A simple and efficient method for the synthesis of amidophenols using iodine as catalyst under neat condition

Article abstract of DOI:10.1016/j.tet.2008.01.075

A convenient and efficient one-pot synthesis of substituted amidophenols using iodine as catalyst at room temperature under neat condition is described.

Full text of DOI:10.1016/j.tet.2008.01.075

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2972e2978
www.elsevier.com/locate/tet
A simple and efficient method for the synthesis
of amidophenols using iodine as catalyst
under neat condition
*
Nagarajan Panneer Selvam, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 12 October 2007; received in revised form 27 December 2007; accepted 17 January 2008
Available online 25 January 2008
Abstract
A convenient and efficient one-pot synthesis of substituted amidophenols using iodine as catalyst at room temperature under neat condition is
described.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
for various organic transformations, affording the correspond-
ing products with high selectivity in excellent yields.4 The
mild Lewis acidity associated with iodine has enhanced its us-
age in organic synthesis to realize several organic transforma-
tions using catalytic amounts to stoichiometric levels. Owing
to numerous advantages associated with iodine, it has been
explored as a powerful catalyst for various organic transforma-
tions. Amide moieties are important constituents of many
biologically significant compounds.5
In a broad programme of developing efficient, selective and
eco-friendly synthetic methods for pharmacologically impor-
tant moieties, herein, we report a simple, improved and one-
pot procedure for the synthesis of substituted amidophenols
catalyzed by iodine under ambient temperature with good
yields (Scheme 1). In our previous communication, we dem-
onstrated that a mixture of substituted phenol and aldehyde,
when heated at 85 ꢀC in acetonitrile in the presence of stoi-
chiometric amount of anhydrous ceric sulfate for 24 h, af-
forded acetamidophenols in moderate yields.6 For further
In recent years there has been considerable interest in the
one-pot multicomponent reaction due to their diversity,
efficiency and rapid access to complex and highly functional-
ized organic molecules. Pioneering work by several research
groups in this area has already established the versatility and
uniqueness of one-pot multicomponent coupling protocols as
a powerful methodology for the synthesis of diverse structural
scaffolds required in the search of novel therapeutic
molecules.1 They also have considerable advantages in terms
of user and environmental friendliness because of the step
reduction and atom economy associated to their use.2 In the
past decade there have been tremendous developments in
three- and four-component reactions and great efforts
have been and still are being made to find and develop new
MCRs.3
2. Results and discussion
CHO
The use of molecular iodine has received considerable at-
tention as an inexpensive, non-toxic, readily available catalyst
OH NHAc
OH
I2 (4 mol%) / CH3CN
R
R'
+
R
R'
AcCl, rt, 3-6h
1
* Corresponding author. Tel.: þ91 44 24913289; fax: þ91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.075

N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
2973
R'
The formation of non-acetylated product is in contrast to
the observation made in the corresponding iodine catalyzed
reactions.4h,i We have no definite explanation for the formation
of this anomaly.
The scope and generality of the reaction were studied with
various phenols and aldehydes under optimized condition and
the results are summarized in Table 1. The reaction was amena-
ble to a wide variation in phenol and aldehydes. The reaction
proceeded well irrespective of the presence of electron with-
drawing or electron donating group on aldehydes and phenols.
The structures of all products (entries 1e19) were con-
firmed by IR, NMR and X-ray analysis [Fig. 2 (entry 11, Table
1)8 and Fig. 3 (entry 2, Table 1)9].
I2
O
H
R'
OCOCH3
OH
CH3COCl
OH
R
R
R''CN
O
R'
N
C
+ R''
H
N
R'
R''
OH
OH
R
H2O
R
Scheme 2.
To demonstrate the versatility of this reaction procedure, we
examined the reactions with various nitriles and substituted alde-
hydes. Only a-hydrogenated nitriles involved in the reaction and
yielded the corresponding amidophenols (Scheme 3) and the re-
sults are summarized in Table 2. Unfortunately reactions with
aromatic nitriles like benzonitrile, 2-chlorobenzonitrile and 2-tri-
fluoromethyl benzonitrile did not yield the desired product, while
bisnaphthols were formed exclusively. This shows that nitrile
moiety was not involved in the reaction pathway (Scheme 4).
optimization and to extend the generality of this methodology,
we explored an alternative procedure, which resulted in an op-
erationally efficient process. Thus, instead of heating the reac-
tion in acetonitrile, we stirred the reaction at room temperature
for 6 h in the presence of catalytic amount of iodine and acetyl
chloride.
Initially, we evaluated the catalyst required for the synthesis
ofamidophenols. Aftersystematicscreening, iodine/acetylchlo-
ride under neat condition was found to be the best. Next, we eval-
uated the amount of iodine required for the transformation and
found 4 mol % to be the optimum. We also monitored the reac-
tion with iodine in the absence of acetyl chloride. With iodine
alone, there was no progress in the reaction. The role of acetyl
chloride for the formation of product is not clear. We have not
yet established a mechanism for the formation of amidophenols,
but a reasonable possibility7 is indicated in Scheme 2.
The isolation of product is very simple and easy as quench-
ing the reaction with minimum amount of saturated sodium
thiosulfate resulted in the precipitation of desired acetamido-
phenol. The precipitated solid was filtered, dried and washed
with diethyl ether to afford the corresponding pure product.
The interesting feature of this method is that no acetylated
product was observed in any case. The reaction with salicylal-
dehyde also gave the corresponding acetamidophenol and not
the eOH acetylated product and the product was confirmed by
1H NMR and X-ray analysis [Fig. 1 (entry 19, Table 1)].10
3. Conclusion
In conclusion, this article describes a simple and efficient
procedure for the synthesis of amidophenols with the use of
commercially available iodine under neat condition. The
methodology described here is a distinct improvement over
our previous protocol in terms of scope, generality, easy prod-
uct isolation with increased yield. The biological evaluation of
these compounds is underway.
4. Experimental
4.1. General
Glassware was dried in hot air oven prior to use. 2-(Trifluoro-
methyl)benzonitrile and benzonitrile were purchased from
Lancaster Research Chemicals. All other reagents were
Figure 1.

2974
N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
Table 1
Synthesis of acetamidophenols
Entry
Producta
t (h)
Yieldb (%)
82
Entry
11
Producta
t (h)
Yieldb (%)
90
NHAc
NHAc
NO2
NO2
1
6
3
OH
OH
NHAc
NHAc
MeO
NO2
OMe
OMe
2
5
80
12
6
75
OH
OH
NHAc
NHAc
NO2
Cl
3
4
6
6
76
65
13
14
6
6
66
72
OH
NHAc
OH
N(CH3)2
NHAc
HO
NO2
OH
OH
NHAc
NHAc
5
6
7
8
9
4
4
5
6
6
3
86
88
82
80
72
88
15
16
17
18
19
5
6
5
6
6
75
68
75
72
62
OH
Cl
Cl
OH
NHAc
Cl
NHAc
OH
Cl
OH
NHAc Cl
NHAc
OH
Cl
OH
OMe
F
NHAc
NHAc
OH
NO2
OH
NHAc
OH
NHAc
OH
OH
NHAc
NO2
10
OH
a
All the products were characterized by IR, NMR and mass spectra.
Isolated yields.
b
purchased from S.D. Fine. Chem. Limited and used as received.
Acetonitrile was distilled from CaH2 under nitrogen and stored
˚
over 4A molecular sieves. DMSO-d6 was purchased from Al-
Analytical TLC was performed on precoated plastic sheets of
silica gel G/UV-254 of 0.2 mm thickness (Macherey-Nagel,
Germany). Elemental analysis data were recorded using
a Thermo Finnigan FLASH EA 1112 CHN analyzer. Column
chromatography was carried out using 100e200 mesh silica
gel.
drich. IR measurements were done as KBr pellets for solids us-
ing Perkin Elmer Spectrum RXI FT-IR. The 1H and 13C NMR
were recorded in DMSO-d6 with JEOL 500 MHz and Bruker
300 MHz high resolution NMR spectrometers. DMSO-d6 was
used as the solvent for the NMR spectral measurements and
spectra were recorded in parts per million with TMS as internal
standards. Multiplicities are abbreviated as follows: singlet (s),
doublet (d), triplet (t), multiplet (m) and broad (br). The mass
was analyzed by using an Electrospray Ionisation Method
with Thermo Finnigan Mass spectrometer. Melting points
were determined in capillary tubes and are uncorrected.
4.2. Representative procedure for the synthesis of
acetamidophenols
A mixture of 4-chlorobenzaldehyde (10 mmol), b-naphthol
(10 mmol) and iodine (0.4 mmol, 4 mol %) was mixed in ace-
tonitrile (2 mL). To that suspension acetyl chloride (2.8 mmol,
0.2 mL) was added and the reaction stirred at room

N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
2975
Table 2
Entry
Amidophenol
Time (h)
Yielda (%)
Cl
Cl
O
1
8
62
N
H
OH
Cl
O
2
3
8
8
65
70
N
H
OH
NO2
O
N
H
OH
NO2
Figure 2.
O
4
5
6
7
8
10
10
10
12
14
10
66
58
63
60
45
62
N
H
OH
O
HN
Cl
Cl
OH
O
HN
NO2
OH
O
HN
NO2
OH
O
HN
OMe
Cl
OH
O
Figure 3.
O
HN
R
CHO
9
HN
OH
+
I2 (4 mol%) / R-CH2-CN
AcCl, rt, 3-6h
R'
OH
R'
a
OH
Isolated yield.
2
Scheme 3.
temperature for the appropriate time as mentioned in Table 1.
After completion of the reaction (as monitored by TLC), sat-
urated sodium thiosulfate in water (5 mL) was added. The pre-
cipitated solid was filtered and dried. The dried sample was
washed with diethyl ether (2ꢁ10 mL) and again dried.
4.2.1. N-[(4-Chloro-phenyl)-(2-hydroxy-phenyl)-methyl]-
acetamide (Table 1, entry 16)
Orange solid. Isolated yield: 68%, mp: 218e220 ꢀC. Rf
1
(50% EA/hexane) 0.32; H NMR (500 MHz, DMSO-d6) d:

2976
N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
4.2.4. N-[(2-Hydroxy-naphthalen-1-yl)-(2-hydroxy-phenyl)-
O
CHO
CN
methyl]-acetamide (Table 1, entry 19)
HN
Ar
White solid. Isolated yield: 62%, mp: 194e196 ꢀC. Rf (50%
I2 (4 mol%) / Ar-CN
+
1
+
R
R'
X
EA/hexane) 0.32; H NMR (500 MHz, DMSO-d6) d: 1.86 (s,
R'
AcCl, rt, 3-6h
OH
3H), 6.64 (t, 1H, J¼6.9 Hz), 6.69 (d, 1H, J¼7.7 Hz), 6.97 (t,
1H, J¼7.7 Hz), 7.12 (m, 2H), 7.20 (t, 1H, J¼7.7 Hz), 7.32
(m, 2H), 7.65 (d, 1H, J¼8.4 Hz), 7.72 (d, 1H, J¼7.7 Hz),
8.11 (d, 1H, J¼9.2 Hz), 8.36 (d, 1H, J¼8.4 Hz, D2O ex-
changeable), 9.42 (s, 1H, D2O exchangeable), 9.86 (s, 1H,
D2O exchangeable). 13C NMR (125 MHz, DMSO-d6) d:
23.2, 45.4, 115.6, 118.8, 119.3, 119.6, 122.7, 124.0, 126.4,
128.1, 128.7, 128.8, 128.8, 129.1, 129.4, 133.2, 153.6,
155.2, 169.1. IR nmax: 3387, 3277, 1629, 1540, 1455, 1437,
1339, 1276, 1208, 754 cmꢂ1. Mass (ESI): 307 (Mþ ion).
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.55; H, 5.52; N, 4.47.
3
OH
I2(4 mol%) / Ar-CN
AcCl, rt, 10h
R
#
4 yield (%)
R
R'
1
2
3
4
5
6
7
4-Cl
H
H
42
45
38
42
40
42
41
OH
OH
3-NO2
4
4-NO2 2-CF3
3-NO2 2-CF3
4-Cl
2-Cl
3-NO2 2-Cl
4-NO2 2-Cl
4.3. Representative procedure for the synthesis of
acetamidophenols (2)
Scheme 4.
1.88 (s, 3H), 5.96 (d, 1H, J¼8.4 Hz), 6.67 (d, 2H, J¼8.4 Hz),
6.70 (d, 2H, J¼8.4 Hz), 7.22 (d, 2H, J¼8.4 Hz), 7.33 (d, 2H,
J¼8.4 Hz), 8.67 (d, 1H, J¼8.4 Hz, D2O exchangeable), 9.37
(s, 1H, D2O exchangeable). 13C NMR (125 MHz, DMSO-d6)
d: 23.1, 55.3, 115.6, 128.7, 129.1, 129.4, 131.8, 132.9,
142.8, 156.9, 169.0. IR nmax: 3273, 3114, 1668, 1526, 1359,
1303, 1257, 1097, 836, 776 cmꢂ1. Mass (ESI): 274 (Mꢂ1
ion). Anal. Calcd for C15H14NO2Cl: C, 65.34; H, 5.12; N,
5.08. Found: C, 65.10; H, 5.18; N, 5.01.
A mixture of 4-chlorobenzaldehyde (10 mmol), b-naphthol
(10 mmol) and iodine (0.4 mmol, 4 mol %) was mixed in
nitrile (10 mmol). To that suspension acetyl chloride
(2.8 mmol, 0.2 mL) was added and stirred at room temperature
for the appropriate time as mentioned in Table 2. After com-
pletion of the reaction (as monitored by TLC), saturated
sodium thiosulfate in water (5 mL) was added and the com-
pound was extracted with ethyl acetate (4ꢁ30 mL). The
organic layers were combined together and washed with water
(2ꢁ25 mL) and dried over sodium sulfate, and concentrated
under vacuum. The residue was purified on a column of silica
gel with petroleum ether/ethyl acetate (8:2). The same proce-
dure was repeated for all acetamidophenol derivatives.
4.2.2. N-[(2,4-Dichloro-phenyl)-(2-hydroxy-phenyl)-methyl]-
acetamide (Table 1, entry 17)
Off white solid. Isolated yield: 75%, mp: 230e232 ꢀC. Rf
1
(60% EA/hexane) 0.31; H NMR (500 MHz, DMSO-d6) d:
1.86 (s, 3H), 6.20 (d, 1H, J¼8.4 Hz), 6.69 (d, 2H,
J¼9.1 Hz), 6.93 (d, 2H, J¼8.4 Hz), 7.43 (s, 2H), 7.53 (s,
1H), 8.72 (d, 1H, J¼8.4 Hz, D2O exchangeable), 9.43 (s,
1H, D2O exchangeable). 13C NMR (125 MHz, DMSO-d6) d:
23.0, 52.9, 115.7, 128.0, 129.3, 129.4, 130.1, 130.8, 132.8,
133.7, 140.0, 157.2, 169.0. IR nmax: 3313, 3118, 1635, 1451,
1252, 823 cmꢂ1. Mass (ESI): 309 (Mþ ion). Anal. Calcd for
C15H13NO2Cl2: C, 58.08; H, 4.22; N, 4.52. Found: C, 57.92;
H, 4.18; N, 4.60.
4.3.1. N-[(2,4-Dichloro-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-2-phenyl-acetamide (Table 2, entry 1)
Pale brown solid. Isolated yield: 62%, mp: 193e195 ꢀC. Rf
1
(20% EA/hexane) 0.34; H NMR (500 MHz, DMSO-d6) d:
3.51 (m, 2H), 7.00 (d, 1H, J¼7.6 Hz), 7.09 (d, 1H, J¼8.5 Hz),
7.16 (m, 1H), 7.23 (m, 5H), 7.30 (d, 1H, J¼8.4 Hz), 7.38
(t, 1H, J¼7.7 Hz), 7.44 (s, 1H), 7.47 (d, 1H, J¼8.4 Hz), 7.71
(d, 1H, J¼9.2 Hz), 7.76 (d, 1H, J¼8.4 Hz), 7.93 (d, 1H,
J¼8.4 Hz), 8.80 (d, 1H, J¼7.6 Hz, D2O exchangeable), 9.85
(s, 1H, D2O exchangeable). 13C NMR (125 MHz, DMSO-d6)
d: 41.8, 47.4, 116.1, 118.5, 122.4, 122.4, 126.3, 126.3, 126.5,
128.1, 128.2, 128.5, 128.6, 129.0, 129.7, 131.1, 131.7, 132.7,
133.0, 136.4, 139.0, 153.7, 169.6. IR nmax: 3374, 3180, 1635,
1516, 1345, 1060, 817, 746, 700 cmꢂ1. Mass (ESI): 435 (Mþ
ion). Anal. Calcd for C25H19NO2Cl2: C, 68.82; H, 4.39; N,
3.21. Found: C, 68.54; H, 4.34; N, 3.18.
4.2.3. N-[(4-Nitro-phenyl)-(2-hydroxy-phenyl)-methyl]-
acetamide (Table 1, entry 18)
Yellowish brown solid. Isolated yield: 72%, mp: 168e
170 ꢀC. Rf (60% EA/hexane) 0.43; 1H NMR (500 MHz,
DMSO-d6) d: 1.89 (s, 3H), 6.07 (d, 1H, J¼7.6 Hz), 6.69 (d,
2H, J¼8.4 Hz), 7.04 (d, 2H, J¼8.4 Hz), 7.49 (d, 2H,
J¼9.2 Hz), 8.15 (d, 2H, J¼9.1 Hz), 8.80 (d, 1H, J¼8.4 Hz,
D2O exchangeable), 9.51 (br s, 1H, D2O exchangeable). 13C
NMR (125 MHz, DMSO-d6) d: 23.0, 55.8, 115.8, 124.1,
4.3.2. N-[(4-Chloro-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-2-phenyl-acetamide (Table 2, entry 2)
128.6, 129.3, 132.0, 146.8, 151.6, 157.2, 169.3. IR nmax
:
Off white solid. Isolated yield: 65%, mp: 208e210 ꢀC.
3413, 3203, 1636, 1516, 1346, 1234, 832, 546 cmꢂ1. Mass
(ESI): 286 (Mþ ion). Anal. Calcd for C15H14N2O4: C, 62.93;
H, 4.93; N, 9.78. Found: C, 63.20; H, 4.98; N, 9.90.
1
Rf (20% EA/hexane) 0.30; H NMR (500 MHz, DMSO-d6)
d: 3.58 (m, 2H), 7.05 (d, 1H, J¼8.5 Hz), 7.09 (d, 2H,
J¼8.4 Hz), 7.18 (d, 2H, J¼8.4 Hz), 7.23 (m, 7H), 7.35 (t,

N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
2977
1H, J¼7.6 Hz), 7.73 (d, 1H, J¼9.2 Hz), 7.77 (d, 1H,
4.3.6. Pentanoic acid [(3-nitro-phenyl)-(2-hydroxy-
naphthalen-1-yl)-methyl]-amide (Table 2, entry 6)
J¼8.4 Hz), 7.82 (br s, 1H), 8.57 (d, 1H, J¼7.6 Hz, D2O ex-
changeable), 10.04 (s, 1H, D2O exchangeable). 13C NMR
(125 MHz, DMSO-d6) d: 42.6, 48.1, 118.7, 118.9, 123.1,
127.0, 127.1, 128.4, 128.5, 128.8, 129.2, 129.7, 130.1,
131.3, 132.7, 136.9, 142.1, 153.8, 170.7. IR nmax: 3396,
3160, 1633, 1510, 1264, 1090, 807, 747, 699 cmꢂ1. Mass
(ESI): 402 (Mþ1 ion). Anal. Calcd for C25H20NO2Cl: C,
74.72; H, 5.02; N, 3.49. Found: C, 74.60; H, 4.95; N, 3.56.
Pale brown solid. Isolated yield: 63%, mp: 188e190 ꢀC. Rf
1
(50% EA/hexane) 0.32; H NMR (500 MHz, DMSO-d6) d:
0.81 (t, 3H, J¼6.9 Hz), 1.23 (m, 2H), 1.47 (m, 2H), 2.20 (m,
1H), 2.34 (m, 1H), 7.15 (m, 3H), 7.37 (m, 1H), 7.50 (s, 2H),
7.76 (m, 3H), 8.01 (s, 1H), 8.53 (d, 1H, J¼7.7 Hz, D2O ex-
changeable), 10.11 (s, 1H, D2O exchangeable). 13C NMR
(125 MHz, DMSO-d6) d: 13.7, 21.8, 27.5, 34.8, 47.6, 117.7,
118.4, 120.4, 121.2, 122.6, 122.7, 126.7, 128.4, 128.7,
129.6, 129.8, 132.2, 132.8, 145.4, 147.7, 153.3, 172.6. IR
nmax: 3404, 2961, 1628, 1522, 1347, 818, 744 cmꢂ1. Mass
(ESI): 379 (Mþ ion). Anal. Calcd for C22H22N2O4: C, 69.83;
H, 5.86; N, 7.40. Found: C, 69.72; H, 5.83; N, 7.47.
4.3.3. N-[(3-Nitro-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-2-phenyl-acetamide (Table 2, entry 3)
White solid. Isolated yield: 70%, mp: 218e220 ꢀC. Rf (30%
EA/hexane) 0.35; 1H NMR (500 MHz, DMSO-d6) d: 3.57 (m,
2H), 7.12 (d, 1H, J¼8.4 Hz), 7.18 (m, 7H), 7.40 (t, 1H,
J¼6.4 Hz), 7.47 (m, 2H), 7.77 (m, 3H), 7.97 (m, 2H), 8.74
(d, 1H, J¼8.4 Hz, D2O exchangeable), 10.16 (s, 1H, D2O ex-
changeable). 13C NMR (125 MHz, DMSO-d6) d: 42.5, 48.3,
118.0, 118.9, 120.9, 121.8, 123.1, 123.2, 127.0, 127.4,
128.8, 129.3, 129.7, 130.1, 130.5, 132.7, 133.3, 136.8,
145.7, 148.2, 153.9, 171.1. IR nmax: 3380, 3220, 1645, 1525,
1439, 1349, 1273, 1064, 810, 704 cmꢂ1. Mass (ESI): 435
(Mþ23 ion). Anal. Calcd for C25H20N2O4: C, 72.80; H,
4.89; N, 6.79. Found: C, 73.08; H, 4.85; N, 6.74.
4.3.7. Pentanoic acid [(4-nitro-phenyl)-(2-hydroxy-
naphthalen-1-yl)-methyl]-amide (Table 2, entry 7)
Off white solid. Isolated yield: 60%, mp: 188e190 ꢀC. Rf
1
(40% EA/hexane) 0.39; H NMR (500 MHz, DMSO-d6) d:
0.80 (t, 3H, J¼7.6 Hz), 1.20 (q, 2H, J¼7.7 Hz), 1.45 (m,
2H), 2.20 (m, 2H), 7.15 (d, 1H, J¼7.7 Hz), 7.20 (d, 1H,
J¼9.2 Hz), 7.23 (t, 1H, J¼7.7 Hz), 7.35 (d, 3H, J¼8.4 Hz),
7.76 (m, 3H), 8.10 (d, 2H, J¼8.4 Hz), 8.49 (d, 1H,
J¼7.7 Hz, D2O exchangeable), 10.12 (s, 1H, D2O exchange-
able). 13C NMR (125 MHz, DMSO-d6) d: 13.68, 21.85,
27.47, 34.73, 47.80, 117.83, 118.37, 122.56, 122.81, 123.20,
126.68, 127.09, 128.38, 128.62, 129.80, 132.16, 145.88,
151.18, 153.28, 172.59. IR nmax: 3429, 3229, 2954, 1639,
1509, 1345, 1267, 1106, 818, 734 cmꢂ1. Mass (ESI): 379
(Mþ ion). Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86;
N, 7.40. Found: C, 70.13; H, 5.92; N, 7.33.
4.3.4. N-[(4-Nitro-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-2-phenyl-acetamide (Table 2, entry 4)
Brown solid. Isolated yield: 66%, mp: 198e200 ꢀC. Rf (30%
EA/hexane) 0.42; 1H NMR (500 MHz, DMSO-d6) d: 3.60 (m,
2H), 7.12 (d, 1H, J¼7.7 Hz), 7.17 (d, 2H, J¼9.2 Hz), 7.25
(m, 5H), 7.32 (d, 2H, J¼9.2 Hz), 7.36 (t, 1H, J¼7.7 Hz), 7.76
(m, 3H), 8.06 (d, 2H, J¼9.2 Hz), 8.68 (d, 1H, J¼8.4 Hz, D2O
exchangeable), 10.12 (s, 1H, D2O exchangeable). 13C NMR
(125 MHz, DMSO-d6) d: 42.4, 48.5, 118.1, 118.9, 123.2,
123.8, 127.0, 127.4, 127.6, 127.6, 128.8, 128.9, 129.2, 129.7,
130.5, 132.7, 136.8, 146.5, 151.5, 153.9, 171.1. IR nmax: 3369,
4.3.8. Pentanoic acid [(3-methoxy-phenyl)-(2-hydroxy-
naphthalen-1-yl)-methyl]-amide (Table 2, entry 8)
White solid. Isolated yield: 45%, mp: 183e184 ꢀC. Rf (40%
1
EA/hexane) 0.43; H NMR (500 MHz, DMSO-d6) d: 0.79 (t,
3H, J¼6.9 Hz), 1.17 (m, 2H), 1.42 (m, 2H), 2.13 (m, 2H),
3.60 (s, 3H), 6.76 (d, 2H, J¼9.2 Hz), 7.02 (d, 3H,
J¼8.4 Hz), 7.17 (d, 1H, J¼8.4 Hz), 7.21 (t, 1H, J¼6.9 Hz),
7.33 (m, 1H), 7.70 (d, 1H, J¼9.2 Hz), 7.75 (d, 1H,
J¼7.7 Hz), 7.82 (s, 1H), 8.33 (d, 1H, J¼8.4 Hz, D2O ex-
changeable), 9.99 (s, 1H, D2O exchangeable). 13C NMR
(125 MHz, DMSO-d6) d: 13.7, 21.8, 27.5, 35.0, 47.4, 55.0,
113.4, 118.5, 118.9, 122.3, 123.2, 126.2, 127.2, 128.4,
129.0, 132.3, 134.4, 153.0, 157.7, 171.9. IR nmax: 3401,
3070, 2957, 2922, 1633, 1579, 1509, 1437, 1247, 1174,
1033, 819, 657 cmꢂ1. Mass (ESI): 389 (Mþ23 ion). Anal.
Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C,
76.32; H, 7.01; N, 3.90.
3236, 2915, 1642, 1517, 1345, 1280, 819, 749, 701 cmꢂ1
.
Mass (ESI): 435 (Mþ23 ion). Anal. Calcd for C25H20N2O4: C,
72.80; H, 4.89; N, 6.79. Found: C, 72.55; H, 4.82; N, 6.86.
4.3.5. Pentanoic acid [(2,4-dichloro-phenyl)-(2-hydroxy-
naphthalen-1-yl)-methyl]-amide (Table 2, entry 5)
Pale brown solid. Isolated yield: 58%, mp: 86e87 ꢀC. Rf
1
(40% EA/hexane) 0.32; H NMR (500 MHz, DMSO-d6) d:
0.78 (t, 3H, J¼6.9 Hz), 1.15 (m, 2H), 1.40 (m, 2H), 2.12 (m,
2H), 6.97 (d, 1H, J¼7.7 Hz), 7.07 (d, 1H, J¼9.2 Hz), 7.23 (t,
1H, J¼6.8 Hz), 7.35 (m, 2H), 7.43 (s, 1H), 7.51 (d, 1H,
J¼8.4 Hz), 7.70 (d, 1H, J¼8.4 Hz), 7.75 (d, 1H, J¼8.4 Hz),
7.92 (d, 1H, J¼8.4 Hz), 8.52 (d, 1H, J¼8.4 Hz, D2O exchange-
able), 9.79 (s, 1H, D2O exchangeable). 13C NMR (125 MHz,
DMSO-d6) d: 13.7, 21.8, 27.5, 34.6, 47.3, 116.4, 118.6, 122.3,
122.5, 126.3, 126.4, 128.4, 128.6, 129.6, 131.1, 131.61, 132.8,
132.9, 139.3, 153.7, 171.7. IR nmax: 3416, 3182, 2957, 1641,
1514, 1468, 1438, 1237, 816, 745 cmꢂ1. Mass (ESI): 425
(Mþ23 ion). Anal. Calcd for C22H21NO2Cl2: C, 65.68; H,
5.26; N, 3.48. Found: C, 65.39; H, 5.32; N, 3.45.
4.3.9. Pentanoic acid [(4-chloro-phenyl)-(2-hydroxy-
naphthalen-1-yl)-methyl]-amide (Table 2, entry 9)
White solid. Isolated yield: 62%, mp: 202e203 ꢀC. Rf (40%
1
EA/hexane) 0.35; H NMR (500 MHz, DMSO-d6) d: 0.82 (t,
3H, J¼7.5 Hz), 1.20 (m, 2H), 1.43 (m, 2H), 2.18 (m, 2H),
7.07 (d, 1H, J¼8.4 Hz), 7.14 (d, 2H, J¼8.4 Hz), 7.21 (m,
4H), 7.36 (t, 1H, J¼7.5 Hz), 7.76 (m, 3H), 8.40 (d, 1H,

2978
N.P. Selvam, P.T. Perumal / Tetrahedron 64 (2008) 2972e2978
(d) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org. Lett. 2003, 5,
1205e1208.
J¼8.4 Hz, D2O exchangeable), 10.08 (s, 1H, D2O exchange-
able). 13C NMR (125 MHz, DMSO-d6) d: 13.7, 21.8, 27.5,
34.9, 47.4, 118.36, 118.4, 122.4, 123.0, 126.4, 127.9, 128.4,
4. For the review: Wang, H. S.; Miao, J. Y.; Zhao, L. F. Chin. J. Org. Chem.
2005, 25, 615e618; For recent references: (a) Yadav, J. S.; Satyanarayana,
M.; Raghavendra, S.; Balanarsh, E. Tetrahedron Lett. 2005, 46, 8745e
8748; (b) Bhosale, R. S.; Sarda, S. R.; Ardhapure, S. S. Tetrahedron
Lett. 2005, 46, 7183e7186; (c) Mori, N.; Togo, H. Tetrahedron 2005,
61, 5915e5925; (d) Sun, J. W.; Dong, Y. M.; Cao, L. Y. J. Org. Chem.
2004, 69, 8932e8934; (e) Ji, S. J.; Wang, S. Y.; Zhang, Y.; Loh, T. P.
Tetrahedron 2004, 60, 2051e2055; (f) Lin, C.; Hsu, J. C.; Sastry,
M. N. V.; Fang, H.; Tu, Z. J.; Liu, J. T.; Yao, C. F. Tetrahedron 2005,
61, 11751e11757; (g) Kosak, A. I.; Hartough, H. D. H. J. Am. Chem. Soc.
1947, 69, 3144; (h) Deka, N.; Kalita, D. J.; Borah, R.; Sarma,
J. C. J. Org. Chem. 1997, 62, 1563e1564; (i) Wahlstrom, J. L.;
Ronald, R. C. J. Org. Chem. 1998, 63, 6021e6022.
128.6, 129.4, 130.6, 132.2, 141.8, 153.2, 172.3. IR nmax
:
3408, 3062, 2955, 1635, 1517, 1438, 1323, 1272, 1088, 820,
751, 649 cmꢂ1. Mass (ESI): 390 (Mþ23 ion). Anal. Calcd
for C22H22NO2Cl: C, 71.83, H, 6.03; N, 3.81. Found: C,
72.10; H, 5.92; N, 3.76.
Acknowledgements
One of the authors N.P.S. thanks the Council of Scientific
and Industrial Research, New Delhi, India for the research
fellowship.
5. Aleman, C.; Puiggali, J. J. Org. Chem. 1995, 60, 910e924 and references
therein.
6. Panneer Selvam, N.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 7481e7483.
7. Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K. Tetrahedron Lett. 2005,
46, 2137e2140.
References and notes
8. Crystal structure of compound (entry 11, Table 1) has been deposited at
the Cambridge Crystallographic Data Center and allocated the reference
no. CCDC 651834.
1. For recent reviews, see: (a) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl.
Chem. 2000, 37, 647e658; (b) Bienayme, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem.dEur. J. 2000, 6, 3321e3329; (c) Ugi, I.; Heck, S.
Comb. Chem. High Throughput Screen. 2001, 4, 1e34.
9. Crystal structure of compound (entry 2, Table 1) has been deposited at the
Cambridge Crystallographic Data Center and allocated the reference no.
CCDC 651835.
2. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27e45.
3. (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestiopolov, A. A.; Rodinov-
skaya, I. A.; Niazimbetova, A. I.; Evans, D. H. Org. Lett. 2002, 4, 423e425;
(b) Bagley, M. C.; Cale, J. W.; Bower, J. Chem. Commun. 2002, 1682e1683;
(c) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett. 2003, 5, 435e438;
10. Crystal structure of compound (entry 19, Table 1) has been deposited at
the Cambridge Crystallographic Data Center and allocated the reference
no. CCDC 652214.