Tandem vinylcyclopropane ring opening/Prins cyclization for the synthesis of 2,3-disubstituted tetrahydropyrans

Article abstract of DOI:10.1016/j.tetlet.2016.03.062

An efficient synthesis of 2,3-disubstituted tetrahydropyrans from aldehyde and cyclopropyl alkenol has been accomplished using HBF₄·OEt₂ as a promoter through a tandem vinylcyclopropane ring-opening/Prins cyclization. It is a convenient process to generate a structurally diverse and biologically relevant 2,3-disubstituted tetrahydropyrans in good yields with high selectivity.

Full text of DOI:10.1016/j.tetlet.2016.03.062

Accepted Manuscript
Tandem vinylcyclopropane ring opening/Prins cyclization for the synthesis of
2,3-disubstituted tetrahydropyrans
B.V. Subba Reddy, V. Swathi, Manika Pal Bhadra, M. Kanaka Raju, A.C.
Kunwar
PII:
S0040-4039(16)30283-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.062
TETL 47450
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 January 2016
11 March 2016
18 March 2016
Please cite this article as: Subba Reddy, B.V., Swathi, V., Bhadra, M.P., Kanaka Raju, M., Kunwar, A.C., Tandem
vinylcyclopropane ring opening/Prins cyclization for the synthesis of 2,3-disubstituted tetrahydropyrans,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.062
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Graphical Abstract
Tandem vinylcyclopropane ring opening/Prins cyclization for
the synthesis of 2,3-disubstituted tetrahydropyrans
Leave this area blank for abstract info.
B. V. Subba Reddy,* V. Swathi, Manika Pal Bhadra, M. Kanaka
Raju, A. C. Kunwar

1
Tetrahedron Letters
Tandem vinylcyclopropane ring opening/Prins cyclization for the synthesis of
2,3-disubstituted tetrahydropyrans
B. V. Subba Reddy,*a V. Swathi,a,b Manika Pal Bhadra,b M. Kanaka Raju,c A. C. Kunwarc
aCentre for Semiochemicals, bCentre for Chemical Biology, cCentre for Nuclear Magnetic Resonance and Structural Chemistry, CSIR-Indian
Institute of Chemical Technology, Hyderabad-500 007, India. E-mail:basireddy@iict.res.in, Fax: 91-40-27160512.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of 2,3-disubstituted tetrahydropyrans from aldehyde and cyclopropyl
alkenol has been accomplished using HBF4.OEt2 as a promoter through a tandem
vinylcyclopropane ring-opening/Prins cyclization. It is a convenient process to generate a
structurally diverse and biologically relevant 2,3-disubstituted tetrahydropyrans in good
yields with high selectivity.
Available online
Keywords:
Cyclopropyl alkenol
Aldehydes
2009 Elsevier Ltd. All rights reserved.
Acid catalysis
2,3-Disubstituted tetrahydropyrans
Thromboxane A2 (TXA2) is a hormone, which is produced
by blood platelets. It is a potent vasoconstrictor and initiates
activation of new platelets and platelet aggregation (Figure
1).1
E/Z isomers. They could not be separated by column
chromatography. Therefore, the Prins cyclization was
performed using 1:1 mixture of E/Z isomers of 1.
Figure 1. Biologically active 2,3-substituted tetrahydropyran
The Prins-type cyclization is one of the most efficient
approaches for the construction of tetrahydropyran ring
(THP), which is a backbone of several natural products.2 In
particular, Prins induced cascade reactions are very useful for
the stereoselective synthesis of fused, bridged, and
spirotetrahydropyran scaffolds.3,4 It has been successfully
employed to the synthesis of tetrahydropyran containing
molecules.5 However, a few methods are known in literature
for the synthesis of 2,3-disubstituted tetrahydropyrans through
a Prins cyclization.6
Scheme 1. Reaction conditions: a) BnBr, NaH, THF, r.t., 12h;
b)
PCC,
celite,
DCM,
r.t.,
4h;
c)
(cyclopropylmethyl)triphenylphosphonium bromide, n-BuLi,
THF, -78 C, 3h; d) Li, naphthalene, THF, -40 C, 1h.
In a preliminary experiment, (E/Z)-5-cyclopropylpent-4-en-1-
ol (1) (1.0 equiv) was treated with benzaldehyde (1.2 equiv)
using HBF4.OEt2 (1 equiv) in dichloromethane. The reaction
proceeded smoothly at 25 C and the product 4a was obtained
in 85% yield with high stereocontrol (entry a, Table 1). Under
the above conditions, we expected the formation of fluoro
derivative 3 through a sequential Prins/fluorination process
involving a tandem vinylcyclopropane ring opening by
HBF4.OEt2. But unexpectedly, the compound 4a was formed
under present conditions (Scheme 2).
Following our interests on Prins-type cyclizations,7 we herein
report an efficient strategy for the stereoselective synthesis of
(E)-4-(tetrahydro-2H-pyran-3-yl)but-3-en-1-ol
derivatives.
The requisite starting material, 5-cyclopropylpent-4-en-1-ol
(1) was prepared by a known procedure (Scheme 1).8
However, the precursor 1 was obtained as a 1:1 mixture of

2
Tetrahedron
1. Further support for the proposed structure was derived from
small equatorial – equatorial and axial - equatorial couplings
3
3
3
3
like: J2-H//3-H = 4.7, J2-H/3-H = 2.5, J2-H/3-H = 2.5, J3-H/4-H
=
2.5, 3J3-H/4-H = 4.0, 3J3-H/4-H = 4.0 and 3J4-H/5-H = 4.0 Hz. Finally
the characteristic NOE correlations, 1-H/2-H, 1-H/4-H, 2-
H/4-H, 3-H/5-H, provide emphatic support for the structure,
with the six-membered ring taking 5CC2C chair conformations.
3
The coupling constant J6-H/7-H = 15.6 Hz and NOE
Scheme 2. Selective formation of 2,3-disubstituted
tetrahydropyran (4a)
correlations, 4-H/6-H and 5-H/7-H, imply trans double bond
between 6-H and 7-H protons. The energy minimized
structure adequately supports the proposed structure of 4aꞌ
(Figure 2).
The effect of other acid catalysts such as BF3.OEt2 and
TMSOTf was studied for this conversion (entries b, c, Table
1). Though, the reaction proceeded at 0 C in the presence of
1 equiv of BF3.OEt2, the product 4a was obtained relatively in
lower yield than HBF4.OEt2 (entry b, Table 1). To our
surprise, TMSOTf also afforded the product 4a comparatively
in lower yield than HBF4.OEt2 (entry c, Table 1). The
reaction was also carried out using different amounts of the
reagent ranging from
a
catalytic (10 mol%) to
stoichiometric. However, the best conversions were
achieved using a stoichiometric amount of Lewis acid. We
further examined the effect of solvent for this reaction (entries
d-g, Table 1). However, the reaction was sluggish either in
THF or CH3CN affording the desired product 4a in trace
amount. To our delight, DCM gave the best results (entries a-
c, Table 1).
Table 1. Optimization of reaction conditions
Figure 2. Energy minimized structure and characteristic
NOEs of 4aꞌ
Encouraged by these initial findings, we extended this method
to a diverse range of aldehydes and the results are
summarized in Table 2. Interestingly, aryl aldehydes such as
4-chloro-, 4-bromo-, 4-fluoro-, 4-nitro-, 3,4-dimethoxy-, 4-
isopropyl-,
3,5-dimethyl-,
4-methoxy-,
4-cyano-
benzaldehydes participated well in this transformation (Table
2). This method was also successful with aliphatic aldehydes
such as cyclohexanecarboxaldehyde, n-hexanal, and
isobutyraldehyde under similar conditions. Acid sensitive α,β-
unsaturated aldehyde (cinnamaldehyde) was also compatible
under the reaction conditions. In all cases, the reactions
proceeded well at ambient temperature with high selectivity.
Only a single diastereomer was obtained in each reaction, the
1
structure of which was established by H and 13C NMR and
To confirm the terminal hydroxyl group, 4a was converted
into its acetate derivative 4aꞌ using acetic anhydride and
DMAP in dichloromethane. The structure and relative
stereochemistry of 4aꞌ were established by 1D and 2D NMR
experiments (Supporting information). The structures of 4aꞌ
were derived by extensive NMR experiments including 2-D
Nuclear Overhauser Effect Spectroscopy (NOESY) and
Double Quantum Filtered Correlation Spectroscopy
(DQFCOSY), Hetero-nuclear Single Quantum Correlations
(HSQC) and Hetero-nuclear Multiple Bond Correlation
(HMBC) experiments. The distinctive doublet at 3.94 ppm in
4aꞌ due to 1-H was used to initiate the assignments with the
help of DQF-COSY and NOESY experiments. From the one
mass spectrometry. This method is highly diastereoselective
affording high yields of products in a short reaction time
(Table 2).
1
dimensional H NMR experiments, large coupling constants
3
like : 3J1-H/5-H = 10.0, 3J2-H/3-H = 13.5, 3J3-H/4-H = 12.0, J4-H/5-
= 13.0 Hz imply the di-axial disposition of the participating
H
protons, which are consistent with the structure having six-
membered ring in chair conformation as shown in the Figure

3
Table 2. Synthesis of 2,3-disubstituted THPs
Based on our previous observations, we proposed a possible
reaction mechanism as shown in Scheme 3. The condensation
of cyclopropyl alkenol with aldehyde in the presence of an
acid catalyst generates an oxo-carbenium ion (A). A
subsequent attack of an internal olefin on A followed by the
ring opening of vinylcyclopropane would give the desired
product (4).
Scheme 3. A plausible reaction mechanism
Though, the stereochemistry of product is totally dependent
on the geometry of olefin in Prins cyclization using a
homoallylic alcohol, there is no such effect was observed in
the present case. Because the olefin used in the present work
behaves differently than homoallylic alcohol. Furthermore, Z-
isomer might be converted rapidly into E-isomer under acidic
conditions.
In summary, we have developed an efficient method for the
synthesis of
a
novel class of 2,3-disubstituted
tetrahydropyrans in good yields. This approach provides a
direct access to biologically relevant tetrahydropyrans with
diverse substitution pattern. The notable features of this
procedure are operationally simple, mild reaction conditions,
short reaction times and high yields, which make it very useful
and attractive.
Acknowledgments
V. S. thanks UGC, New Delhi for the award of a fellowship.
Supplementary data
1
Experimental details, characterization data, copies of H and 13C
NMR spectrum of products can be found, in the online version, at
http:// dx.doi.org/
References and Notes
1.
2.
Gryglewski, R. J, Dembínska-Kieć A, Korbut, R. Acta Biol Med
Ger. 1978, 37, 715.
Reviews on Prins reaction: (a) Olier, C.; Kaafarani, M.; Gastaldi, S.
S.; Bertrand, M. P. Tetrahedron 2010, 66, 413. (b) Crane, E. A.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316. (c) M. Pastor,
I. M. Yus, Curr. Org. Chem. 2012, 16, 1277. (d) Han, X.; Peh, G. R.;
Floreancig, P. E. Eur. J. Org. Chem. 2013, 1193.
3.
(a) Elsworth, J. D.; Willis, C. L. Chem. Commun. 2008, 1587. (b)
Barbero, A.; Varga, A. D.; Pulido, F. J. Org. Lett. 2013, 15, 5234. (c)
Li, B.; Lai, Y. C.; Zhao, Y.; Wong, Y. H.; Shen, Z. L.; Loh, T. P.

4
Tetrahedron
Angew. Chem. Int. Ed. 2012, 51, 10619. (d) Li, L.; Sun, X.; He, Y.;
Gao, L.; Song, Z. Chem. Commun. 2015, 14925.
4.
5.
(a) Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi,
J. H.; Chang, M. H. Org. Lett. 2002, 4, 2025. (b) Overman, L. E.;
Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581. (c) Chavre, S. N.;
Ullapu, P. R.; Min, S. J.; Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S.
Org. Lett. 2009, 11, 3834. (d) Spivey, A. C.; Luca, L.; Bayly, A. R.;
Rzepa, H.S.; White, A. J. P. Org. Lett. 2010, 12, 900. (e) Chen, Z.
H.; Tu, Y. Q.; Zhang, S. Y.; Zhang, F. M. Org. Lett. 2011, 13, 724.
(a) Lee, H. M.; Oberhuber, C. N.; Shair, M. D. J. Am. Chem. Soc.
2008, 130, 16864. (b) Kwon, M. S.; Woo, S. K.; Na, S.W.; Lee, E.
Angew. Chem. Int. Ed. 2008, 47, 1733. (c) Cons, B. D.; Bunt, A. J.;
Bailey, C. D.; Willis, C. L. Org. Lett. 2013, 15, 2046. (d) Fenster, E.;
Fehl, C.; Aube, J. Org. Lett., 2011, 13, 2614. (e) Gesinski, M. R.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2011, 133, 9727. (f)
Manaviazar, S.; Hale, K. J. Angew. Chem., Int. Ed. 2011, 50, 8786.
(g) Bunt, A. J.; Bailey, C. D.; Cons, B. D.; Edwards, S. J.; Elsworth,
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(a) Ghosh, A. K.; Nicponski, D. R. Org Lett. 2011, 13, 4328. (b)
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3699.
6.
7.
(a) Reddy, B. V. S.; Swathi, V.; Swain, M.; Bhadra, M. P.; Sridhar,
B.; Satyanarayana, D.; Jagadeesh, B. Org. Lett. 2014, 16, 6267. (b)
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Righi, P. Tetrahedron 2007, 63, 12763.
8.
9.
General experimental procedure: To a stirred solution of 5-
cyclopropylpent-4-en-1-ol (1 mmol) and aldehyde (1.2 mmol) in
dichloromethane (5 mL) was added HBF4.OEt2 (1 mmol). The
resulting mixture was allowed to stir at 25 oC for the appropriate
time (Table 2). After completion, the reaction mixture was quenched
with water and extracted with ethyl acetate. The organic layer was
dried over Na2SO4 and concentrated in vacuo to give the crude
product, which was purified by column chromatography.

5



Tetrahydropyrans are obtained from aldehyde
and (E)-cyclopropyl alkenol.
It provides the products in good yields with
high selectivity.
It is
a
first example on
a
tandem
vinylcyclopropane
cyclization.
ring
opening/Prins

It proceeds under extremely mild conditions in
short reaction times.