Monofluorinated di- and tetrahydropyrans via Prins-type cyclisations

Article abstract of DOI:10.1039/b606121d

The synthesis of a range of fluorinated heterocycles is described via a Lewis acid-mediated Prins-type cyclisation. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606121d

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Monofluorinated di- and tetrahydropyrans via Prins-type cyclisations
a
Adrian P. Dobbs,* Levan Pivnevi, Mark J. Penny, Sa˘sa Martinovic, James N. Iley and
b
a
c
b
´
Peter T. Stephensond
Received (in Cambridge, UK) 2nd May 2006, Accepted 26th May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b606121d
vinylepoxides (see Scheme 1) gave the desired homoallylic alcohols
The synthesis of a range of fluorinated heterocycles is described
in good yield.
via a Lewis acid-mediated Prins-type cyclisation.
Reaction of 2-fluoro-3-buten-1-ol with phenylacetaldehyde and
indium trichloride in a 1 : 1 : 1 molar ratio (as we have previously
reported6) in dichloromethane at room temperature only furnished
a trace of the expected tetrahydropyran by GCMS. After
investigating various molar ratios and the reaction temperature,
it was found that using a molar ratio of alcohol : aldehyde : indium
trichloride 1 : 1.5 : 2 and heating the reaction mixture at reflux
temperature for between 2 and 12 h gave the desired tetrahy-
dropyran in very good yield and as a single diastereoisomer
(Scheme 2).
Although naturally occurring fluorinated organic molecules are
rare, the introduction of fluorine into natural products is currently
the focus of much synthetic interest due to the profound effect that
the fluorine atom may have on the properties of the compound.
Strategically positioned fluorine atom(s) may greatly influence the
biological properties of a compound.1,2 For example, deoxyfluoro-
sugars have been used to probe the mechanism of action of various
enzymes.1 Methods for the preparation of fluorinated sugars and
related heterocycles are currently the focus for considerable
synthetic effort. For example, Linclau et al. have recently reported
the enantioselective synthesis of tetrafluoroethylene-containing
monosaccharides3 and Percy et al. have developed routes to a
range of difluorinated sugar mimetics.4 The search for a rapid and
efficient method for the synthesis of simple monofluorinated
compounds, however, is still ongoing.
Further aldehydes were then investigated in the reaction and all
gave good yields of the fluorinated tetrahydropyran, again as a
single diastereomer in each case.
Entries 1–5 in Table 1 show that the cyclisation proceeds
efficiently for most aldehydes, with the exception of aromatic
aldehydes, where the yield is lower (entries 6 & 7). This observation
is in keeping with previously reported findings on the Prins
cyclisation using indium trichloride.6 Entries 8–1010 show that the
reaction is not limited to using aldehydes as a substrate, and that
epoxides and acetals may also be employed without compromising
The Prins cyclisation is a well-established method for the
preparation of a range of heterocycles, most notably tetrahydro-
pyrans5 and more recently dihydropyrans.6 A range of Lewis acids
have been reported in recent years to promote the Prins reaction
and indeed have been used to incorporate fluoride into the
4-position of tetrahydropyrans.7 We have gained considerable
experience of using indium trichloride6 as a Lewis acid for Prins
cyclisation reactions and embarked on a project to apply this
methodology to the synthesis of fluorinated heterocycles.
Indium trichloride promotes the Prins cyclisation of various
simple and complex homoallylic alcohols and homopropargylic
alcohols to the corresponding pyran.6,8 We reasoned that by
incorporating fluorine into the homoallylic alcohol, it may be
possible to build fluorinated pyrans using the Prins cyclisation.
The method of Hedhli and Baklouti9 appeared ideal for the
preparation of the desired fluorinated homoallylic alcohols.
Reaction of triethylamine trihydrogen fluoride with various
Scheme 2 Synthesis of monofluorinated tetrahydropyrans.
Table 1 Synthesis of simple 2-alkyl-4-chloro-5-fluorotetrahydropyrans
Control % yield
% Yielda,b (no fluorine)c
Entry Aldehyde
1
2
3
4
5
6
7
Phenylacetaldehyde
Hexanal
Cyclohexanecarboxaldehyde 80
2-Ethylbutyraldehyde
Diphenylacetaldehyde
Benzaldehyde
74
75
72
69
79
63
64
44
66
68
57
39
54
4-Nitrobenzaldehyde
Scheme 1 Preparation of monofluorinated homoallylic alcohols.
Alternative substrates
Styrene oxide
p-Methylstyrene oxide
1,1-Dimethoxyhexane
aDepartment of Chemistry, Queen Mary, University of London, Mile
End Road, London, UK E1 4NS. E-mail: A.Dobbs@qmul.ac.uk
bDepartment of Chemistry, The Open University, Walton Hall, Milton
Keynes, UK MK7 6AA
8
9
10
a
49
59
63
55
58
58
All are purified yields and all products gave satisfactory
cDepartment of Chemistry, University of Exeter, Stocker Road, Exeter,
UK EX4 4QD
b
spectroscopic data. Reaction performed at reflux temperature.
c
Reactions not performed at reflux temperature but at room
temperature for the same period of time.
dDiscovery Chemistry, Pfizer Global R&D, Sandwich, Kent, UK
CT13 9NJ
3134 | Chem. Commun., 2006, 3134–3136
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The reaction similarly proceeded efficiently when employing
2-fluoro-2-methyl-3-buten-1-ol (prepared in an identical manner
and in 63% yield from 2-methyl-2-vinyloxirane) and gave only a
single diastereomeric product (see Scheme 3), although it has thus
far been impossible to determine from NMR studies which
conformation of the methyl group and fluorine atom has been
obtained. All crystallisation attempts have failed.
Fig. 1 Relative stereochemistry of the fluorinated tetrahydropyrans.
Turning our attention to alternative Lewis acid promotors
(Scheme 4 and Table 2), it was found that both trimethylsilyl
triflate and indium tribromide were also efficient promotors for the
reaction. Despite its wide use as a Lewis acid, including for Prins-
type reactions, to the best of our knowledge, this is the first
example of the triflate anion becoming trapped and isolated in the
product of a Prins cyclisation reaction.{ It is interesting to note
that the reaction with indium tribromide required the use of
dibromomethane as solvent, since employing dichloromethane led
to a mixture of 4-chlorinated and brominated products, pre-
sumably by halogen exchange from the Lewis acid with the
solvent.12
Scheme 3
Interestingly, we observed a trace (ca. 5%) of what appeared to
be a mixture of eliminated products as a minor product in entries
1–3 in Table 2. Therefore we decided to investigate further the
possibility of eliminating the C(4) group to give a dihydropyran.
No elimination products were observed when using either chloride
or bromide at the C(4) position, irrespective of the base employed.
When the triflate group was present, however, elimination
occurred in reasonable to good yields, giving a mixture of the
two possible dihydropyran products as an inseparable mixture.{13
Both sodium hydride and LHMDS showed a preference for
forming A (Scheme 5 and Table 3), while potassium tert-butoxide
showed a preference for forming the isomeric dihydropyran B, for
reasons we are still examining.
the yield significantly (there is literature precedent for epoxides
generally being lower yielding in Prins reactions compared to
aldehydes). Both epoxides and acetals gave single diastereomeric
tetrahydropyran products.
The reaction is believed to proceed by the accepted Prins
cyclisation mechanism, with the formation of a carbocation
adjacent to the fluorine atom. It does not appear that the presence
of the highly electronegative fluorine atom has any bearing on the
outcome of the reaction, since yields are consistent (within
experimental error) with those obtained in the absence of fluorine,
as indicated by the control results in Table 1. Interesting, however,
was the requirement to perform the reaction in dichloromethane at
reflux temperature in order to obtain the fluorinated tetrahydro-
pyrans, yet it would proceed rapidly at room temperature in the
absence of fluorine.
Given the success of the Prins reaction in the preparation of
monofluorinated tetrahydropyrans, the formation of difluorinated
tetrahydropyrans was examined. 3,3-Difluoronon-1-en-4-ol was
prepared from 1-bromo-1,1-difluoroprop-3-ene in the presence of
indium powder in almost quantitative yield. The Prins cyclisation
was attempted using both cyclohexanecarboxaldehyde and the
more reactive ethyl glyoxylate (Scheme 6). Unfortunately, no
product was obtained, using either indium trichloride or
trimethylsilyl triflate, presumably now because of the instability
of the intermediate carbocation due to the presence of the two
adjacent fluorine atoms. Work is currently directed at overcoming
this problem and will be reported in due course.
The relative configuration of the substituents was obtained by
nOe studies, which clearly showed that the product in each case
was the all cis configuration, with the fluorine adopting an axial
orientation at the C-5 position (see Fig. 1).11 Similar diastereo-
selectivity was observed for each of the fluorinated products
obtained.
In summary, we have reported the first example of a Prins
cyclisation reaction incorporating fluorine at the position a to the
intermediate carbocation generated and demonstrated this as a
synthetically useful route to fluorinated tetrahydropyrans in good
Scheme 4 Alternative Lewis acid promoters.
Table 2 Effect of employing different Lewis acids in the Prins reaction of simple aldehydes with 2-fluoro-3-buten-1-ol
Entry
Aldehyde
Lewis acid/conditions
X in product
% Yielda
1
2
3
4
5
6
a
Phenylacetaldehyde
Hexanal
Cyclohexanecarboxaldehyde
Hexanal
Hexanal
TMSOTf/278 uC, DCM
TMSOTf/278 uC, DCM
TMSOTf/278 uC, DCM
InBr3/DCM, rt to reflux
InBr3/CH2Br2, rt to reflux
InBr3/CH2Br2, rt to reflux
b
OTf
OTf
OTf
Br : Clb (1.2 : 1)
Br
Br
36
48
56
—
63
66
Cyclohexanecarboxaldehyde
All are purified yields and all products gave satisfactory spectroscopic data. Two compounds inseparable by column chromatography, ratio
obtained from GC-MS.
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2-substituted-4-halo-5-fluorotetrahydropyrans involved identical molar
ratio equivalents of reagents being added in the same order, but with the
addition occurring at room temperature (rather than 278 uC) and the
reaction subsequently being heated to reflux temperature for 5–15 h, as
indicated by consumption of the starting material.
{ Representative procedure for the triflate elimination from substituted
4-trifluoromethanesulfonyl-5-fluorotetrahydropyrans: to a solution of the
4-triflate-substituted tetrahydropyran (range 1–3 mmol, 1 eq.) in dry THF
(5 ml) under a nitrogen atmosphere was added the base either at 0 uC
(NaH) or at room temperature (KOtBu and LHMDS, equivalents in
Table 3). The reaction was stirred at room temperature for variable periods
of time, until no further change was observed by t.l.c. (indicative times for
each base given in Table 3). The reaction was quenched with water (10 ml)
and stirred for a further 20 mins. The aqueous solution was extracted with
diethyl ether (3 6 15 ml), the organic phases combined, dried (MgSO4),
filtered and concentrated in vacuo to give the crude product, which was
purified by flash column chromatography (typically 10% ethyl acetate in
petroleum ether (40–60 fraction)).
Scheme 5 Base-mediated triflate elimination from tetrahydropyrans.
Table 3 Bases and conditions used to promote triflate elimination
from fluorinated tetrahydropyrans
Entry
Base and Conditions
% Yield
Ratio A : B
1
2
3
KOtBu (3 eq.), rt, 3 h
NaH (5 eq.), 0 uC to rt, 18 h
LHMDS (3 eq.), THF, rt to
reflux, 3 days
45
63
58
1 : 2
9 : 1
2.4 : 1
1 For an excellent recent treatment of the emerging role of fluorine in
synthetic, medicinal, pharmaceutical and biological systems, see the
Special Issue: Fluorine in the Life Sciences, ChemBioChem, 2004, 4,
557–726.
2 C. Isanbor and D. O’Hagan, J. Fluorine Chem., 2006, 127, 303.
3 A. J. Boydell, V. Vinader and B. Linclau, Angew. Chem., Int. Ed., 2004,
43, 5677.
4 L. R. Cox, G. A. DeBoos, J. J. Fullbrook, J. M. Percy and N. Spencer,
Tetrahedron: Asymmetry, 2005, 16, 347; C. Audouard, J. Fawcett,
G. A. Griffiths, J. M. Percy, S. Pintat and C. A. Smith, Org. Biomol.
Chem., 2004, 2, 528; G. A. Griffith, J. M. Percy, S. Pintat, C. A. Smith,
N. Spencer and E. Uneyama, Org. Biomol. Chem., 2005, 3, 2701.
5 For an excellent recent review on the formation of tetrahydropyrans via
Prins and related reactions: P. A. Clarke and S. Santos, Eur. J. Org.
Chem., 2006, 2045.
´
6 A. P. Dobbs and S. Martinovic, Tetrahedron Lett., 2002, 43, 7055.
7 L. D. M. Lolkema, H. Hiemstra, C. Semeyn and W. N. Speckamp,
Tetrahedron, 1994, 50, 7115; J.-I. Yoshida, M. Sugawara and N. Kise,
Tetrahedron Lett., 1996, 37, 3157; J.-I. Yoshida, M. Sugawara,
M. Tatsumi and N. Kise, J. Org. Chem., 1998, 63, 5950; J.-I. Yoshida
and K. Nishiwaki, J. Chem. Soc., Dalton Trans., 1998, 2589; E. H. Al-
Mutairi, S. R. Crosby, J. Darzi, J. R. Harding, R. A. Hughes,
C. D. King, T. J. Simpson, R. W. Smith and C. L. Willis, Chem.
Commun., 2001, 835; J. J. Jaber, K. Mitsui and S. D. Rychnovsky,
J. Org. Chem., 2001, 66, 4679.
8 Examples of the use of InCl3 in Prins-type reactions: (a) J. Yang and
C.-J. Li, Synlett, 1999, 717; (b) G. S. Viswanathan, J. Yang and C.-J. Li,
Org. Lett., 1999, 1, 993; (c) Y. S. Cho, H. Y. Kim, J. H. Cha, A. N. Pae,
H. Y. Koh, J. H. Choi and M. H. Chang, Org. Lett., 2002, 4, 2025; (d)
X.-F. Yang, J. T. Mague and C.-J. Li, J. Org. Chem., 2001, 66, 739; (e)
Scheme 6 Attempted preparation of difluorinated tetrahydropyrans.
yields. A range of anions may be incorporated during the
cyclisation process, some of which may be subsequently eliminated
to give fluorinated dihydropyrans. We are currently exploring this
methodology for the preparation of more complex tetrahydropyr-
ans in enantiopure form and their subsequent elaboration to
fluorinated sugur analogues.
We thank The Open University (studentship to LP), Queen
Mary, University of London and Pfizer (EPSRC DTA (originally
held at University of Exeter, prior to closure of the Department of
Chemistry, July 2005) and CASE awards to MJP) and Universities
UK (ORS award to SM) for funding.
´
A. P. Dobbs, S. J. J. Guesne´, S. Martinovic, S. J. Coles and
M. B. Hursthouse, J. Org. Chem., 2003, 68, 7880.
9 A. Hedhli and A. Baklouti, J. Fluorine Chem., 1995, 70, 141.
10 Previous use of epoxides: ref. 6, ref. 8e and J. Li and C.-J. Li,
Tetrahedron Lett., 2001, 42, 793–796; previous use of acetals:
unpublished results in our own work, S. J. J. Guesne´, PhD Thesis,
University of Exeter, 2005 and T. C. Gahman and L. E. Overman,
Tetrahedron, 2002, 58, 6473.
Notes and references
11 Precedent for fluorine demonstrating an axial preference at this position
in related systems: D. O’Hagan and H. S. Rzepa, Chem. Commun.,
1997, 645; C. R. S. Briggs, M. J. Allen, D. O’Hagan, D. J. Tozer,
A. M. Z. Slawin, A. E. Goeta and J. A. K. Howard, Org. Biomol.
Chem., 2004, 2, 732; A. Sun, D. C. Lankin, K. Hardcastle and
J. P. Snyder, Chem.–Eur. J., 2005, 11, 1579 and many examples in ref. 1.
12 Halogen exchange of this type is not unprecedented: P. O. Miranda,
D. D. D´ıaz, J. I. Padro´n, J. Barmejo and V. S. Mart´ın, Org. Lett., 2003,
5, 1979.
{ Representative procedure for the formation of 2-substituted-4-trifluoro-
methanesulfonyl-5-fluorotetrahydropyrans: a solution of the aldehyde (2 eq.,
in range 5–10 mmol) in dry dichloromethane (15 ml) was cooled to 278 uC
and treated with trimethylsilyl trifluoromethanesulfonate (2.5 eq.) and
stirred for 30 mins at this temperature. 2-Fluorobut-3-en-1-ol (1 eq.) was
added and the reaction stirred for 3–4 h at 278 uC. The reaction mixture
was then warmed to room temperature over 16 h before adding water
(20 ml). The two layers were separated and the aqueous layer extracted
with dichloromethane. The combined dichloromethane layers were dried
(MgSO4) and concentrated in vacuo to give the crude product, which was
purified by flash column chromatography. The method to prepare
13 Only previous example of triflate elimination from a glycoside:
A. E. Nemr and T. Tsuchiya, Carbohydr. Res., 1997, 303, 267.
3136 | Chem. Commun., 2006, 3134–3136
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