Facile one-pot synthesis of inden-1-ol derivatives

Article abstract of DOI:10.1055/s-0030-1261196

A facile one-pot synthesis of a novel class of inden-1-ol/indanone derivatives has been developed and formation of ionic clusters by lithium perchlorate has been demonstrated using UV-vis studies. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1261196

LETTER
2163
Facile One-Pot Synthesis of Inden-1-ol Derivatives
Synthesis of In
u
den-1-ol De
b
r
ivatives biah Nagarajan, Paneerselvam Muthuvel, Thangamuthu Mohan Das*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: tmdas_72@yahoo.com
Received 26 April 2011
tylidene-b-D-glucopyranosyl)propan-2-one (1a), 1-(4,6-
O-benzylidene-b-D-glucopyranosyl)propan-2-one (1b),
1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)propan-2-
one (1c), and 1-(2,3,4-tri-O-acetyl-b-D-xylopyrano-
syl)propan-2-one (1d) were synthesized following litera-
ture procedures.13,14 For the optimization of the reaction
conditions and the identification of the best catalyst and
Abstract: A facile one-pot synthesis of a novel class of inden-1-ol/
indanone derivatives has been developed and formation of ionic
clusters by lithium perchlorate has been demonstrated using UV-vis
studies.
Key words: methyl ketones, o-phthaldialdehyde, inden-1-ol deriv-
atives, b-anomer, XRD analysis
solvent,
1-(4,6-O-butylidene-b-D-glucopyranosyl)pro-
pan-2-one (1a) and o-phthaldialdehyde were chosen as
model substrates, and the one-pot reaction provided the
desired product in low but promising yields. The results
are summarized in Table 1.
Carbon–carbon bond formation remains an important
challenge for synthetic organic chemists.1,2 Among differ-
ent C–C bond-formation reactions the Morita–Baylis–
Hillman reaction (MBH)3–5 has received growing interest
since the mid 1990’s as it converts simple starting materi-
als, in the presence of a catalyst such as trialkylphos-
phine,6 pipecolic acid, N-methylimidazole,7 or
triphenylphosphine8 into highly functionalized com-
pounds, which can be used for further transformations.4 In
addition, intramolecular BH ring-closing reactions offer
additional opportunities in synthetic design.9 In one in-
stance, the substrates for cyclization were prepared by ox-
idative cleavage of vicinal cyclohexenediols10 through the
initially formed Z-isomers, which rearranged to the corre-
sponding E-isomers followed by intramolecular MBH re-
action with Ph3P catalyst in tert-BuOH (Scheme 1). A
study of Michael acceptor stereochemistry on the efficien-
cy of intramolecular MBH reactions has been reported in
the literature,8 but involves complex procedures and re-
sults in poor yields.11,12 Several indenones have synthe-
sized by using a palladium-mediated [3+2]-cycloaddition
process between ortho-halobenzaldehydes and diaryl pro-
pynones.12f To the best of our knowledge, this is the first
report on the synthesis of inden-1-ol from readily avail-
able aryl-/alkyl-substituted methyl ketones.
For aryl-/sugar-substituted methyl ketones, moderate
yields (53–85%) were obtained using CHCl3 as solvent
with a catalytic amount of pyrrolidine at room tempera-
Table 1 Optimization of Reaction Conditionsa
H
O
Pr
O
O
HO
OH
H
O
O
1
O
Pr
conditions
O
+
HO
OH
CHO
OH
O
3
CHO
2
Entry
Organocatalyst
pyrrolidine
pyridine
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
THF
Yield (%)
1
2
3
4
5
6
7
8
9
52
21
b
O
HO
R
NaOH
–
OH
O
H
HO
O
R
R
c
KOt-Bu
–
b
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
MeOH
MeCN
CHCl3
THF
–
Scheme 1 Synthesis of inden-1-ol derivatives through intramolecu-
15
72
43
24
lar MBH reaction8
In the present study, we report a facile one-pot synthesis
of inden-1-ol derivatives which exhibit keto–enol tauto-
merism. Sugar-substituted methyl ketones 1-(4,6-O-bu-
CHCl3 + MeOH (3:1)
a (4,6-O-butylidene-b-D-glucopyranosyl)propan-2-one (1a),
o-phthaldialdehyde, pyrrolidine (35%), r.t., 12 h.
b No reaction.
SYNLETT 2011, No. 15, pp 2163–2166
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1261196; Art ID: D12911ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
c KOt-Bu was used as base and dry THF as a solvent for aliphatic sub-
strates, such as acetone and 4-methylpentan-2-one.

2164
S. Nagarajan et al.
LETTER
Table 2 Synthesis of Aryl-/Alkyl-/Sugar-Substituted Inden-1-ol
Derivatives 3a–k (continued)
ture; whereas, in case of aliphatic ketones (acetone and 4-
methylpentan-2-one), improved yields (27% and 15%)
were obtained by using dry THF as solvent and KOt-Bu
as base. Different substituted inden-1-ol derivatives 3a–k
were synthesized directly from the reaction of aryl-/alkyl-
substituted methyl ketones with o-phthaldialdehyde in the
presence of 35% pyrrolidine as an organocatalyst
(Table 2).
CHO
35% pyrrolidine
CHCl3, r.t.
R
+
R
CHO
O
OH
O
1
2
3
Entry 3a–k R
1a–k (mg/ Reaction Yieldin
Table 2 Synthesis of Aryl-/Alkyl-/Sugar-Substituted Inden-1-ol
Derivatives 3a–k
mL)
time (h) mg (%)
150
(53)
9
330
12
CHO
35% pyrrolidine
R
O2N
+
R
3i
CHCl3, r.t.
CHO
O
OH
O
1
2
3
154
10
163
36
(39)c
N
Entry 3a–k R
1a–k (mg/ Reaction Yieldin
mL)
HO
time (h) mg (%)
O
3j
H
203
(42)
11
0.22
36
O
S
280
(72)
1
548
12
O
OH
3k
O
HO
a KOt-Bu was used as base and dry THF as a solvent.
b Compound 3f was derived from acetone (1f).
3a
H
c Compound 3j was derived from 2,6-diacetylpyridine (1j).
In the case of sugar-based inden-1-ol derivatives 3a–d,
the sugar moiety is in b-anomeric form, confirmed by 1H
NMR spectroscopic analysis.15 Notably compound 3c ex-
hibited a large coupling constant (JH-1,H-2 = 8.6 Hz) indi-
cating a trans diaxial orientation of H-1 and H-2. A
plausible mechanism involves aldol condensation fol-
lowed by MBH reaction, which results in the formation of
aryl-/sugar-substituted inden-1-ol derivatives via [1,3]-
proton shift. Amongst the two aldehyde groups present in
the o-phthaldialdehyde (2), only one aldehydic group is
involved in the aldol condensation with the methyl ke-
tone. The lack of involvement of the second aldehydic
functionality may be due to the steric hindrance.
360
(85)
O
2
3
616
24
O
O
HO
OH
3b
OAc
328
(65)
O
776
632
18
AcO
AcO
OAc
3c
O
310
(72)
AcO
AcO
4
5
18
OAc
3d
3e
In order to understand the reaction pathway, the reaction
between 1d and 2 was quenched with ice water after 1
hour, extracted with CH2Cl2 and the crude product was
subjected to NMR analysis. The existence of the E-isomer
of the intermediate a,b-unsaturated ketone [3d: d = 6.63
ppm (d, J = 16.2 Hz)] was determined from coupling-con-
stant values and a singlet observed at d = 10.24 ppm
showed the presence of a free aldehydic group (see ESI).
Thus the free availability and close proximity of the alde-
hydic group in the intermediate favors the intramolecular
MBH reaction, giving rise to the inden-1-ol derivatives
(Scheme 2).
117
0.25
24
(27)a
087
6
0.15
48
(15)a,b
OH
3f
130
(55)
7
8
240
24
3g
Formation of sugar based inden-1-ol 3a and also the exist-
ence of extended p-conjugation was confirmed from sin-
gle-crystal XRD studies; the ORTEP representation of 3a
is shown in Figure 1. The torsion angle [H(10)–C(9)–
C(10)–H(10) = 176.58°] shows that the 4,6-O-butylidene-
D-glucopyranosyl moiety is in the b-anomeric form and
180
(66)
310
8
Cl
3h
Synlett 2011, No. 15, 2163–2166 © Thieme Stuttgart · New York

LETTER
Synthesis of Inden-1-ol Derivatives
2165
CHO
CHO
••
R
N
aldol condensation
pyrrolidine
H
+
R
CHO
O
1a–k
2
O
MBH reaction
[1,3]-proton shift
R
enol form
R
H
HO
O
OH
O
3a–k
Figure 2 UV absorbance spectra of 3a (1×10–6 M) in different ratios
of LiClO4 (1×10–6 M) in MeOH: (a) 1:10; (b) 2:10; (c) 3:10; (d) 4:10;
(e) 5:10; (f) 6:10; (g) 7:10; (h) 8:10; (i) 9:10; (j) 1:1.
Scheme 2 Mechanism for the formation of substituted inden-1-ol
derivatives
ported to have tubulin polymerization properties and have
also been used for the treatment of Alzheimer’s disease,
and investigations in this direction are in progress.
the inden-1-ol coupled with the sugar is planar within the
limits of standard deviation. The crystal forms a two-di-
mensional hydrogen bonded (O–H···O) network
(Table 3), which is parallel to the (001) plane [see ESI for
H-bonding interaction of 3a], and the enol form is stabi-
lized through an intramolecular hydrogen bond.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors acknowledge DST New Delhi, India for financial sup-
port. T.M. thanks DST, New Delhi for access to the NMR facility,
Department of Organic Chemistry, University of Madras, Chennai,
India. S.N. thanks CSIR, New Delhi for a Senior Research Fel-
lowship.
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