HBF4·OEt2 as a versatile reagent for the Hosomi-Sakurai allylation and Prins cyclization: one-pot synthesis of symmetrical 4-fluorotetrahydropyrans

Article abstract of DOI:10.1016/j.tetlet.2010.03.082

The synthesis of symmetrical 2,6-disubstituted 4-fluorotetrahydropyran derivatives has been achieved using HBF₄·OEt₂ via a tandem allylation and Prins cyclization. This is a highly efficient and diastereoselective approach for the preparation of 4-fluorotetrahydropyrans in a single step. The use of readily available and easy to handle reagent HBF₄·OEt₂ makes this method simple, convenient and practical.

Full text of DOI:10.1016/j.tetlet.2010.03.082

Tetrahedron Letters 51 (2010) 2872–2874
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HBF4ÁOEt2 as a versatile reagent for the Hosomi–Sakurai allylation and Prins
cyclization: one-pot synthesis of symmetrical 4-fluorotetrahydropyrans
*
J. S. Yadav , B. V. Subba Reddy, B. Anusha, U. V. Subba Reddy, V. V. Bhadra Reddy
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:
The synthesis of symmetrical 2,6-disubstituted 4-fluorotetrahydropyran derivatives has been achieved
using HBF4ÁOEt2 via a tandem allylation and Prins cyclization. This is a highly efficient and diastereose-
lective approach for the preparation of 4-fluorotetrahydropyrans in a single step. The use of readily avail-
able and easy to handle reagent HBF4ÁOEt2 makes this method simple, convenient and practical.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 January 2010
Revised 19 March 2010
Accepted 20 March 2010
Available online 25 March 2010
Keywords:
Prins cyclization
Allyltrimethylsilane
HBF4ÁOEt2
4-Fluorotetrahydropyrans
Diastereoselective
The synthesis of fluorine-containing molecules has received
considerable attention in pharmaceutical industry.1 The introduc-
tion of fluorine onto organic molecule often increases the stability
and also alters the lipophilicity and reactivity.1 Therefore, we have
attempted the synthesis of 4-fluoro-substituted tetrahydropyrans
as they are structural components in one of our research projects
in bioorganic and medicinal chemistry. The tetrahydropyran ring
is a core structure in various natural products such as avermectins,
aplysiatoxins, oscillatoxins, latrunculins, talaromycins and
acutiphycins and is also a part of the backbone of several important
carbohydrates, polyether antibiotics and marine macrolides.2 Tet-
rahydropyran derivatives are usually prepared via Prins-cycliza-
tion using acid catalysis.3 Recently, several efforts have been
made to introduce various substituents at C-4 position of the pyran
ring using various nucleophiles such as halides, hydroxyls, organic
nitriles, azide, thiocyanate and thiols.4–6 Only a few methods have
been reported for the synthesis of fluorinated tetrahydropyrans.7
In most cases, the products are formed as a mixture of 4-fluoropy-
rans and 4-hydroxypyrans approximately in 1:1 ratio. Subse-
quently, HF/ionic liquid system has also been reported for the
synthesis of fluorinated tetrahydropyran derivatives.8 However,
to the best of our knowledge, there have been no reports on the
synthesis of symmetrical 2,6-disubstituted 4-fluorotetrahydropy-
ran derivatives from aldehyde and allyltrimethylsilane using
HBF4ÁOEt2.
In continuation of our research programme on the Prins cycliza-
tion in the total synthesis of biologically active natural products,9
we herein report a one-pot method for the synthesis of symmetri-
cal 2,6-disubstituted 4-fluorotetrahydropyrans from aldehydes
and allyltrimethylsilane by means of a tandem allylation and
Prins-cyclization using a ethereal solution of tetrafluoroboric acid.
Initially, we have attempted the coupling of benzaldehyde
(2.2 equiv) with allyltrimethylsilane (1.0 equiv) using HBF4ÁOEt2
(1.0 equiv) in dichloromethane. The reaction went to completion
within 25 min at room temperature and the corresponding 4-flu-
oro-2,6-diphenyl-tetrahydro-2H-pyran 3a was isolated in 80%
yield with all cis-selectivity (Scheme 1).
This result encouraged us to extend this process to various alde-
hydes. Interestingly, aryl aldehydes such as 4-chloro-, 2-nitro-, 4-
nitro-, 4-methyl- and 3-nitrobenzaldehydes underwent smooth
coupling with allyltrimethylsilane to give the corresponding 2,6-
diaryl-4-fluorotetrahydropyrans in high yields (Table 1, entries
b–f). This method is also effective for sterically hindered substrate,
for example, 2-naphthaldehyde (Table 1, entry g). Next, we exam-
ined the reaction of allyltrimethylsilane with aliphatic aldehydes
under similar conditions. For example, the treatment of cyclohex-
F
.
CHO
(1.0 eq)
HBF4 OEt2
SiMe3
+
DCM, rt
Ph
O
Ph
1a
2a
3a
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. A tandem allylation and Prins cyclization of benzaldehyde.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.082

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2872–2874
2873
Table 1
Other aliphatic aldehydes such as 3-phenylpropanaldehyde,
2-methylbutyraldehyde, n-hexanaldehyde, 4-(benzyloxy)butanal,
n-butyraldehyde and n-pentanaldehyde also underwent smooth
coupling with allyltrimethylsilane to give the corresponding 2,6-
dialkyl-4-fluorotetrahydropyrans in high yields (Table 1, entries
h–n). However, no reaction was observed in the absence of
HBF4.OEt2 even after an extended reaction time (15 h). As solvent,
dichloromethane gave the best result. In all cases, the reactions
proceeded rapidly at room temperature under mild conditions.
The reactions were clean and the products were obtained in excel-
lent yields and with all cis-diastereoselectivity as determined from
the NMR spectra of the crude products. Only a single diastereoiso-
mer was obtained from each reaction. The formation of the prod-
ucts may be explained by initial allylation and a subsequent
hemi-acetal formation followed by Prins-type cyclization and fluo-
rination (Scheme 3). A rationale for the all cis-selectivity involves
the formation of an (E)-oxocarbenium ion via a chair-like transition
state, which has increased stability relative to the open oxocarbe-
nium ion due to delocalization. The optimal geometry for this delo-
calization places the hydrogen atom at C4 in a pseudo-axial
position, which favours equatorial attack of the nucleophile.10
The scope and generality of this process are illustrated with re-
spect to various aldehydes and the results are presented in Table
1.11 As shown in Table 1, this method works well with both elec-
tron-donating and electron withdrawing aldehydes.
One-pot synthesis of symmetrical 4-fluorotetrahydropyrans using HBF4ÁOEt2
Entry Aldehyde
Product (3)a
Yieldb Time
(%)
(min)
F
CHO
a
80
25
Ph
Cl
O
Ph
F
CHO
b
75
78
82
30
35
30
O
Cl
Cl
F
CHO
NO2
NO2
NO2
c
O
F
CHO
CHO
d
O
O2N
O2N
NO2
F
e
70
40
O
Me
Next, we attempted the coupling of 1 equiv of benzaldehyde
with 1.2 equiv of 3-buten-1-ol in the presence of 1 equiv of
HBF4ÁOEt2. Interestingly, the reaction was complete in 20 min
and the corresponding 2-phenyl-4-fluoro-tetrahydropyran in 76%
yield with cis-selectivity (Scheme 4).
In this way, we have extended our method to prepare unsym-
metrical 4-fuorotetrahydropyran derivatives (Table 2).
In all cases, 4-fluorotetrahydropyrans were obtained exclu-
sively without the formation of hydroxypyrans under present reac-
tion conditions.
Me
Me
F
O2N
CHO
CHO
f
75
75
36
35
O2N
NO2
O
F
g
O
F
In summary, we have developed a direct one-pot method for
the preparation of 4-fluorotetrahydropyrans by means of a tandem
allylation and Prins-cyclization using HBF4ÁOEt2. This method of-
fers significant advantages including mild conditions, operational
CHO
h
i
75
70
78
75
85
75
70
30
45
45
50
35
55
50
Ph
Ph
O
Ph
F
CHO
CHO
C6H11
O
F
C6H11
F
j
.
HBF4 OEt2
CHO
SiMe3
O
+
O
F
DCM, rt
3i
k
l
CHO
CHO
Scheme 2. Preparation of 2,6-dicyclohexyl-4-fluoro-tetrahydropyran 3i.
C5H11
BnO
O
C5H11
F
(+)
O
(+)
O
BnO
.
O
H
OBn
HBF4 OEt2
H
SiMe3
O
+
+
F
R
H
R
H
H
OH
R
R
..
m
n
CHO
C3H7
C4H9
O
F
C3H7
(+)
OH
H
R
OH
CHO
(+)
R
O
(+)
R
O
R
O
C4H9
R
R
O
H
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
a
b
F
F(-)
(+)
R
O
R
anecarboxaldehyde with allyltrimethylsilane in the presence of
HBF4ÁOEt2 gave the 2,6-dicyclohexyl-4-fluoro tetrahydro-2H-pyran
3i in 70% yield (Scheme 2).
R
O
R
Scheme 3. A plausible reaction mechanism.

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2872–2874
F
References and notes
1. (a) Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y., Eds.;
Kodansha/Elsevier Biomedical Press: Tokyo, Amsterdam-New York-Oxford,
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Welch, J. T., Eds.; ACS Symp. Ser. No. 639; American Chemical Society:
Washington, DC, 1996.; (c) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127,
303; (d) Bégué, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992; (e)
Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013; (f) Böhm, H.-J.; Banner, D.; Bendels,
S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem
2004, 5, 637. and references cited therein.
CHO
.
HBF4 OEt2
O
+
HO
DCM, rt
Scheme 4. Preparation of 2-phenyl-4-fluoro-tetrahydropyran.
2. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996.
3. (a) Prins, H. J. Chem. Weekbl. 1919, 16, 1072; (b) Arundale, E.; Mikeska, L. A.
Chem. Rev. 1952, 51, 505; (c) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661;
(d) Chandrasekhar, S.; Reddy, B. V. S. Synlett 1998, 851; (e) Clarisse, O.;
Mustapha, K.; Stephane, G.; Michele, P. B. Tetrahedron 2010, 66, 413.
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Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912; (c) Epstein, O. L.; Tomislav
Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480; (d) Yadav, J. S.; Subba Reddy, B. V.;
Maity, T.; Narayana Kumar, G. G. K. S. Tetrahedron Lett. 2007, 48, 7155; (e)
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J. Tetrahedron Lett. 2007, 48, 5177; (h) Kailas, B. S.; Fei, D.; Michael, P. J.
Tetrahedron Lett. 2006, 47, 939.
Table 2
Preparation of unsymmetrical 4-fluorotetrahydropyrans using HBF4ÁOEt2
Entry Aldehyde
Product (4)a
Yieldb (%) Time (min)
F
CHO
a
76
78
20
25
Ph
O
F
CHO
b
O
Cl
5. (a) Wei, Z. Y.; Li, J. S.; Wang, D.; Chan, T. H. Tetrahedron Lett. 1987, 28, 3441; (b)
Perron, F.; Albizati, K. F. J. Org. Chem. 1987, 52, 4130; (c) Wei, Z. Y.; Wang, D.; Li,
J. S.; Chan, T. H. J. Org. Chem. 1989, 54, 5768; (d) Coppi, L.; Ricci, A.; Taddei, M. J.
Org. Chem. 1988, 53, 913; (e) Viswanathan, G. S.; Yang, J.; Li, C. J. Org. Lett. 1999,
1, 993.
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Kumar, G. G. K. S.; Reddy, M. G. Tetrahedron Lett. 2007, 48, 4903.
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D.; Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835; (c) Jaber,
J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679.
8. (a) Yuichiro, K.; Shinsuke, I.; Toshio, F. Eur. J. Org. Chem. 2009, 103; (b) Shinsuke,
I.; Yuta, D.; Yuichiro, K.; Toshio, F. Chem. Commun. 2009, 2932.
9. (a) Yadav, J. S.; Padmavani, B.; Reddy, B. V. S.; Venugopal, C.; Rao, A. B. Synlett
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R. Tetrahedron Lett. 2008, 49, 5427; (c) Yadav, J. S.; Thrimurtulu, N.; Gayathri, K.
U.; Reddy, B. V. S.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 6617; (d) Yadav, J. S.;
Lakshmi, K. A.; Reddy, N. M.; Prasad, A. R.; Reddy, B. V. S. Tetrahedron 2010, 44,
334; (e) Yadav, J. S.; Narayana Kumar, G. G. K. S. Tetrahedron 2010, 66, 480.
10. (a) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002, 124, 4960; (b)
Ramesh, J.; Rychnovsky, S. D. Org. Lett. 2006, 8, 2175; (c) Biermann, U.; Lutzen,
A.; Metzger, J. O. Eur. J. Org. Chem. 2006, 2631.
Cl
F
O2N
CHO
c
75
72
65
35
30
35
O2N
O
F
MeO
CHO
OMe
d
e
MeO
O
OMe
F
CHO
O
F
CHO
f
68
74
40
45
11. General procedure:
A mixture of aldehyde (2.2 mmol), allyltrimethylsilane
O
F
(1 mmol) and HBF4ÁOEt2 complex (1 mmol) in dichloromethane (5 mL) was
stirred at 23 °C for the specified amount of time (Table 1). After completion of
the reaction as indicated by TLC, the reaction was quenched with saturated
NaHCO3 solution and 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, 100–200 mesh, ethyl
acetate–hexane, 0.5:9.5) gave the pure 4-fluorotetrahydropyran. The products
thus obtained were characterized by IR, NMR and mass spectroscopy. Spectral
data for selected compounds: Compound 3a: 4-fluoro-2,6-diphenyl-tetrahydro-
CHO
g
O
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
a
b
2H-pyran (Table 1): Light yellow solid, mp 68–70 °C; IR (KBr):
m 3030, 2922,
2851, 1494, 1451, 1059, 754, 695 cmÀ1 1H NMR (CDCl3, 500 MHz): d 7.42–7.21
;
(m, 10H), 5.02–4.85 (m, 1H), 4.52 (d, J = 11.7 Hz, 2H), 2.45–2.39 (m, 2H), 1.83–
1.74 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 141.2, 128.3, 127.5, 125.7, 90.5, 88.2,
40.3. ESI-MS: m/z: 279 (M+Na)+. HRMS (ESI) [M+Na] calcd for C17H17OFNa:
279.1161, found: 279.1164. Compound 3g: 4-fluoro-2,6-di(naphthalen-2-yl)-
simplicity of the reagent, no formation of by-products and short
reaction times. This method provides an easy access to 4-fluoro-
tetrahydropyrans with diverse chemical structures for biological
evaluation.
tetrahydro-2H-pyran (Table 1): Colourless solid, mp 164–168 °C; IR (KBr):
m
2922, 2852, 1463, 1367, 1067, 818, 747 cmÀ1 1H NMR (CDCl3, 300 MHz): d
;
8.80–7.76 (m, 14H), 5.18–4.91 (m, 1H), 4.76 (d, J = 11.5 Hz, 2H), 2.60–2.51 (m,
2H), 2.00–1.87 (m, 2H); ESI-MS: m/z: 357 (M+H)+, 374 (M+NH4)+, 379 (M+Na)+.
HRMS (ESI) [M+Na] calcd for C25H21OFNa: 379.1474, found: 379.1479.
Acknowledgements
Compound
(Table 1): White solid, mp 58–60 °C; IR (KBr):
1096, 999,736, 697 cmÀ1 1H NMR (CDCl3, 300 MHz): d 7.35–7.18 (m, 10H),
3l:
2,6-bis(3-(benzyloxy)propyl)-4-fluoro-tetrahydro-2H-pyran
m
2922, 2852, 1453, 1364,
;
U.V.S.R. thanks UGC and V.V.B.R. thanks CSIR, New Delhi for the
award of fellowship. We also thank DST for the financial assistance
under J. C. Bose fellowship scheme.
4.69–4.40 (m, 5H), 3.49–3.37 (m, 4H), 3.23–3.13 (m, 2H), 1.83–1.52 (m, 12H);
ESI-MS: m/z: 401 (M+H)+, 423 (M+Na)+. HRMS (ESI) [M+Na] calcd for
C25H33O3FNa: 423.2311, found: 423.2317.