LiBF4-catalyzed formation of fused pyrano- and furanobenzopyrans

Article abstract of DOI:10.1016/S0040-4039(01)01257-6

Lithium tetrafluoroborate efficiently catalyzes an unusual cyclization of o-hydroxybenzaldimines with 2,3-dihydrofuran and 3,4-dihydro-2H-pyran at ambient temperature to afford a class of new pyrano- and furanobenzopyran derivatives in excellent yields with high diastereoselectivity.

Full text of DOI:10.1016/S0040-4039(01)01257-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6381–6384
LiBF4-catalyzed formation of fused pyrano- and
furanobenzopyrans†
J. S. Yadav,a,* B. V. Subba Reddy,a Ch. Madhuri,a G. Sabitha,a B. Jagannadh,a S. Kiran Kumarb
and A. C. Kunwarb
aDivision of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
bCentre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 17 April 2001; accepted 12 July 2001
Abstract—Lithium tetrafluoroborate efficiently catalyzes an unusual cyclization of o-hydroxybenzaldimines with 2,3-dihydrofuran
and 3,4-dihydro-2H-pyran at ambient temperature to afford a class of new pyrano- and furanobenzopyran derivatives in excellent
yields with high diastereoselectivity. © 2001 Elsevier Science Ltd. All rights reserved.
2H-1-Benzopyrans (2H-chromenes) and 3,4-dihydro-
2H-1-benzopyrans (chromans) have attracted much
synthetic interest because of the biological activity1,2of
naturally occurring representatives. 4-Aminobenzopy-
rans and their derivatives are found to exhibit a wide
range of biological activities3,4 including antihyperten-
sive and antiischemic behaviour. Particularly, fused tet-
rahydropyranobenzopyran derivatives are frequently
found in naturally occurring bioactive molecules and
direct methods for their synthesis are highly desired.5
Recently, angularly fused pyranobenzopyrans have
been reported by intramolecular cycloaddition of o-
quinonemethides using protic acid as a catalyst.6 How-
ever, there is no report on the synthesis of linearly fused
chromans from o-hydroxybenzaldimines and cyclic enol
ethers. Recently, lithium tetrafluoroborate in acetoni-
trile (LTAN) has received much attention as a powerful
reaction medium for effecting various transforma-
tions7,8 including the hydrolysis of acetals, desilylation
of ethers, dithioacetalization of aldehydes and glycosi-
tonitrile. The treatment of salicylaldehyde Schiffs base
with 2,3-dihydrofuran9 in the presence of lithium tetra-
fluoroborate at ambient temperature affords the cis-
fused furanochroman in 90% yield (Scheme 1).
Similarly, several o-hydroxybenzaldimines (formed in
situ from o-hydroxybenzaldehydes and anilines in the
presence of anhydrous Na2SO4 in acetonitrile) reacted
well to give the corresponding cis-fused acetals in excel-
lent yields. The reactions proceed smoothly at ambient
temperature with high diastereoselectivity. In all reac-
tions the product was obtained as a single isomer, the
1
structure of which was confirmed by detailed H NMR
and NOESY studies. The six-membered tetra-
hydropyran and five-membered tetrahydrofuran rings
are cis fused, as depicted by the coupling constant
J3–4=5.4 Hz between H4 (l 5.89)–H3 (l 3.11) and the
presence of a strong cross peak between them in the
NOESY spectrum of the product 3a. Also, J3–5=4.8 Hz
(H5-l 4.99) and the presence of a NOE cross peak,
H4–H5, support that H5 is cis to H3. Molecular
mechanics calculations indicate a structure with the
six-membered pyran ring in the boat conformation,
Fig. 1, which also depicts the important NOEs in
assigning the stereochemistry of 3a.
−
−
dation reactions. Unlike ClO4 , the counterion BF4 is
non-nucleophilic and non-oxidizing and hence it pro-
vides convenient reaction and work-up conditions.
In this report, we describe a new and highly efficient
protocol for the synthesis of fused pyrano- and fura-
nochromans using a catalytic amount of LiBF4 in ace-
Keywords: lithium tetrafluoroborate; o-hydroxyaldimines; cyclic enol
ethers; cis-fused chromans.
* Corresponding author. Fax: +91-40-7170512; e-mail: yadav@
iict.ap.nic.in
†
IICT communication No. 4775.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01257-6

6382
J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 6381–6384
Figure 1. Important NOEs, the energy-minimized structure and the chemical structure of 3a.
Scheme 2.
Table 1. LiBF4-catalyzed formation of furano- and pyranochromansa

J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 6381–6384
6383
Figure 2. Important NOEs, the energy-minimized structure and the chemical structure of 4b.
The reactions probably proceed through the activation
of the imine by a lithium ion, followed by addition and
subsequent cyclization of the enol ether resulting in the
formation of the fused acetal (Scheme 3).
Further, the treatment of o-hydroxyaldimines with 3,4-
dihydro-2H-1-pyran in the presence of LiBF4 in acetoni-
trile resulted in the formation of fused pyrano-
chromans as a mixture of 4 and 5 in high yields (Scheme
2).
The reaction conditions are very mild so that no side
products or decomposition of the products is observed.
No additives or acidic promoters are required to promote
the reaction. The procedure does not require anhydrous
solvents or stringent reaction conditions. Due to the
neutral reaction conditions, this method is compatible
with acid sensitive aldehydes and unstable imines.11 It is
of interest to note that the reaction of cyclic enol ethers
with aldimines without a hydroxyl group at the ortho
position gave the corresponding pyrano and fura-
noquinolines in high yields. The best results were
obtained when acetonitrile was used as the solvent.
Several examples illustrating this novel and rapid proce-
dure for the synthesis of fused chromans are summarized
in Table 1.
The reactions are clean and highly diastereoselective,
affording the corresponding cis-fused acetal 4 with minor
amounts of the other isomer 5. However, in the case of
ortho substituted N-arylimines, product 5 was obtained
as the major isomer with a trace amount of 4 (entry e,
Table 1). The ratio of 4 and 5 was determined by the 1H
NMR spectrum of the products. The assignment of the
stereochemistry of product 4b was based on the coupling
constants and NOE cross peaks in the NOESY spectrum.
In this product also, like product 3a, the two six-mem-
bered rings are cis fused. The coupling constants J4–5
=
2.5 Hz and J4–6=5.5 Hz (H5 l 5.57, H6 l 5.01, H4 l 2.51)
and the presence of NOE cross peaks H4–H5, H5–H6
and H4–H6 again show that these protons are on the
same side of the ring. While the middle six-membered
ring is in the half chair conformation, the tetra-
hydropyran ring takes a chair conformation, which is
consistent with the presence of NOE cross peaks
(between H1ax–H3ax and H2ax–H4) and couplings
(J1ax–2ax=12.3 Hz, J3ax–4=12.9 Hz) (Fig. 2). The product
5e differs from 4b having a different configuration at C6.
This is supported by cross peaks between H3eq–H6,
H3ax–H6 and H5–NH, as well as the absence of cross
peaks between H5–H6 (Fig. 3), which is further sup-
ported by molecular mechanics calculations.10
In summary, we have demonstrated a novel and practical
method for the synthesis of cis fused pyrano- and
furanobenzopyrans using a catalytic amount of lithium
tetrafluoroborate under neutral conditions. In addition
to its simplicity and mild reaction conditions, this proce-
dure has advantages of high yields of products, easy
availability and flexibility of starting materials, short
reaction times, operational simplicity, useful diastereose-
lectivity and simple experimental and work-up proce-
dures, which makes it a very useful and attractive process
for the synthesis of fused benzopyrans.
Figure 3. Important NOEs, the energy-minimized structure and the chemical structure of 5e.
Scheme 3.

6384
J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 6381–6384
mmol) and lithium tetrafluoroborate (0.5 mmol) in aceto-
Acknowledgements
nitrile (10 mL) was stirred at ambient temperature for the
appropriate time. After completion of the reaction, as
indicated by TLC, the reaction mixture was quenched by
addition of water (10 mL) and extracted with ethyl
acetate (2×15 mL). The combined organic layers were
dried over anhydrous Na2SO4, concentrated in vacuo and
the resulting product was purified by column chromatog-
raphy on silica gel (Merck, 100–200 mesh, ethyl acetate–
hexane, 0.5:95) to afford pure cis-fused acetal. Spectral
data for product 3a: solid, mp 95°C, 1H NMR (500 MHz,
CDCl3) l: 1.62 (m, 1H, H2, J=8.2, 8.7, 12.2 Hz), 1.92
(m, 1H, H2%, J=4.0, 7.5, 12.2 Hz), 3.11 (dddd, 1H, H3,
J=4.8, 5.4, 8.7, 10.6 Hz), 3.80 (brs, NH), 3.85 (ddd, 1H,
H1, J=8.7, 8.2, 7.5 Hz), 3.92 (ddd, 1H, H1%, J=8.7, 8.7,
4.0 Hz), 4.99 (d, 1H, H5, J=4.8 Hz), 5.89 (d, 1H, H4,
J=5.4 Hz), 6.65 (d, 2H, J=7.8 Hz), 6.67 (t, 1H, J=7.3
Hz), 6.85–6.95 (m, 2H), 7.15–7.25 (m, 3H), 7.30 (d, 1H,
J=7.3 Hz). 13C NMR (50 MHz, CDCl3, proton decou-
pled) l: 24.0, 43.80, 48.85, 68.0, 96.2, 102.4, 113.8, 117.3,
118.4, 122.0, 124.7, 126.0, 128.5, 130.0, 147.5, 153.8.
EIMS: m/z. 267 M+, 197, 145, 107, 91, 77, 71, 55, 41. 4b:
B.V.S., Ch.M. and S.K.K. thank CSIR, New Delhi for
the award of fellowships.
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11. Experimental procedure: A mixture of o-hydroxyben-
zaldimine (5 mmol), dihydrofuran or dihydropyran (6
.