A facile synthesis of aryldihydropyrans using a Sonogashira-selenoetherification strategy

Article abstract of DOI:10.1016/S0040-4039(02)00065-5

A high yielding and convenient synthesis of 2-aryl-2,5-dihydro-2H-pyrans is reported. Sonogashira coupling of 4-pentyn-1-ol and 5-hexyn-2-ol with a range of phenyl and naphthyl bromides affords the appropriate aryl acetylenic alcohols which then undergo r

Full text of DOI:10.1016/S0040-4039(02)00065-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1735–1738
A facile synthesis of aryldihydropyrans using a
Sonogashira–selenoetherification strategy
Margaret A. Brimble,* Gabrielle S. Pavia and Ralph J. Stevenson
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 15 November 2001; accepted 4 January 2002
Abstract—A high yielding and convenient synthesis of 2-aryl-2,5-dihydro-2H-pyrans is reported. Sonogashira coupling of
4-pentyn-1-ol and 5-hexyn-2-ol with a range of phenyl and naphthyl bromides affords the appropriate aryl acetylenic alcohols
which then undergo ready reduction to the corresponding (E)-1-aryl-5-hydroxyalkenes. Subsequent selenoetherification of the
(E)-5-hydroxyalkenes proceeds via a 6-endo-trig pathway cleanly affording the trans-2-aryl-3-phenylselenyltetrahydropyrans.
Finally oxidative elimination of the selenides afforded the 2-aryl-2,5-dihydro-2H-pyrans which are convenient intermediates for
the synthesis of C-aryl glycosides in that they contain a double bond which is available for further oxygenation. © 2002 Elsevier
Science Ltd. All rights reserved.
C-Aryl glycosides are a class of natural product which
have attracted considerable interest due to their ability
to form stable complexes with DNA.1 Molecular recog-
nition involving van der Waals and/or hydrogen bond-
ing interactions between the sugar substituent and the
DNA helix are implicated. Whereas the more common
O-glycosides are susceptible to acidic or enzymatic
hydrolysis, C-glycosides are largely inert towards these
processes. The literature dealing with this subject is
extensive2 and methods available for the synthesis of
aryl C-glycosides fall into two broad categories: (i)
grafting an aryl group onto an appropriately function-
alized carbohydrate or (ii) de novo synthesis of an
aryl-containing carbohydrate.
Methods belonging to the first category dominate the
field and include reactions between carbohydrate C-1
carbocation equivalents and aromatic nucleophiles,3
addition of carbohydrate C-1 carbanions to aryl cation
equivalents4 and palladium-mediated coupling of C-1
substituted stannyl, borane and zinc glycals with aryl
halides.5 To date cycloaddition reactions between aro-
matic aldehydes and silyloxydienyl ethers have consti-
tuted the main approach for the de novo synthesis of
C-aryl glycosides.6 We therefore herein report a novel
approach for the de novo synthesis of C-aryl glycosides
whereby an aryl dihydropyran precursor is assembled
via an electrophile-initiated etherification7 of an aryl
bishomoallylic alcohol. The aryl bishomoallylic alcohol
OH
R
OH
PdCl2(PPh3)2
CuI, Et3N
ArBr
R
+
4
Ar
3
1 R = H
2 R = Me
R
R
OH
O
O
LiAlH4
H2O2, py
PhSeCl
R
Ar
Ar
Ar
5
7
SePh
6
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00065-5

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M. A. Brimble et al. / Tetrahedron Letters 43 (2002) 1735–1738
in turn is readily assembled via Sonogashira coupling of
an acetylenic alcohol with an aromatic bromide fol-
lowed by stereoselective partial reduction to an (E)-
alkene (Scheme 1). Hart et al.8 have reported an
approach to C-aryl glycosides using an electrophile-ini-
tiated cyclization of an unsaturated alcohol, however, a
limiting factor was the need to develop better methods
for the preparation of the olefin cyclization precursors
in order to advance this synthetic strategy. This issue is
addressed in the present work by using a Sonogashira
reaction in tandem with an electrophilic cyclization.
There has been considerable interest in the stereoselec-
tive synthesis of oxygenated heterocyclic rings via the
intermediate formation of a seleniranium ion9 hence, we
opted for the use of selenium as the electrophilic
reagent in the present work. We required that the key
selenoetherification proceeded regioselectively following
a 6-endo-trig mode of cyclization. Although 6-endo-trig
cyclizations are not favored by Baldwin’s rules10 similar
5-endo-trig iodo- and seleno-cyclizations of homoallylic
alcohols have been reported.11 These cyclizations do
not contravene Baldwin’s rules as they are electrophile-
Table 1. The synthesis of aryldihydropyrans using a Sonogashira–selenoetherification strategy

M. A. Brimble et al. / Tetrahedron Letters 43 (2002) 1735–1738
1737
H
H
Ph
Se+
Ar
H
OH
OH
Ar
H
6-endo
5-exo
H
Ar
3
SePh
Ar
O
SePh
O
H
2
H
J2ax,3ax = 11 Hz
H
Scheme 2.
tion observed can be explained by assuming the inter-
mediacy of a partial chair-like transition state (Scheme
2) arising from addition of selenium across the double
bond, followed by attack of the oxygen of the hydroxyl
rather than nucleophile-driven and proceed via a late
transition state. In our case it was reasoned that the
ability of the aryl group to stabilize an electron
deficient benzylic centre should promote cyclization
proceeding via the 6-endo-trig mode leading to the
formation of the tetrahydropyran at the expense of the
competing 5-exo-trig etherification which leads to the
undesired tetrahydrofuran.
1
group from the opposite side. The H NMR spectra
(including 2D) of the selenide-tetrahydropyrans 616 thus
obtained, confirmed that the phenylselenenyl and aryl
groups occupied equatorial positions (J2ax,3ax=11 Hz).
In contrast to these results, use of the isomeric (Z)-
alkenes gave a complex mixture of products. Finally,
oxidative–elimination of the selenides 6 proceeded
regioselectively using 30% hydrogen peroxide and pyri-
dine in THF providing the 2-aryl-2,5-dihydro-2H-
pyrans 7 in good yield.
Early work by Mihailovic et al.12 on the electrochemical
phenylselenoetherification of simple unsaturated alco-
hols suggested that the geometry of the double bond
has a pronounced influence on the regioselectivity of
the ring closure. In particular, electrolysis of (Z)-4-
hexen-1-ol in the presence of diphenyl diselenide
afforded five-membered cyclic ethers whereas in the
case of (E)-4-hexen-1-ol the corresponding six-mem-
bered cyclic ethers were produced. These experimental
results suggested that in our case the use of (E)-
alkenols in the key selenocyclization would also lead to
more of the desired tetrahydropyran product. These
postulations required experimental evidence to support
their claims and are addressed in the work reported
herein.
In conclusion, we have developed a practical, high
yielding synthesis of 2-aryl-2,5-dihydro-2H-pyrans by
union of an acetylenic alcohol with an aromatic bro-
mide by means of a Sonogashira coupling. Subsequent
selenoetherification and oxidative elimination of the
(E)-alkene derived from the initial coupled product
proceeded stereo- and regioselectively forming the 2-
aryl-2,5-dihydro-2H-pyran product cleanly. The key
reactions proceed under mild conditions and offer a
practical method for the synthesis of C-aryl glycosides
by carrying out further oxygenation of these aryl dihy-
dropyrans or by using a more functionalized acetylenic
alcohol as a coupling partner in the initial Sonogashira
reaction.
Sonogashira coupling13 of homopropargylic alcohols
with aryl bromides provides an efficient method for the
synthesis of the (E)-arylhydroxyalkene cyclization pre-
cursors. A series of aryl bromides 3 underwent smooth
Sonogashira reactions with 4-pentyn-1-ol 1 or 5-hexyn-
2-ol 2 using PdCl2(PPh3)2 and CuI as catalysts in
triethylamine (Table 1).14 An excess of the acetylene
(1.5 equiv.) was required to effect complete reaction
and the products were readily purified by flash chro-
matography. The resultant substituted acetylenes 4 then
underwent smooth and clean reduction to the (E)-
alkenols 5 using LiAlH4 in THF. No trace of the
corresponding (Z)-alkenol was observed.
Acknowledgements
Financial assistance from The Royal Society of New
Zealand Marsden Fund is gratefully acknowledged.
References
With the (E)-alkenols 5 in hand, smooth and clean
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hydropyrans 6 was effected in good yield using
phenylselenenyl chloride in dichloromethane.15 None of
the regioisomeric tetrahydrofuran products were
observed. The excellent levels of regio- and stereoselec-
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1
and HRMS data.
15. A representative example of the experimental proce-
dure—tetrahydro-2-naphthyl-3-(phenylselenenyl)-2H-pyran
6g: Phenylselenenyl chloride (0.18 g, 0.94 mmol) was
added to a cooled solution (−78°C) of trans-5-naph-
thylpent-4-en-1-ol 5g (0.10 g, 0.47 mmol) in dichloro-
methane (3 mL) under nitrogen. After 4 h, the reaction
was diluted using dichloromethane (7 mL) and sequen-
tially washed with two portions of saturated sodium
bicarbonate (7 mL). The aqueous fraction was then fur-
ther extracted using three portions of dichloromethane
(10 mL). The organic fractions were combined, washed
with brine and dried over MgSO4. The organic fraction
was reduced under vacuum to yield a white solid. Recrys-
tallization of the crude product from ethyl acetate:hexane
(1:19) afforded the title compound 6g as opaque crystals
(86%).
16. Spectroscopic data for 6g: lH (300 MHz, CDCl3) 1.62–
1.67 (1H, m, H-5A), 1.70–1.84 (2H, m, H-4A, H-5B),
2.22–2.27 (1H, m, H-4B), 3.42 (1H, ddd, J2ax,3ax 11.0,
J3ax,4ax 11.0, J3ax,4eq 3.9 MHz, H-3ax), 3.57 (1H, ddd,
J6ax,6eq 11.6, J6ax,5ax 11.6, J6ax,5eq 2.2, H-6ax), 4.03–4.09
(1H, m, H-6eq), 4.38 (1H, d, J2ax,3ax 10.4 Hz, H-2ax),
6.90–7.70 (12H, m, ArH). lC (300 MHz) 27.9 (CH2, C-4),
32.6 (CH2, C-5), 46.1 (CH, C-3), 68.7 (CH2, C-6), 85.7
(CH, C-2), 125.0 (CH, Ar), 125.7 (CH, Ar), 127.0 (CH,
Ar), 127.4 (CH, Ar), 127.5 (CH, Ar), 127.9 (CH, Ar),
128.0 (CH, Ar), 128.4 (CH, Ar), 133.0 (quat., Ar), 133.3
(quat., Ar), 135.5 (CH, Ar), 137.5 (quat., Ar).
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