Acid controlled generation of indanes and oxazolines from β-hydroxyarylethanamide

Article abstract of DOI:10.1016/j.tetlet.2013.02.033

Simple and efficient protocols for the construction of substituted indanes and oxazolines through intramolecular cyclization of β- hydroxyarylethanamide using trifluoromethanesulfonic acid and titanium tetrachloride in 1,2-dichloroethane respectively have

Full text of DOI:10.1016/j.tetlet.2013.02.033

Tetrahedron Letters 54 (2013) 2315–2320
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acid controlled generation of indanes and oxazolines
from b-hydroxyarylethanamide
Rajendran Suresh a, Shanmugam Muthusubramanian a, , Muthusamy Boominathan a,
⇑
Govindaswamy Manickam b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Syngene International Limited, Biocon, Bangalore 560 099, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and efficient protocols for the construction of substituted indanes and oxazolines through intra-
molecular cyclization of b-hydroxyarylethanamide using trifluoromethanesulfonic acid and titanium tet-
rachloride in 1,2-dichloroethane respectively have been described. The selectivity due to different acid
catalysts was explored and optimized to achieve good to excellent yield.
Received 25 December 2012
Revised 10 February 2013
Accepted 12 February 2013
Available online 27 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Product selectivity
Indanes
Oxazolines
b-Hydroxyarylethanamide
Trifluoromethanesulfonic acid
Titanium tetrachloride
Indane derivatives have outstanding biological properties and a
wide range of applications as pharmaceutical and synthetic inter-
mediates.1 They exhibit promising behaviour like antitumor, anti-
cancer, anti-allergenic and significant increased mast cell
stabilization activities.2,3 They also act as aspartic protease inhibi-
tors, antiretroviral agents and smooth muscle relaxants and are in-
volved in the melatonin receptor agonism, inhibition of the
and one such attempt of getting indane and oxazoline derivatives
from b-hydroxyarylethanamide is described is this article.
The
a-azido chalcones 1 were prepared by reacting the respec-
tive chalcones with sodium azide and ceric ammonium nitrate in
acetonitrile to give
a-azido-b-nitrato ester followed by sodium
acetate in acetone treatment.14 Complete reduction of 1 by sodium
borohydride with catalytic amount of nickel chloride hexahydrate
in tetrahydrofuran–ethanol mixture under argon atmosphere15
gives aminoalcohol16 2 in 84% yield (Scheme 1).
production of inflammation factor TNF-a, inhibition of HIV integr-
ease independent of COX-inhibitors and treatment of Alzheimer’s
disease and asthma. Due to these versatile biological importances,
these derivatives attract the attention of synthetic chemists and
many strategies are dedicated to access this framework.4–6
Though there can be two diastereomers for 2, only one isomer
was obtained and the crude NMR spectrum of 2 does not show sep-
arate peaks for two different isomers. The aminoalcohol 2 was then
converted into their b-hydroxyamides 3 by reacting with different
carboxylic acids. The reaction was carried out in the presence of
triethylamine and T3P (propylphosphonic anhydride) and the
amides were obtained in good yields.17 Though the NMR spectra
of the amine 2 suggest the presence of a single diastereomer, the
amides 3 obtained were found to be a diastereomeric mixture in
all the cases, the ratio of the diastereomers being not consistent
and varying vastly between different systems. The separation of
the individual diastereomers from the mixture was not successful.
In the NMR spectra of the mixture, the chemical shift values of the
different hydrogens and carbons of the two diastereomers do not
differ widely and the coupling constants between the hydrogens
in the chain are also not appreciably different for these isomers
making the assignment of the configurations around the chiral
centre difficult. It may be taken that the major isomer may have
Oxazoline is the heterocyclic nucleus commonly found in many
biologically active natural products and pharmaceuticals.7 Chiral
oxazoline derivatives are extensively used as ligands or chiral pools
in asymmetric synthesis and provide useful means for the protec-
tion of amino alcohols or carboxylic acids. Achiral oxazolines are
also valuable intermediates in organic synthesis and polymer
chemistry. Oxazolines are the structural entities found in naturally
occurring iron chelators, cytotoxic cyclic peptides and antimitotic
and neuroprotective agents.8–10 Different methods for the synthe-
sis of oxazoline derivatives have been reported.11–13 It is interest-
ing to generate both carbocyclic and heterocyclic compounds
from the same open chain precursor exhibiting product selectivity
⇑
Corresponding author. Tel.: +91 452 2458246; fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.033

2316
R. Suresh et al. / Tetrahedron Letters 54 (2013) 2315–2320
O
OH
NiCl2.6H2O / NaBH4
N3
THF/ EtOH
0°C
NH2
2
R1
R1
1
OH
R2COOH,
T3P / Et3N
NH
R2
DCM
R1
O
3
Scheme 1. Synthesis of b-hydroxyarylethanamide.
3, as a diastereomeric mixture, was treated with different acidic re-
agents to bring about the cyclization. It is expected that the b-
hydroxyamide 3 may undergo dehydration to give dihydroisoquin-
oline or oxazoline following Pictet–Gams route.18
In order to select the suitable acid to promote effective cycliza-
tion, the reaction has been screened with the parent b-hydroxya-
mide 3m with different Lewis acids and mineral acids (Table 1).
The reaction has gone with the removal of water, but the expected
dihydroquinoline did not form.
H
H
H
HO
Ph
Ph
Bz
O
N
H
Bz
NHCOR
HCOR
H
Y
X
Figure 1. Newman projection of 3.
When we used different Lewis acids and phosphorus reagents in
stoichiometric amount, the dehydration has gone in the chain itself
avoiding the electrophilic attack on either of the available aromatic
rings. Thus a set of oxazoline (4,5-dihydrooxazole) 4 (Table 2) has
been obtained in good yield. The choice between toluene, 1,2-
dichloroethane, 1,4-dioxane and acetonitrile as a solvent has been
optimized. It is noteworthy that (i) titanium tetrachloride is the
effective reagent for oxazoline formation, (ii) 1,2-dichloroethane
a preferred arrangement X, where the vicinal hydroxyl and amido
groups enjoy hydrogen bonding between them. The other diaste-
reomer may have the preferred conformation as shown in Y
(Fig. 1). It can be noticed that the dihedral angle between the
hydrogens is same in both the arrangement, justifying the close
coupling constant values. For the subsequent reactions, the amide
Table 1
Screening impact of solvents and acids in the cyclization of 3m
OH
Protic or
N
Lewis acid
super acid
O
O
NH
NH
O
3m
5m
4m
Entry
Reagent (100 mol %)
Condition
Yielda (%) 4m
Yielda (%) 5m
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
POCl3
1,2-Dichloroethane, 70 °C, 12 h
Toluene, 110 °C, 12 h
85 °C, 5 h
56
38
44
48
8
12
43
74
41
43
96
81
86
50
18
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
P2O5
PPAb
Eaton’s reagentb
p-TsOH
CSA
80 °C, 5 h
Toluene, 80 °C, 12 h
Toluene, 80 °C, 12 h
Toluene, 80 °C, 12 h
CH3CN, 80 °C, 5 h
CH3CN, 80 °C, 12 h
1,2-Dichloroethane, 70 °C, 12 h
1,2-Dichloroethane, 70 °C, 30 min
Toluene, 110 °C, 30 min
1,4-Dioxane, 70 °C,30 min
85 °C, 3 h
100 °C, 3 h
70 °C, 1 h
1,2-Dichloroethane, 70 °C, 1 h
1,2-Dichloroethane, 70 °C, 1 h
60 °C, 30 min
InCl3
BF3.Et2O
SnCl2
Ti(iOPr)4
TiCl4
TiCl4
TiCl4
TFAb
Conc. HClb
b
Conc. H2SO4
ClSO3H
CF3SO3H
CF3SO3Hb
CF3SO3Hb
21
36c
58c
42c
93
—
—
—
—
0 °C to rt, 30 min
a
b
c
Isolated yield. The figures in bold indicate the optimized yields.
3–5 equiv reagent used.
Polymerized/decomposed product also obtained.

R. Suresh et al. / Tetrahedron Letters 54 (2013) 2315–2320
2317
Table 2
Synthesis of 4-benzyl-2-alkyl/aryl-5-phenyl-4,5-dihydrooxazoles 4
OH
NH
N
O
R2
TiCl4, 1,2-C2H4Cl2
R1 70 °C, 30 min
R1
O
R2
3
4
N
O
N
O
N
O
CN
4c; 86%
88-89 °C
4b; 91%
4a; 94%
143-144 °C
N
O
N
O
N
Br
NO2
N
O
4f; 88%
4e; 90%
120-122 °C
127-128 °C
4d; 87%
Cl
N
O
N
N
O
O
O
4h; 84%
4i; 88%
4g; 91%
112-113 °C
130-132 °C
F
OMe
OMe
Cl
N
O
N
O
N
O
CF3
4l; 80%
4k; 91%
92-93 °C
4j; 89%
84-86 °C
F
NO2
N
O
N
N
O
CN
O
4m; 96%
4o; 89%
83-85 °C
4n; 82%
117-118 °C
N
O
S
O
N
O
F
4q, 83%
112-114 °C
4p; 81%
98-100 °C
OH
N
R2
TiCl4, 1,2-C2H4Cl2
70 °C, 30 min
R1
O
NH
R2
R1
O
3
4
Scheme 2. Synthesis of 4-benzyl-2-alkyl/aryl-5-phenyl-4,5-dihydrooxazoles.
is found to be superior as solvent over toluene and 1,4-dioxane and
(iii) p-toluenesulfonic acid and camphorsulfonic acid are not effec-
tive in this conversion.
The reaction has been carried out under the optimized condi-
tions (100 mol % of TiCl4, 70 °C, 30 min) for various b-hydroxya-
mides 3 to get different oxazoline derivatives 4 (Scheme 2; see
Supplementary data for characterization data). Surprisingly, when
b-hydroxyarylethanamide 3m was treated with sulfuric or sulfonic
acid, unexpected indane derivative 5m with no trace of either
oxazoline 4m or dihydroisoquinoline derivative has been obtained.
It has been realized that when trifluoromethanesulfonic acid in
1,2-dichloroethane was employed, indane was obtained along with
some decomposed/polymerized product. However, in neat trifluo-
romethanesulfonic acid at 0 °C to room temperature, indane

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R. Suresh et al. / Tetrahedron Letters 54 (2013) 2315–2320
Table 3
Synthesized 1-phenyl-2-aryl/alkyl amidoindanes 5
OH
NH
CF3SO3H
R1
0 °C - rt,
30 min
O
NH
R1
R2
O
R2
5
3
NH
O
NH
NH
O
CN
O
5a; 89%
5c; 90%
138-140 °C
5b; 91%
136-137 °C
183-185 °C
NH
NH
NH
O
Br
NO2
N
O
O
5e; 65%
5d; 92%
5f; 85%
185-187 °C
175-177°C
208-210 °C
Cl
NH
O
NH
O
NH
O
O
5i; 89%
5h; 62%
5g; 83%
176-178°C
238-239 °C
163-165 °C
F
O
Cl
NH
NH
O
NH
O
O
5k; 88%
O
5l; 78%
CF3
5j; 84%
169-170 °C
142-144 °C
182-183 °C
Cl
Cl
NH
NH
O
NH
O
O
5m; 93%
5n; 80%
5o; 80%
203-204 °C
159-160 °C
140-142 °C
NH
NH
O
O
NH
N
O
O
5p; 63%
5r; 89%
5q; 94%
191-193 °C
204-205 °C
197-199 °C
NH
O
NH
NH
N
O
Br
O
5t; 91%
162-163 °C
5u; 87%
5s; 87%
205-207 °C
187-189 °C

R. Suresh et al. / Tetrahedron Letters 54 (2013) 2315–2320
2319
formation has been found to be efficient. Trifluoroacetic acid led to
oxazoline as the major product. The details are presented in Ta-
ble 1. The optimized protocol has been employed to create a library
of indanes 5 (Table 3) (Scheme 3; see Supplementary data for char-
acterization data).
The compounds obtained have been adequately characterized
by 1H NMR, 13C NMR and mass spectral data. The regiochemistry
of the products formed has been unambiguously assigned by the
single crystal X-ray analysis of 4c and 5b19 (Fig. 2). In all the cases,
only one isomer has been obtained in both the series (4 and 5) of
the possible two, in spite of the fact that the amide precursor is
not diastereomerically pure. The yield of the product is also not
correlating with the percentage of the starting diastereomers. This
clearly shows that the stereochemical relationship of the carbons
carrying the secondary alcohol and the NHCOR groups has not
been retained during the cyclization. With TiCl4, the iminum ion
might have been initially formed, which would have been attacked
by oxygen of the secondary hydroxyl in preference to a Bishchler
Napierski type attack, ultimately yielding the oxazoline. Formation
of carbocation by the removal of secondary hydroxyl group may be
the initial step with CF3SO3H and subsequent internal Friedel Craft
OH
CF3SO3H
R1
O
R2
NH
0 °C - rt, 30min
R1
NH
O
R2
5
3
Scheme 3. Synthesis of 1-phenyl-2-aryl/alkyl amidoindanes.
Figure 2. X-ray structures of 4c and 5b.
OH
R1
O
NH
R2
N
R1
O
N
O
H
R1
4
O
R2
TiCl3
R2
Cl3Ti
Ti Cl4
R1
OH
CF3SO3H
NH
R2
NH
R2
R1
R1
R2OCHN
O
O
5
3
Scheme 4. Possible mechanism for the formation of oxazoline and indane derivatives.

2320
R. Suresh et al. / Tetrahedron Letters 54 (2013) 2315–2320
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Facile and efficient methods of synthesizing oxazoline/indane
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Acknowledgments
R.S. is grateful to the Syngene International Limited, Bangalore
for providing necessary facilities. S.M. thanks CSIR, New Delhi for
the financial assistance under a major research project.
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033.
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