BF3·OEt2-catalyzed tandem Prins Friedel-Crafts reaction: A novel synthesis of sugar fused diarylhexahydro-2H-furo[3,2-b]pyrans

Article abstract of DOI:10.1016/j.tetlet.2011.03.114

d-Glucose based homoallylic alcohol reacts smoothly with various aldehydes in the presence of arenes and a catalytic amount of BF₃· OEt₂ under mild conditions to afford a novel series of 5,7-diaryl-hexahydro-2H-furo[3,2-b]pyrans in g

Full text of DOI:10.1016/j.tetlet.2011.03.114

Tetrahedron Letters 52 (2011) 2961–2964
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
BF3ꢀOEt2-catalyzed tandem Prins Friedel–Crafts reaction: a novel synthesis
of sugar fused diarylhexahydro-2H-furo[3,2-b]pyrans
⇑
Basi V. Subba Reddy , Dudhmal N. Chaya, Jhillu S. Yadav, Deepak Chatterjee, A. C. Kunwar
Discovery Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
D-Glucose based homoallylic alcohol reacts smoothly with various aldehydes in the presence of arenes
Received 15 January 2011
Revised 16 March 2011
Accepted 24 March 2011
Available online 1 April 2011
and a catalytic amount of BF3ꢀOEt2 under mild conditions to afford a novel series of 5,7-diaryl-
hexahydro-2H-furo[3,2-b]pyrans in good yields with high cis-selectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Prins Friedel–Crafts reaction
Sugar homoallylic alcohol
Lewis acid
Diaryl hexahydro-2H-furo[3,2-b]pyrans
The Prins type cyclization is one of the direct and simple meth-
ods for the construction of six-membered tetrahydropyran scaf-
folds.1 In particular, furo[3,2-b]pyran motif is frequently found in
some natural products (Fig. 1).2
OCOPh
OH
O
O
Ph
Ph
O
O
O
O
O
OH
OH
The coupling of homoallylic alcohols with aldehyde in the pres-
ence of acid catalyst, known as Prins cyclization has been reported
to produce a large number of tetrahydropyran derivatives.3,4 Re-
cently, intramolecular version of Prins cyclization has been devel-
Altholactone
Orthodiffene A
OH
O
OCOPh
OH
OEt
O
oped to construct angularly fused tetrahydropyran derivatives.5
A
tandem ene-Prins cyclization has also been reported for the syn-
thesis of tetrahydropyran scaffolds.6 However, to the best of our
knowledge, there are no reports on the Prins Friedel–Crafts type
cyclization of homoallylic alcohols derived from sugars.7
O
O
O
OH
OH
Orthodiffene D
Etharvensin
In continuation of our interest on the use of Prins cyclization for
tetrahydropyran scaffolds,8 we herein report a novel approach for
the synthesis of sugar fused diaryl tetrahydropyrans via Prins
Friedel–Crafts cyclization under mild conditions. Initially, we at-
tempted the coupling of m-chlorobenzaldehyde (1) with a homoal-
Figure 1. Examples of some natural products bearing furopyran skeleton.
Ph
lylic alcohol (2) derived from
D
-glucose in benzene using a catalytic
O
O
O
O
amount of BF3ꢀOEt2 (0.1 equiv). The reaction proceeded smoothly
at 25 °C and the corresponding product 3a was obtained in 72%
yield with all cis-selectivity (Scheme 1).
BF3.OEt2
O
H
O
O
+
benzene, 25 ºC
O
HO
Cl
3a
1
2
The product 3a was characterized thoroughly with the help of
various NMR experiments including 2D nuclear overhauser effect
spectroscopy (NOESY, Fig. 2) and double quantum filter correlation
spectroscopy (DQFCOSY). The coupling constants (3JH3–H4 = 1.9,
Cl
Scheme 1. Prins cyclization of 3-chlorobenzaldehyde with sugar homoallylic
alcohol.
3
3
3
3
0
0
JH4–H6 = 12.4, JH5–H6 = 3.5, JH6–H7 = 11.4, and JH6 –H7 = 1.9 Hz)
are consistent with 3C6 chair form of the six-membered ring. Fur-
thermore, NOE cross peaks between H3/H5, H3/H7, and H5/H7
support their diaxial disposition and are consistent with the equa-
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.114

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B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2961–2964
torial position of the m-chlorophenyl and phenyl groups. NOE cross
peaks between CH3(pro-S) and H1 and H2 also support enveloped
conformation for the isopropylidene ring (Fig. 3).The energy mini-
mized structure provides further support for the above assigned
conformation.
The above result provided the incentive to extend this reaction
for other aldehydes.
ppm
3.2
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
Interestingly, various aldehydes, such as benzaldehyde, n-
hexanaldehyde, isobutyraldehyde, and n-butyraldehyde partici-
pated well in this reaction (Table 1, entries b, c, d, and g). Notably,
styrene oxide also gave the desired product in good yield without
the formation of side products (Table 1, entries f and i). Similarly,
cyclohexanone participated well in this reaction to furnish the
respective spirocyclic tetrahydropyran (Table 1, entry e). It is note-
worthy to mention that the reaction works not only with benzene
but also with anisole, toluene, and o-xylene. Furthermore, acid sen-
sitive cinnamaldehyde also gave the desired product in moderate
yield under similar conditions (Table 1, entry l). The reaction con-
ditions are mild and compatible with a highly acid sensitive aceto-
nide. Though the reaction proceeds well with 5 mol % of Sc(OTf)3,
the cleavage of acetonide was observed. Both aliphatic and aro-
matic aldehydes participated effectively and desired six-mem-
bered
tetrahydropyrans
were
formed
with
complete
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
ppm
diastereocontrol in good yield. The scope and generality of this
reaction are illustrated with respect to various aldehydes and are-
nes and the results are summarized in Table 1.9 The reactions pro-
ceeded only in the presence of an acid catalyst, affording the cis-
tetrahydropyrans exclusively. The reactions were clean with high
diastereoselectivity as determined from the NMR spectrum of the
crude product. A single diastereoisomer was obtained from each
reaction, the structure of which was confirmed by NMR experi-
ments. Mechanistically, the reaction proceeds via the formation
of hemi-acetal from aldehyde and homoallylic alcohol. Thus
formed hemi-acetal may undergo dehydration to generate the
oxocarbenium ion. Subsequent addition of olefin onto oxocarbeni-
um ion generates the b-carbocation which is trapped in situ by
arene to give the desired product (Scheme 2).10
Figure 2. Expansion of the NOESY spectrum of 3a showing the characteristic NOE
correlations.
H
Ph
6
7
H
O
5
4
3
1
A rationale for the all cis-selectivity involves the formation of an
(E)-oxocarbenium ion via a chair-like transition state, which has
increased the stability relative to the open oxocarbenium ion due
to delocalization. The optimal geometry for this delocalization
places the hydrogen atom at C4 in a pseudo-axial position, which
O
Cl
2
O
H
H
O
Figure 3. Characteristic NOE’s and energy-minimized structure of 3a.
Table 1
Synthesis of diaryl hexahydro-2H-furo[3,2-b]pyrans via Prins Friedl–Crafts reaction
Entry
Aldehyde
Cl CHO
Alcohol
Arene
Producta(3)
Ph
Temp (°C)
Temp (h)
6.0
Yieldb(%)
72
O
O
O
O
a
25
O
O
HO
Cl
O
CHO
O
Ph
O
O
O
b
c
25
25
25
25
6.5
6.0
6.5
8.0
70
75
74
65
O
O
HO
Ph
O
CHO
O
Ph
O
O
O
O
O
HO
O
O
Ph
CHO
O
O
d
e
O
O
O
HO
O
O
O
O
Ph
O
O
O
HO
O
O

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2961–2964
2963
Table 1 (continued)
Entry
Aldehyde
Alcohol
Arene
Producta(3)
Temp (°C)
Temp (h)
8.0
Yieldb(%)
O
O
Ph
O
O
f
25
65
O
HO
O
O
O
Ph
O
R
O
CHO
O
Me
Me
O
O
g
ꢁ78
ꢁ78
ꢁ78
ꢁ40
7.0
7.0
7.5
6.0
72c
O
HO
O
O
R = tolyl
R
Cl
CHO
O
O
O
O
HO
h
i
70c
70c
68c
Cl
O
O
R = tolyl
O
O
Me
Me
R
O
O
O
O
O
HO
Ph
Cl
O
R = tolyl
R
Cl
CHO
O
O
Me
O
O
O
HO
j
O
O
R = xylyl
CHO
O
Me
R
O
O
Me
O
O
O
k
ꢁ40
ꢁ78
7.0
6.5
66c
65c
O
HO
R = xylyl
CHO
O
OMe
R
O
O
O
O
HO
l
Ph
O
O
R = anisyl
a
All product were characterized by NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
1:1 ratio of ortho/para isomers was obtained.
b
c
In summary, we have demonstrated a tandem Prins Friedel–
Crafts reaction for the synthesis of a novel series of diaryl hexahy-
drofuro[3,2-b]pyrans under mild conditions. The use of BF3 makes
this method simple, convenient, and practical. This method pro-
vides an easy access for a new class of sugar annulated pyrans in
a single step operation which may find application in drug discov-
ery and also in natural products synthesis.
H
+
O
+
H+
O
O
H O-H
O
+
O
H
R1
HO
..
-H2O
H
O
O
R1
..
O
Ar
Ar
R1
H
O
O
R1
(+)
O
O
O
O
R1
O
O
Acknowledgment
H
+
O
O
H
O
O
D.N.C. and D.C. thank CSIR, New Delhi for the award of a
fellowship.
Scheme 2. A plausible reaction mechanism.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.114.
º
a) TFA: H20 9:1, 0 C-r.t, 7h
b) NaIO4,THF:H2O(4:1), 0 oC-r.t, 3h
O
OH
OH
References and notes
º
c) NaBH4, MeOH, 0 C-r.t, 6h
O
O
O
O
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Cl
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p
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hydropyran derivative 4h by a sequence of reactions as depicted
in Scheme 3.

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B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2961–2964
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stirred at appropriate temperature for the specified amount of time (Table 1).
After completion of the reaction as indicated by TLC, the reaction mixture was
quenched with water and extracted with dichloromethane (2 ꢂ 10 mL). The
combined organic layers were washed with brine solution and dried over
anhydrous Na2SO4. Removal of the solvent followed by purification on silica gel
(Merck, 100–200 mesh, ethylacetate/hexane, 0.5:9.5) gave the pure sugar
annulated diaryl tetrahydropyran. The products thus obtained were
characterized by IR, NMR and mass spectroscopy (see Supplementary data
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9. General procedure. A mixture of sugar based homoallylic alcohol (1 mmol),
aldehyde (1.2 mmol), and BF3ꢀOEt2 (0.1 mmol) in the suitable arene (5 mL) was