The silyl-Prins reaction: A novel method for the synthesis of dihydropyrans

Article abstract of DOI:10.1016/S0040-4039(02)01558-7

Reaction of 4-trimethylsilyl-3-buten-1-ols with aldehydes under mild Lewis acid conditions gives substituted dihydropyrans in excellent yields and with good stereocontrol.

Full text of DOI:10.1016/S0040-4039(02)01558-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7055–7057
The silyl–Prins reaction: a novel method for the synthesis of
dihydropyrans
Adrian P. Dobbs* and Sasˇa Martinovic´
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 29 May 2002; accepted 26 July 2002
Abstract—Reaction of 4-trimethylsilyl-3-buten-1-ols with aldehydes under mild Lewis acid conditions gives substituted dihydropy-
rans in excellent yields and with good stereocontrol. © 2002 Published by Elsevier Science Ltd.
Substituted pyrans are a common structural motif of
many natural products. The dihydropyran skeleton is a
particularly attractive target since it both occurs in
many natural products and furthermore the olefin func-
tion is a synthetically useful handle for further func-
tionalisation, making it a key intermediate to many
polysubstituted tetrahydropyrans. The literature now
contains many versatile methods for the synthesis of
dihydropyrans,1 such as the hetero-Diels–Alder reac-
tion, the intramolecular Sakurai reaction and ring-clos-
ing olefin metathesis. Unfortunately, the Sakurai
reaction approach involves a lengthy synthesis of a
bis-silylated homoallylic alcohol precursor, while the
metathesis approach often requires the synthesis of
complex precursors. Speckamp1b has also utilised vinyl-
silane chemistry in an approach to this structural motif,
but this method requires extra steps in the formation of
a hemiacetal intermediate and always gives an ester as
one of two substituents in the products. By contrast,
the Prins cyclisation, which involves treatment of a
homoallylic alcohol with a carbonyl compound and
usually a Brønsted acid, is a powerful methodology for
the synthesis of tetrahydropyrans, although it often
leads to complex mixtures of products.2 Li has recently
reported a Lewis acid mediated synthesis of dihydropy-
rans using a novel carbonyl allylation–Prins cyclisation
method, using 3-trimethylsilylallyltributylstannane as
the cyclisation precursor.3 However, there are two
drawbacks associated with this process: the use of tin,
which is undesirable due to the associated separation
and toxicity problems and the use of two equivalents of
an aldehyde means that only identical substituents may
be introduced in the product. Finally, Brimble has
reported the synthesis of aryldihydropyrans using a
Sonogashira-selenoetherification strategy.4 However, a
simple and general route to dihydropyrans, permitting
the incorporation of varying substituents, is still a
synthetic need. Herein we describe a novel method for
the synthesis of dihydropyrans, using mild Lewis acids,
which overcomes many of the drawbacks of the alterna-
tive methods.
The desired substrate for our initial studies was Z-4-
trimethylsilyl-3-buten-1-ol 1. This was easily prepared
in two steps using literature methods1c (silylation using
Table 1. The synthesis of simple dihydropyrans6
O
Lewis Acid
R1
OH
+
R1
H
CH2Cl2
O
1
TMS
Entry
R1
Lewis acid
Conditions
% Yielda
1
2
3
4
5
6
7
8
9
PhCH2
PhCH2
PhCH2
n-C5H11
Cyclohexyl
Ph2CH
InCl3
Rt
88
86
90
65
72
85
39
86
54
80
TMSOTf
BF3·OEt2
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
−78°C
−78°C
Rt
Rt
Rt
Rt
Rt
Rt
0.5 equiv.
InCl3; rt
0.1 equiv.
InCl3; rt
Ph
4-NO2-Ph
4-CF3-Ph
PhCH2
10
11
PhCH2
InCl3
63
* Corresponding author. Tel.: +44 1392 263410; fax: +44 1392
263434; e-mail: a.dobbs@exeter.ac.uk
a All reactions were performed with alcohol:aldehyde:Lewis acid in a
1:1:1 ratio in dichloromethane unless otherwise stated.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01558-7

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A. P. Dobbs, S. Martino6ic´ / Tetrahedron Letters 43 (2002) 7055–7057
n-butyllithium/trimethylsilyl chloride followed by
DiBAL reduction) from 3-butyn-1-ol in 74% overall
yield.
After Lewis acid activation of the aldehyde, the reac-
tion is believed to proceed via nucleophilic attack from
the alcohol, followed by cationic cyclisation to give a
carbocation stabilised by the b-effect from silicon. Sub-
sequent collapse and elimination of the silicon moiety
gives the observed dihydropyran product. A chair-like
transition state 3 with equatorial substituents in the
developing six-membered ring could account for the
stereoselective production of cis-2,6-disubstituted
dihydropyrans.
In order to test the feasibility of 1 as a precursor for a
silyl-Prins type reaction, initial cyclisation studies were
performed using 1 with phenylacetaldehyde with a
range of Lewis acids (Table 1). Of the Lewis acids
screened, indium trichloride (Table
1
entry 1),
trimethylsilyltriflate (entry 2) and boron trifluoride
etherate (entry 3) were the most successful. Pleasingly,
all three gave a single dihydropyran product and in
comparable yields. Therefore, indium trichloride was
the Lewis acid of choice for further studies, since it is
both a mild, crystalline Lewis acid (that does not
require rigorously anhydrous reaction conditions) and
the reaction could be performed at room temperature,
compared to the low temperature (−78°C) required for
the two alternative Lewis acids. Excellent yields were
obtained for the indium trichloride mediated reaction
using a range of different aldehydes (Table 1, entries
4–9). The use of various benzaldehydes in this reaction
is particularly interesting (Table 1, entries 7–9). Ben-
zaldehyde is surprisingly low yielding, but this is in
keeping with related methods that have also reported
lower1c or no3 products with aromatic aldehydes. Both
p-NO2 and p-CF3 substituted benzaldehydes gave sig-
nificantly enhanced yields of dihydropyran product,
compared to benzaldehyde, with the p-NO2 benzalde-
hyde proving particularly reactive in this method. This
presumably results from an electronic effect from the
nitro group.
It is not only simple substituted dihydropyrans that are
of interest and a method towards trisubstituted and
fused ring systems would also be of synthetic value. The
combination of diethylaluminium chloride/lithium
trimethylsilylacetylide is a powerful method for the
opening of epoxides.1c This approach was utilised with
cyclohexene and cyclopentene oxides to yield the corre-
sponding silylhomopropargylic alcohols. Subsequent
DiBAL reduction gave the silylhomoallylic alcohols 4
and 5 that were subjected to our standard cyclisation
conditions (Scheme 1). Both 5,6- and 6,6-ring-fused
dihydropyrans were obtained in good yields and excel-
lent selectivity for the conformations shown. The stere-
ochemistry observed is in accord with anti-opening of
the epoxide precursor and cis selectivity in the dihy-
dropyran ring closure. Relative stereochemistry was
again established with the aid of NOE experiments.
Finally, Li has reported that epoxides may also act as
suitable precursors for the synthesis of aryl-substituted
tetrahydropyrans, in a related Lewis acid mediated
reaction.5 Therefore we have initiated a programme of
When using catalytic amounts of indium trichloride, the
desired dihydropyran was still obtained in good yields,
although slightly lower than observed in the stoichio-
metric reaction (Table 1, entries 10 and 11). Neverthe-
less, the yields obtained suggest that the reaction is
truly catalytic, albeit with low catalyst turnovers. This
aspect of the chemistry is part of an ongoing study.
Table 2. Synthesis of disubstituted dihydropyrans6,7
Entry
R1
% Yielda
The methyl substituted version of 1 was prepared using
an analogous route to that employed for 1 (71% overall
yield from commercially available 2-methylpent-4-yn-1-
ol) in order to investigate the synthesis of disubstituted
dihydropyrans. Pleasingly, reaction of Z-5-trimethylsi-
lylpent-4-en-2-ol 2 with a range of aldehydes gave
dihydropyrans in good yields and with excellent
stereoselectivity for the 2,6-cis derivatives, as deter-
mined by NOE studies.
1
2
3
4
5
PhCH2
50
65
69
78
60
n-C5H11
Cyclohexyl
Ph2CH
4-NO2-Ph
a All reactions were performed with alcohol:aldehyde:Lewis acid in a
1:1:1 ratio in dichloromethane unless otherwise stated.
A 6.0% NOE was observed between the two hydrogen
atoms at C(2) and C(6)7. No evidence for the 2,6-trans
product could be detected, even in the crude reaction
mixtures.
4
H
H
R
O
6
Me
O
H
2
Ph
2.2%
Me
3.4%
H
H
TMS
6.0%
3
Scheme 1. Synthesis of fused dihydropyrans.

A. P. Dobbs, S. Martino6ic´ / Tetrahedron Letters 43 (2002) 7055–7057
7057
catalysts in hetero Diels–Alder reactions; Ali, T.;
Chauhan, K. K.; Frost, C. G. Tetrahedron Lett. 1999, 40,
5621; (c) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speck-
amp, W. N. J. Org. Chem. 1997, 62, 3426–3427; (d)
Marko´, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141;
(e) Marko´, I. E.; Dobbs, A. P.; Scheirmann, V.; Chelle´, F.;
Bayston, D. J. Tetrahedron Lett. 1997, 38, 2899; (f)
Schmidt, B.; Westhus, M. Tetrahedron 2000, 56, 2421; (g)
de Rosa, M.; Solladie´-Cavallo, A.; Scettri, A. Tetrahedron
Lett. 2000, 41, 1593.
Scheme 2. Synthesis of dihydropyrans from epoxide precur-
sors.
2. Snider, B. B. The Prins and Carbonyl Ene Reactions,
Chapter 2.1. In Comprehensive Org. Synth., Heathcock, C.
H., Vol. 2 (editor-in-Chief B. M. Trost).
3. Viswanathan, G. S.; Yang, J.; Li, C.-J. Org. Lett. 1999, 1,
993.
study to investigate the use of epoxides in the synthesis
of dihydropyrans. Treatment of styrene oxide with
indium trichloride and either 1 or 2 generated the
corresponding dihydropyran, in yields comparable to
that obtained from phenylacetaldehyde and with simi-
lar levels of stereoselectivity (Scheme 2).
4. Brimble, M. A.; Pavia, G. S.; Stevenson, R. J. Tetrahedron
Lett. 2002, 43, 1735.
5. Li, J.; Li, C.-J. Tetrahedron Lett. 2001, 42, 793.
6. Typical experimental procedure for indium trichloride
mediated reaction: the aldehyde (3 mmol) and alcohol (3
mmol) were dissolved in dry dichloromethane (25 ml)
under an inert argon atmosphere at room temperature and
indium trichloride (3 mmol) added in one portion. The
reaction was stirred at room temperature for between 5
and 12 h. Water (50 ml) was added to the reaction mixture
and the organic phase was separated. This was subse-
quently washed with water and brine, dried (MgSO4) and
concentrated to an oil that was purified by flash chro-
matography (typically hexane:ethyl acetate, 4:1) to give the
desired product. All compounds were in good agreement
with previously reported data or gave satisfactory analyti-
cal data.
In conclusion, we have demonstrated a rapid and high
yielding stereospecific synthesis of dihydropyrans from
aldehydes and silylated homoallylic alcohols using mild
Lewis acid reagents. It is also a useful route to trisubsti-
tuted dihydropyrans. Furthermore, epoxides may be
employed as the reaction partners in place of aldehydes.
The latter two areas form part of an ongoing pro-
gramme of research and these results will be reported in
due course. As such, this method represents a shorter
and easier method than currently exists in the literature
and has the added flexibility of permitting the incorpo-
ration of many differing substituents.
Acknowledgements
7. Representative data, including NOE, for syn-2-(2-phenyl-
methyl)-6-methyloxacyclohex-3-ene (Table 2, entry 1): lH
(400 MHz, CDCl3) 7.24–7.33 (5H, m, Ar), 5.80 (1H, m,
C(4)H), 5.63 (1H, m, C(3)H), 4.36 (1H, m, C(2)H; 5.95%
NOE enhancement on irradiation of C(6)H), 3.72 (1H, m,
C(6)H; 6.02% NOE enhancement on irradiation of C(2)H),
3.03 (1H, dd, J=13.8 and 6.3, one of benzylic CH2), 2.70
(1H, dd, J=13.8 and 6.3, one of benzylic CH2), 1.98 (2H,
m, C(5)H2), 1.26 (3H, d, J=7.7, CH3); lC (100 MHz;
CDCl3) 138.3 (ipso-C), 129.7 (Ar), 129.0 (C(3)H), 128.4
(Ar), 126.2 (Ar), 124.9 (C(4)H), 75.8 (C(2)H), 70.1
(C(6)H), 42.1 (benzylic CH2), 32.9 (C(5)H2), 21.7 (Me).
We gratefully acknowledge the University of Exeter
and CVPC (ORS award to S.M.) for financial support
of this project.
References
1. (a) Hetero-Diels–Alder reaction: Boger, D. L.; Weinreb, S.
M. Hetero Diels–Alder Methodology in Organic Synthesis,
Academic Press: New York, 1987; (b) for use of indium