
C(15)-C(16)-C(17)
C(8)-C(9)-C(10)
C(17)-C(8)-C(9)
C(8)-C(17)-C(16)
C(8)-C(17)-C(12)
C(9)-C(10)-C(11)
C(10)-C(11)-C(12)
C(11)-C(12)-C(17)
C(11)-C(12)-C(13)
C(17)-C(12)-C(13)
C(12)-C(13)-C(14)
C(12)-C(17)-C(16)
C(13)-C(14)-C(15)
C(14)-C(15)-C(16)
C(15)-C(16)-C(17)
Several attempts were made to expedite the reaction
course by addition of oxidizing agents (viz., H2O2, MnO2,
DDQ, and O2). No decline in the reaction time could be
achieved; rather, undesired products and complex mixtures
were obtained. No attempts were made to identify the unde-
sired products. The results suggest that the first elementary
step (formation of B or C, Scheme 2) is rate-limiting and the
presence of oxidizing agents lead to undesired reactions with
the starting materials. We are in the process of optimizing
the conditions.
We prepared additional analogs (1–11, Table 4) by modi-
fying a reported microwave-assisted procedure (26) for
which we achieved an appreciable improvement in yields
and reaction time (Scheme 3). Sharifi et al. (26) have re-
ported the synthesis of related compounds on acidic alumina
support under solvent-free conditions and microwave irradia-
tion with an average yield of 64% in the reaction time range
of 4–8 min, compared to an average yield of 75.1% and a re-
action time of 1 min under our conditions. The irradiation
time was split into two 30 s pulses with a nearly 30 s inter-
vening gap to avoid superheating and charring the reaction
contents. Our procedure involved solvent-free conditions
and the use of only catalytic amounts of p-TSA, thus avoid-
ing the use of excessive acidic alumina. Numerous trials of
microwave-assisted reaction under solvent-free conditions
using 2-nitrobenzaldehyde (for compound 4) were not success-
ful and violent splashing of the contents was noticed within
the irradiation period of ~10 s; TLC did not indicate the for-
mation of any product even after continued irradiation for up
to 2 min. The use of solvent (DMF) and solid support (silica
gel) under microwave irradiation did not change the out-
come.
Although the Mannich bases of 2-naphthols with hetero-
cyclic amines were reported in the past (24, 26, 27, 51), their
© 2006 NRC Canada

Jha et al.
849
Table 4. Comparative reaction data for compounds synthesized by two different procedures.
Scheme 1
Scheme 2
No.
R
X
Time: 7 days
Time 1 min
Yield (%) mp (°C) Yield (%) mp (°C)
Lit. mp (°C)
CH2
CH2
22.0
194 to 195 79.7
192–194 198 to 199 (27)
1
2
17.5
145–147
187–190
82.7
83.3
144–146
186–188
—
—
H3C
O2N
CH2
CH2
CH2
29.5
18.5
Ndb
3
4
5
NO2
194 to 195
Nsa
—
—
—
72.0
165 to 166
—
Cl
CH2
CH2
O
Nd
Nd
Nd
82.4
43.1
85.8
185–187
88–90
—
6
7
8
—
—
—
N
H
95 to 96 (51)
177–179 181–183 (27)
132–134
O
O
Nd
Nd
Nd
71.7
72.0
78.1
—
9
—
—
—
Cl
178 to 179 177–179 (27)
138–140
10
11
O2N
NCH3
—
aNs (Not successful).
bNd (Not done).
detailed NMR behavior has not been examined, to the best
of our knowledge; some NMR peaks are reported in broad
range (27). We consistently noted interesting NMR activities
of the compounds under investigation, as they often gave
poorly resolved heterocyclic proton and carbon peaks in
their respective spectra at ambient temperature. We decided
to systematically investigate this behaviour. Besides the in-
dispensable use of NMR spectroscopy in structure elucida-
tion, it remains a powerful technique for stereochemical
analysis of organic molecules. From the point of view of
conformational analysis, six-membered saturated carbo-
cycles and heterocycles have been studied (52–55). A recent
study on 1-(2-hydroxy-2,2-diarylethyl)piperidin-4-ones de-
scribes a new mechanism of N-inversion — a concerted H-
bond dissociation – N inversion process (56). The piperidine
ring is a common structural fragment of many alkaloids and,
therefore, conformational analysis of these biologically ac-
tive amines is necessary for the comprehension of the mo-
lecular mechanisms of their action.
ing the interpretation ambiguous. Thus, we resorted to re-
cording the NMR experiments at lower temperatures. As ex-
pected, the 1H NMR spectrum of compound 1 at 273 K gave
better resolved peaks. The peak at δ 14.1, integrating for one
proton of -OH group at position 2 of the naphthalene ring,
clearly indicated strong H-bonding with the N of the
piperidine ring. In addition, most of the protons on the
piperidine ring gave discrete peaks, making it obvious that
the symmetry of the piperidine ring was lost. This observa-
tion was also supported by the 13C NMR spectrum of com-
pound 1 at 273 K, which not only resulted in better resolved
peaks but also showed distinct peaks for each CH2 of the
piperidene ring. This was another indication that the mag-
netic equivalence of the two pairs of methylene carbons is
destroyed by restricted rotation of the piperidine ring with
two flanking aromatic rings and the H bond. The NMR ex-
periments that were recorded in a temperature span of 50 °C
1
(three each for H and 13C) clearly demonstrated an increase
in molecular dynamics with the rise in temperature. The por-
tion of NMR plots of compound 1 that were most affected
by the temperature change is shown in Fig. 3. The five C
peaks of nonsymmetric piperidine at 273 K converge into
The 1H and 13C NMR spectra obtained at ambient temper-
ature (300 K) suffered from the broadening of several peaks
suggesting dynamism in the piperidine conformation, mak-
© 2006 NRC Canada

850
Fig. 3. Stack plot of (a) a portion of H NMR and (b) 13C NMR of compound 1 at various temperatures.
Can. J. Chem. Vol. 84, 2006
1
three C peaks of symmetric piperidine at 323 K. A similar
observation was made in the H spectrum at corresponding
temperatures, albeit at the cost of resolution.
piperidine -NCH2, appearing at 51.83 and 54.77 ppm, ob-
served at 273 K coalesce to a broad peak at ~53.30 ppm
when recorded at 323 K, it can be qualitatively said that a
temperature increase of 50 °C leads to approximately 800
conformational interchanges per second (based on the ex-
pression for the rotational rate constant at the coalescence
point (57) (kcoal = π (∆ν)/%2). Thus, at the coalescence tem-
perature, the interchanging conformations have a lifetime of
about 1.25 ms (1/kcoal). Contrary to this, for the C-3 and C-5
carbons of piperidine that are away from the crowded centre,
a similar effect is achieved with a temperature increase of
The molecular model shown in Fig. 2 also demonstrates
the existence of a very strong H bond (calculated distance =
1.83 Å) and a consequent loss of symmetry. This is more ev-
ident in Fig. 3b, where methylene Cs on the right side of N
are magnetically nonequivalent to those on the left side be-
cause of restricted rotation. At lower temperature, this sys-
tem may be regarded as a hindered spirocyclic system. As
the temperature is increased, the H bond is disrupted allow-
ing rotation of the piperidine ring along the benzylic C—N
axis with concurrent ring flipping and (or) N-inversion. Be-
ing rather fast for the NMR timescale, the convergence of a
pair of piperidine methylene takes place with loss of resolu-
tion in the 13C NMR. As seen in Fig. 3, as the two discrete
1
~27 °C (kcoal ~ 75 s–1). The H NMR also shows this behav-
iour where peak broadening is more severe.
The HSQC experiment with shaped pulse recorded at
273 K resulted in the expected correlations (Fig. 4). In addi-
tion to the presence of piperidine methylenes (inverted
© 2006 NRC Canada

Jha et al.
851
Fig. 4. HSQC with shaped pulse for inversion of compound 1 recorded at 273 K.
peaks), the HSQC experiment also showed the presence of
at least eight magnetically nonequivalent protons on the
piperidine ring. A pronounced disparity in the appearance of
seemingly similar diastereotopic methylene (C2, C6 pair)
protons was observed. The more deshielded protons on the
two carbons are 0.65 ppm apart, while the more shielded
ones are 0.20 ppm apart. Also, the amount of shielding and
deshielding on the protons on these carbons is considerably
disparate (1.23 vs. 0.78 ppm).
Similar NMR behaviour was consistently noticed for all
the compounds (except compound 7) irrespective of the
heterocycle substituents. At 273 K, piperidinyl, morpholinyl,
and N-methylpiperzinyl groups showed magnetic non-
equivalence of all constituent carbons and hydrogens. Com-
pound 7, being devoid of an aryl group compared to others
in the series, has significantly reduced crowding near the
heterocyclic nitrogen atom and, therefore, the heterocyclic
ring retains the symmetry even at 273 K.
spection of the bond lengths and angles of the heterocyclic
ring (shown in bold face in Tables 2 and 3) reveal that the
ring is slightly distorted, compounding the magnetic non-
equivalence of Hs and Cs on seemingly symmetric
heterocyclic rings.
Conclusion
2-Naphthol Mannich bases with heterocyclic amines were
synthesized using two different approaches. Variable-
temperature NMR investigations proved helpful in resolving
complicated NMR spectra of these rather simple molecules.
Molecular modeling and X-ray crystallography supported
the NMR results. These results can be explained by the loss
of magnetic equivalence of certain heterocyclic Cs and Hs
caused by restricted rotation of the heterocyclic ring when N
is involved in strong H-bonding with phenolic -OH.
Finally, X-ray crystal structures of compounds 9 and 11
were solved to compare the NMR solution- and solid-phase
crystal conformations. The prominent feature of both com-
pounds 9 and 11 is an internal hydrogen bond from the hy-
drogen atom of the OH group to N(1), the nitrogen of the
piperidine or morpholine ring, which are bonded to C(1). It
can be seen in Fig. 5 that the O—H bond approaches the
piperidine or morpholine ring obliquely so that the C(18)
and C(21) carbon atoms of this ring are not equivalent. This
is a strong hydrogen bond; the observed H(20)—N(1) and
H(24)—N(1) distances in 9 and 11 are 1.78 and 1.75 Å, re-
spectively. This H-bonding also persists in solution as evi-
denced by the appearance of the hydrogen-bonded -OH peak
Acknowledgements
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Nova Scotia
Health Research Foundation (NSHRF) for their financial
support. Ms. J. Beal is thanked for preliminary investiga-
tions. The Atlantic Region Magnetic Resonance Centre
(ARMRC) and the Maritime Mass Spectrometry Laboratory
(MMSL) at Dalhousie University are acknowledged for pro-
viding NMR and MS support, respectively. Dr. Michael
Lumsden of ARMRC is thanked for technical suggestions.
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