BF3·OEt2-catalyzed synthesis of 1-(tetrahydropyran-3-yl)-1,3-dihydroisobenzofuran and trans-fused hexahydropyrano[3,2-c]chromene derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.05.083

A novel intramolecular Prins cyclization of (E)-5-(2-(hydroxymethyl)phenyl) pent-4-en-1-ol with aldehydes has been achieved using 10 mol % BF ₃·Et₂O to produce 1-(tetrahydropyran-3-yl)-1,3- dihydroisobenzofuran derivatives in good to excellent yields with high selectivity. Similar type of coupling with salicylaldehydes provides the trans-fused hexahydropyrano[3,2-c]chromene derivatives in excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.05.083

Accepted Manuscript
BF3.OEt2-catalyzed synthesis of 1-(tetrahydropyran-3-yl)-1,3-dihydroisoben-
zofuran and trans-fused hexahydropyrano[3,2-c]chromene derivatives
Ch. Syama Sundar, M. Ramana Reddy, B. Sridhar, S. Kiran Kumar, C. Suresh
Reddy, B.V. Subba Reddy
PII:
S0040-4039(14)00884-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.083
TETL 44674
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 April 2014
19 May 2014
19 May 2014
Please cite this article as: Syama Sundar, Ch., Ramana Reddy, M., Sridhar, B., Kiran Kumar, S., Suresh Reddy, C.,
Subba Reddy, B.V., BF3.OEt2-catalyzed synthesis of 1-(tetrahydropyran-3-yl)-1,3-dihydroisobenzofuran and
trans-fused hexahydropyrano[3,2-c]chromene derivatives, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.05.083
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Graphical Abstract
BF3.OEt2-catalyzed synthesis of 1-(tetrahydropyran-3
-yl)-1,3-dihydroisobenzofuran and trans-fused
hexahydropyrano[3,2-c]chromene derivatives
Leave this area blank for abstract info.
Ch. Syama Sundar, M. Ramana Reddy, B. Sridhar, S. Kiran Kumar, C. Suresh Reddy, B. V. Subba Reddy

1
Tetrahedron Letters
journal homepage: www.elsevier.com
BF3.OEt2-catalyzed synthesis of 1-(tetrahydropyran-3-yl)-1,3-dihydroisobenzofuran
and trans-fused hexahydropyrano[3,2-c]chromene derivatives
Ch, Syama Sundara, M. Ramana Reddyb, B. Sridharc, S. Kiran Kumard, C. Suresh Reddya,
B. V. Subba Reddyb
aDepartment of Chemistry, Sri Venkateswara University, Tirupathi, 517 502, A.P, India.bNatural Product Chemistry, cLaboratory of X-ray
Crystallography, dCentre for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
E-mail: basireddy@iict.res.in, Fax: 91-40-27160512
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel intramolecular Prins cyclization of (E)-5-(2-(hydroxymethyl)phenyl)pent-4-en-1-ol with
aldehydes has been achieved using 10 mol% BF3.Et2O to produce the 1-(tetrahydropyran-3-yl)-
1,3-dihydroisobenzofuran derivatives in good to excellent yields with high selectivity. Similar
type of coupling with salicylaldehydes provides the trans-fused hexahydropyrano[3,2-
c]chromene derivatives in excellent yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Prins cascade cyclization
C-O, C-C bond formation
BF3.Et2O
Aldehydes
The trans-fused hexahydropyrano[3,2-c]pyran moiety is a
core structure of blepharocalyxin D (Figure 1). It is a unique
member of dimeric diarylheptanoid natural products isolated
from the seeds of Alpinia blepharocalyx and is used in the
Chinese traditional medicine for the treatment of stomach
disorders.1 It also acts as an antiproliferative agent (ED50 3.61
mµ) against murine colon 26-L5 carcinoma cells.2
Prins cyclization is
a
simple method for the
stereoselective synthesis of functionalized tetrahydropyran
rings, which are core structural units of many natural
products.3,4 It has been successfully employed for the total
synthesis of tetrahydropyran (THP)-containing polyether
antibiotics and other complex natural products.5,6 Recently, an
intramolecular version of Prins cyclization has been
developed through the trapping of carbenium ion with
tethered nucleophiles like hydroxyl and aryl groups to afford
the corresponding heterobicycles and tricycles respectively.7,8
However, there are no reports on the synthesis of 1-
(tetrahydropyran-3-yl)-1,3-dihydroisobenzofurans and trans-
fused hexahydropyrano[3,2-c]chromenes through a Prins
cascade process.
Following our interest on Prins type cyclizations,9 we
herein report an efficient approach for the stereoselective
synthesis of fused tetrahydropyran derivatives namely, 1-
(tetrahydropyran-3-yl)-1,3-dihydroisobenzofurans and trans-
fused hexahydropyrano[3,2-c]chromenes by means of Prins
bicyclization. As a preliminary experiment, we performed the
Figure 1. Structure of blepharocalyxin D
———
B. V. Subba Reddy; Tel.: +91-40-27191642; fax: +91-40-27160512; e-mail: basireddy@iict.res.in

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Tetrahedron Letters
coupling of (E)-5-(2-(hydroxymethyl)phenyl)pent-4-en-1-ol
After optimizing the reaction conditions, we extended
this process to other aldehydes and the results are summarized
in Table 2. The substituents present on aromatic ring had
shown some effect on the conversion. It was observed that
aromatic aldehydes bearing strong electron-withdrawing
substituents such as cyano- and nitro- groups (entries a, f and
g, Table 2) gave the products in slightly lower yields than
halogenated aromatic counterparts (entries b, c and d, Table
2). Remarkably, a sterically hindered 2-naphthaldehyde also
afforded the desired product in good yield (entry h, Table 2).
with 4-cyanobenzaldehyde in the presence of 10 mol%
BF3.Et2O in dichloromethane. Interestingly, the reaction
proceeded smoothly at room temperature affording the
corresponding 1-(tetrahydropyran-3-yl)-1,3-dihydroisobenzo-
furan 2a as a sole product in 80% yield (Scheme 1).
Table 2. Synthesis of 1-(tetrahydropyran-3-yl)-1,3-dihydroiso-
benzofuransa
Scheme 1. Synthesis of 1-(te trahydropyran-3-yl)-1,3-
dihydroiso-benzofuran 2a
The structure and stereochemistry of 2a were confirmed by
X-ray crystallography (Figure 2).10
Figure 2. ORTEP diagram of 2a
To evaluate the efficacy of the catalyst, various Lewis and
Brønsted acids were screened for this conversion and the
results are summarized in Table 1. Among them, 10 mol%
BF3.Et2O was found to be most effective to furnish the
product 2a (entry c, Table 1). Other Lewis acids like InCl3,
ZnCl2, In(OTf)3, Sc(OTf)3, Yb(OTf)3) and Brønsted acids
such as TsOH, CSA, benzoic acid) were found to be
ineffective for this reaction. Next, we examined the effect of
solvents such as dichloromethane, acetonitrile and
tetrahydrofuran. Of these, dichloromethane gave the best
results.
aReaction was performed at 0.5 mmol scale with respect to aldehyde
bIsolated yield
The above results provided a gateway to extend this
process to various salicylaldehydes. Accordingly, treatment of
(E)-5-(2-(hydroxymethyl)phenyl)pent-4-en-1-ol (1) with
salicylaldehyde under similar conditions gave the trans-fused
hexahydropyrano[3,2-c]chromene 3a in 82% yield (Scheme
2).
Table 1. Catalyst Optimization in the formation of 2aa
Entry
Catalyst
Time (h)
Yield (%)b
a
b
c
d
e
f
InCl3
4
4
3
3
4
6
6
6
6
70
52
80
75
48
45
35
38
30
ZnCl2
BF3.Et2O
Sc(OTf)3
In(OTf)3
Yb(OTf)3
TsOH
g
h
i
CSA
Scheme 2. Synthesis of trans-fused hexahydropyrano-
[3,2-c]chromene derivatives
Benzoic acid
aReaction was performed at 0.5 mmol scale with respect to aldehyde
bIsolated yield
The relative stereochemistry of 3a was confirmed by
extensive NMR experiments including 2D double quantum

3
filtered correlation spectroscopy (DQFCOSY) and nuclear
Overhauser effect spectroscopy (NOESY). The assignments
were made with the help of DQFCOSY and NOESY
experiments (Figure. 3). The large coupling constants between
As depicted in Table 3, 2-hydroxy-1-naphthaldehyde (entry
g, Table 3) gave higher yields than simple salicylaldehyde
(entry a, Table 3).
This method provides a variety of 1-(tetrahydropyran-3-
yl)-1,3-dihydroisobenzofuran and hexahydropyrano[3,2-
c]chromene derivatives in good yields with excellent
diastereoselectivity. The high stereoselectivity is achieved by
the trapping of a more stable benzylic carbocation with a
tethered hydroxyl group approaching from the less sterically
hindered equatorial side of the more stable chair
conformation. Furthermore, intramolecular cyclizations are
highly favorable and faster than the intermolecular reactions.
All the products were characterized and confirmed by NMR,
IR and mass spectrometry.11
3
H5-H6 ( 4.44 ppm, JH5-H6 = 9.9 Hz), H5-H10 ( 5.74 ppm,
3JH5-H10 = 10.8 Hz) along with the presence of NOE cross
peaks between H6/H10, H5/H(ortho-Ph) suggest that H5, H6
and H10 are relatively in trans orientation to each other as
represented in Figure 3.
In conclusion, we have demonstrated an intramolecular
version of Prins cyclization for the stereoselective synthesis of
1-(tetrahydropyran-3-yl)-1,3-dihydroisobenzofuran and trans-
fused hexahydropyrano[3,2-c]chromene derivatives under
mild conditions. This approach generates two heterocyclic
rings with three new stereogenic centers in a one-pot
operation.
Figure 3. Characteristic NOE cross correlations of 3a
Encouraged by the above results, we extendend our
efforts to study the effect of various salicyladehydes
containing different electron withdrawing and donating
substituents. As shown in Table 3, the corresponding trans-
fused hexahydropyrano[3,2-c]chromene derivatives were
obtained in good to excellent yields. The substituents present
on the aromatic ring had shown some effect on the
conversion. It was observed that both activated (entry d, Table
3) and deactivated salicylaldehydes (entry e, Table 3) gave the
products in slightly lower yields than halogenated aromatic
counterparts (entries b and c, Table 3).
Acknowledgments
CH.S.S acknowledges DRDO, New Delhi for providing
financial assistance (ERIP/ER/1103894M/01/1346). M.R.R
thanks CSIR, New Delhi for the award of a senior research
fellowship.
Supplementary data
Table 3. Synthesis of hexahydropyrano[3,2-c]chromenesa
Supplementary data (compound characterization) associated
with this article can be found, in the online version, at http://
dx.doi.
References and notes
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4
Tetrahedron Letters
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a stirred solution of homoallylic diol (1, 0.50 mmol) and aldehyde
(0.60 mmol) or salicylaldehyde (0.60 mmol) in dry 1,2-
dichloromethane (5 mL) was added BF3.Et2O (0.05 mmol). The
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Cambridge
Crystallographic
Data
Centre
via
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