Sc(OTf)3-catalyzed one-pot ene-Prins cyclization: a novel synthesis of octahydro-2H-chromen-4-ols

Article abstract of DOI:10.1016/j.tetlet.2010.03.100

(R)-Citronellal undergoes initial ene reaction followed by Prins cyclization with aldehydes in the presence of 5 mol % of scandium triflate at ambient temperature to furnish octahydro-2H-chromen-4-ols in good yields and with high cis-selectivity. The use of scandium triflate makes this procedure simple, more convenient, and practical.

Full text of DOI:10.1016/j.tetlet.2010.03.100

Tetrahedron Letters 51 (2010) 2963–2966
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sc(OTf)3-catalyzed one-pot ene-Prins cyclization: a novel synthesis
of octahydro-2H-chromen-4-ols
*
J. S. Yadav , B. V. Subba Reddy, A. V. Ganesh, G. G. K. S. Narayana Kumar
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:
(R)-Citronellal undergoes initial ene reaction followed by Prins cyclization with aldehydes in the presence
of 5 mol % of scandium triflate at ambient temperature to furnish octahydro-2H-chromen-4-ols in good
yields and with high cis-selectivity. The use of scandium triflate makes this procedure simple, more con-
venient, and practical.
Received 12 December 2009
Revised 20 March 2010
Accepted 24 March 2010
Available online 1 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Citronellal
ene-Prins cyclization
Isopulegol
Aldehydes
Octahydro-2H-chromen-4-ols
The rapid construction of natural product-like molecules from
readily available precursors with the control of stereochemistry
in a single-step operation is a versatile technique in synthetic
chemistry.1 In this context, ‘Tandem’ reactions, in which multiple
reactions are combined into single operation in a convergent
way, have been reported extensively.2 The advantages of Tandem
reactions are the formation of several bonds by a single catalyst
in a one-pot operation. High degree of selectivity, efficiency, and
atom economy can be achieved without the change of reaction
conditions or any further addition of reagents. The Prins cyclization
is one of the best examples of such a process and has received
much attention in recent years.3 Generally, Lewis acids and Bron-
sted acids are known to catalyze the coupling of homoallylic alco-
hols with aldehydes to produce a wide range of tetrahydropyran
derivatives under mild conditions.4,5 This approach has been suc-
cessfully employed to the synthesis of complex natural products.6,7
The Lewis acid-catalyzed intramolecular carbonyl-ene reaction
is one of the most attractive methods for ring closure, leading to
the formation of two contiguous stereocenters with a high degree
of stereoselectivity.8 (R)-Citronellal is known to undergo intramo-
lecular carbonyl-ene reaction to produce a mixture of diastereo-
meric products. The diastereoselectivity generally depends on the
reaction conditions including the nature of the Lewis acid9 used.
In particular, the trans diastereomer isopulegol is favored with a
diastereomeric ratio of up to 94:6.10
In continuation of our interest on the Prins-cyclization,5,7 we
herein report a simple and direct ene-Prins reaction for the synthesis
of pyran derivatives from (R)-citronellal and aldehydes using a cat-
alytic amount of scandium triflate under mild conditions. Initially,
we attempted the coupling of (R)-citronellal with benzaldehyde in
the presence of 5 mol % of scandium triflate in dichloromethane.
The reaction was carried out at À78 °C to room temperature and
the corresponding productwas obtained as diastereomeric mixtures
3a and 4a in a ratio of 9:1 with 88% overall yield. The isomers were
separated by column chromatography (Scheme 1).
The structure and stereochemistry of the product were estab-
lished by making a comparison of the spectral data with authentic
sample.11 This result provided incentive for further study of reac-
tions with various aromatic aldehydes such as 1-naphthaldehyde,
p-chlorobenzaldehyde, p-bromobenzaldehyde, p-toluraldehyde,
p-anisaldehyde, p-nitrobenzaldehyde, and o-nitrobenzaldehyde.
In all cases, the respective chromanes were obtained in good yields
(Table 1, entries b–h). Furthermore, the reaction of (R)-citronellal
with hydrocinnamaldehyde gave 3i and 4i as separable isomers
in a ratio of 8:2 (Table 1, entry i). Next, we studied the reactivity
of aliphatic aldehydes such as propanaldehyde, cyclohexanecarb-
oxaldehyde, and isovelaraldehyde which gave the corresponding
chromanes in good yields (Table 1, entries j–l). Interestingly, acid
sensitive trans-cinnamaldehyde also participated effectively in this
reaction (Scheme 2, Table 1, entry m).
In the absence of catalyst, no reaction was observed under sim-
ilar conditions. As solvent, dichloromethane was found to give the
best results. All the products were characterized by NMR, IR, and
mass spectrometry. Mechanistically, the reaction proceeds via
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.100

2964
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2963–2966
H
O
H
O
5 mol% Sc(OTf)3
CHO
CHO
+
-78 oC- rt
,
+
CH2Cl2
H
H
H
H
HO
HO
2
1
3a
4a
9:1
Scheme 1. Preparation of 3a and 4a.
Table 1
Sc(OTf)3-catalyzed one-pot ene-Prins cyclization with R-citronellal and various aldehydes
Entry
Aldehyde
Alcohola (3)
Alcohola (4)
Time (h)
10.0
Yieldb (%) (3:4)
CHO
H
H
O
a
88(9:1)
O
H
H
H
H
H
H
HO
HO
H
H
O
CHO
b
c
10.5
10.5
86(9:1)
83(9:1)
O
H
H
H
HO
HO
CHO
H
H
O
O
H
H
H
H
H
Cl
HO
HO
Cl
Cl
CHO
CHO
H
H
O
O
d
e
f
11.0
10.0
12.0
82(9:1)
84(9:1)
78(9:1)
H
H
H
Br
HO
HO
Br
Br
H
H
O
O
H
H
H
H
H
Me
HO
HO
Me
OMe
NO2
Me
OMe
NO2
CHO
H
H
O
O
H
H
H
MeO
HO
HO
CHO
H
H
O
O
g
13.0
14.0
76(9:1)
70(9:1)
H
H
H
O2N
HO
HO
NO2
H
H
O
CHO
h
O
NO2
NO2
H
H
H
H
HO
HO

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2963–2966
2965
Table 1 (continued)
Entry
Aldehyde
Alcohola (3)
Alcohola (4)
Time (h)
10.5
Yieldb (%) (3:4)
CHO
H
H
O
i
O
90(8:2)
90(8:2)
88(8:2)
86(8:2)
85(9:1)
H
H
H
H
HO
HO
CHO
H
H
O
j
10.0
11.0
10.0
12.0
O
H
H
H
H
H
H
HO
HO
CHO
H
H
O
k
O
H
H
HO
HO
H
H
O
CHO
l
O
H
H
H
H
H
H
HO
HO
CHO
H
H
O
m
O
H
H
HO
HO
a
All products were characterized by 1H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
H
O
H
O
CHO
H
H
H
+
H
+
5 mol% Sc(OTf)3
CH2Cl2
CHO
HO
-78 oC- rt
HO
,
3m
4m
9:1
Scheme 2. Preparation of 3m and 4m.
ene-reaction of citronellal. The resulting homoallylic alcohol sub-
sequently may undergo the Prins cyclization with aldehyde afford-
ing the desired product (Scheme 3). The scope and generality of
this process are illustrated in Table 1.12 The efficiency of various
acid catalysts such as ZnBr2, FeCl3, and AlCl3 has been tested for
this transformation and the results are presented in Table 2.
Sc(III)
O
''''''''
H
..
+
O
OH
R
R
CHO
Carbonyl ene
H
H
(R)-Citronellal
Isopulegol
H
H
O
H
R
+
R
R
O
O
-
OH
OH
+
H
H
H
OH
H
H
H
3
4
Scheme 3. A plausible reaction mechanism.

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2963–2966
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A comparative study of various Lewis acids for the preparation of 3a
S. No.
Lewis acid (equiv)
Reaction time (h)
Yielda (%)
a
b
c
Sc(OTf)3 (0.05)
ZnBr2 (1.0)
FeCl3 (0.1)
10.0
14.0
11.0
12.0
88
48
12
20
d
AlCl3 (0.1)
4. (a) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, Ch. V. S. R. Tetrahedron
Lett. 2001, 42, 89; (b) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.;
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a
Isolated yield after chromatography.
Of these, Sc(OTf)3 was found to be the catalyst in terms of
yields.
In summary, we have demonstrated a tandem ene-Prins cycli-
zation using Sc(OTf)3 as a catalyst. The coupling of (R)-citronellal
with aldehydes provides a simple and convenient route for the
synthesis of chromane derivatives. Further studies to the reactions
are in progress.
Acknowledgments
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A.V.G. and G.G.K.S.N.K. thank CSIR, New Delhi for the award of
fellowships and also thank DST for financial assistance under the
J. C. Bose fellowship scheme.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.100.
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12. General procedure: To
a
solution of R-citronellal (5.0 mmol), in
dichloromethane (10 mL) was added scandium triflate (0.25 mmol) at
À78 °C. After completion of the ene reaction (1.5 h) as indicated by TLC,
aldehyde (5.0 mmol) in dichloromethane (6 mL) was added to the reaction
mixture at the same temperature. Then temperature was slowly brought to rt.
The reaction mixture was stirred at room temperature for a specified amount
of time (Table 1). After completion of the reaction as indicated by TLC, the
reaction mixture was extracted with dichloromethane (2 Â 10 mL). The
combined organic layers were dried over anhydrous Na2SO4. Removal of the
solvent followed by purification on silica gel (Merck, 60–120 mesh, ethyl
acetate–hexane, 1.0–9.0) gave the pure products.
3. (a) Barluenga, J.; Fernandez, A.; Dieguez, A.; Rodriguez, F.; Fananas, F. J. Chem.
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