Tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization between vinyl ether boronates and vinyl halides: A concise approach to polysubstituted furans

Article abstract of DOI:10.1021/ol4014574

Polysubstituted 2-(ω-hydroxyalkyl)furans were prepared by tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization starting from appropriately substituted 3-haloallylic alcohols and dihydrofuran-, dihydropyran- or glycal-derived pinacol boronates.

Full text of DOI:10.1021/ol4014574

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Tandem Suzuki-Miyaura Coupling/Acid-
Catalyzed Cyclization between Vinyl Ether
Boronates and Vinyl Halides: A Concise
Approach to Polysubstituted Furans
Alexey N. Butkevich,† Lieven Meerpoel,‡ Ian Stansfield,§ Patrick Angibaud,§
Andrei Corbu,† and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231
Paris Cedex 05, France, Janssen Research & Development, Division of Janssen-Cilag
S.A., Oncology and Medicinal Chemistry, Campus de Maigremont, 27106 Val de Reuil,
Cedex, France, and Janssen Research & Development, Division of Janssen
Pharmaceutica NV, Turnhoutsweg 30, 2340 Beerse, Belgium
janine.cossy@espci.fr
Received May 23, 2013
ABSTRACT
Polysubstituted 2-(ω-hydroxyalkyl)furans were prepared by tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization starting from
appropriately substituted 3-haloallylic alcohols and dihydrofuran-, dihydropyran- or glycal-derived pinacol boronates.
The furan ring is a ubiquitous structural motif in many
classes of natural products such as pheromones,1 terpenes2
and alkaloids (e.g., selaginoidine3a, nakadomarin A3b), as
well as in numerous synthetic compounds. In a recent
compilation of pharmacologically active furans,4 it has
been demonstrated that a variety of furans, fused furans
and furanones exhibit antimicrobial,5 anti-inflammatory,
antiarrhythmic or antihypertensive activities. Two among
the most potent hallucinogenic compounds, salvinorin A6
(neoclerodane diterpenoid and κ-opioid receptor agonist
from Salvia divinorum) and bromo-DragonFLY7 (syn-
thetic 5-HT2 serotonin receptor agonist), contain a furan
ring. Furanosteroid viridin,8 the naturally occurring fra-
grance rosefuran,9 the phytotoxin perilla ketone10 and
unsaturated ketones rehmanones AÀC,11 all of which are
diversely substituted furans, demonstrate the great variety
of furan-derived natural products.
Several recent reports illustrated the synthetic utility
of 2-(ω-hydroxyalkyl)furan building blocks.12À14 These
(6) Ortega, A.; Blount, J. F.; Manchand, P. S. J. Chem. Soc., Perkin
Trans. 1 1982, 2505–2508.
(7) Parker, M. A.; Marona-Lewicka, D.; Lucaites, V. L.; Nelson,
D. L.; Nichols, D. E. J. Med. Chem. 1998, 41, 5148–5149.
(8) Grove, J. F.; McCloskey, P.; Moffatt, J. S. J. Chem. Soc. C 1966, 743.
(9) Buechi, G.; Kovats, E.; Enggist, P.; Uhde, G. Org. Lett. 1968, 33,
1227–1229.
† ESPCI ParisTech.
‡ Janssen Research & Development, Janssen Pharmaceutica N.V.
§ Janssen Research & Development, Oncology and Medicinal Chemistry,
Campus de Maigremont.
(1) Bosma, W. B.; Bartelt, R. J.; Momany, F. A. J. Org. Chem. 2006,
71, 4748–4758.
(10) Matsuura, T. Bull. Chem. Soc. Jpn. 1957, 30, 430–431.
(11) Quiroz-Florentino, H.; Aguilar, R.; Santoyo, B. M.; Dı
ꢀ
~
´
n, J.; de la Torre, M. C.; Ortego, F.; Castanera, P.;
(2) Lopez-Olguı
´
Rodrıguez, B. Phytochemistry 1999, 50, 749–753.
´
az, F.;
Tamariz, J. Synthesis 2008, 1023–1028.
(3) (a) Panichanun, S.; Bick, I. R. C. Tetrahedron 1984, 40, 2685–
2689. (b) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org.
Chem. 1997, 62, 9236–9239.
(4) Banerjee, R.; HKS, K.; Banerjee, M. Int. J. Rev. Life Sci. 2012, 2,
7–16.
(12) (a) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.;
Hoarau, C. Org. Lett. 2004, 6, 3861–3863. (b) Wu, B.; Feast, G. C.;
Thompson, A. L.; Robertson, J. J. Org. Chem. 2012, 77, 10623–10630.
(13) Zhu, L.; Song, L.; Tong, R. Org. Lett. 2012, 14, 5892–5895.
(14) Palmer, L. I.; de Alaniz, J. R. Org. Lett. 2013, 15, 476–479.
(5) Miura, K.; Reckendorf, H. K. Prog. Med. Chem. 1967, 5, 320–381.
r
10.1021/ol4014574
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compounds have served as starting materials for the
preparation of spiroacetal natural products,12 cis-fused
bicyclic ethers13 by a tandem Achmatowicz reaction/
spiroacetalization approach, and spirocyclic ethers by
Piancatelli rearrangement.14 2-(ω-Hydroxyalkyl)furans
are generally prepared by alkylation15 or acylation16 of
2-lithiofurans or by addition of organolithium reagents
to furfural.17 In addition, furans with a polyhydroxylated
Employing the conditions optimized for the cross-
coupling of aryl bromides and aryl iodides [Pd(dppf)Cl2
(2 mol %), NaOH (2 equiv), dioxane/H2O (4:1), microwave
irradiation (MW), 100 °C, 10 min followed by pTsOH
(2.2 equiv), rt, 10 min] to a panel of subsituted 3-bromo-
or 3-iodoallylic alcohols, a series of polysubstituted 2-(ω-
hydroxyalkyl)furans were successfully prepared in moder-
ate to excellent yields (Table 1).23
sidechain can beconvenientlysynthesizedusingtheGarcıa
´
18
ꢀ
Gonzalez reaction. Allylation of dienol carbonates fol-
lowed by a Cope rearrangement/reduction/dehydration
sequence, recently proposed by our group, leads to a
variety of polysubstituted furans.19 A number of metal-
catalyzed furan syntheses have been developed using Au-,
Hg-, Ir-, Rh-, Ru-, Pd- and Cu-catalyzed transformations
of suitably substituted alkynes, allenes and cyclopropenes.20
Strong base-catalyzed21 and oxidative22 cyclizations of
2-penten-4-yn-1-ols can also lead to polysubstituted fur-
ans, and acidic treatment of γ-hydroxy-R,β-unsaturated
ketones has been reported to induce furan ring closure
under mild conditions.23
Table 1. Preparation of Furans 13À23
Recently, we have reported a rapid and high-yielding
preparation of spiroacetals based on a tandem Suzuki-
Miyaura/acid-catalyzed spiroacetalization.24 Herein, we dis-
close the outcome of a process involving (Z)-3-haloallylic
alcohols instead of 2-halobenzylic alcohols. Upon in situ
acidic treatement of the Suzuki-Miyaura coupling prod-
ucts, substituted furans were formed instead of the ex-
pected spiroacetals (Scheme 1).
Scheme 1. Tandem Suzuki-Miyaura Coupling/Acid-catalyzed
Cyclization
a Yield increased to 34% when the cross-coupling was performed
under anhydrous conditions (MeCN, 2 equiv Cs2CO3); 3 equiv of TsOH
was used for cyclization.
The halogenated allylic alcohols were prepared accord-
ing to literature procedures.25 From a reactivity stand-
point, there was no difference between bromo- and
iodoalkenes under the Suzuki-Miyaura coupling condi-
tions, so the substrates were chosen according to their ease
of access. The alcohols 3À12 were treated with boronate 1
or 2 under the previously described conditions.24 The cou-
pling with dihydrofuranyl boronate 1 (Table 1, entry 1)
suffered from significantly lower yield because of the
sensitivity of the starting boronate and the cross-coupling
intermediate. The yields with boronate 2 were generally
good to excellent for both 3-bromo- and 3-iodoallylic
alcohols. 2,3-, 2,4-, 2,5-disubstitued furans (Table 1,
entries 1À4), 2,3,4- and 2,3,5-trisubstituted (Table 1,
(15) (a) Stevens, K.; Madder, A. Nucleic Acids Res. 2009, 37, 1555–1565.
(b) Craft, D. T.; Gung, B. W. Tetrahedron Lett. 2008, 49, 5931–5934.
(16) (a) Tofi, M.; Montagnon, T.; Georgiou, T.; Vassilikogiannakis,
G. Org. Biomol. Chem. 2007, 5, 772–777. (b) Nicolaou, K. C.; Aversa,
R. J.; Jin, J.; Rivas, F. J. Am. Chem. Soc. 2010, 132, 6855–6861.
(17) (a) Princival, J. L.; de Barros, S. M. G.; Comasseto, J. V.; Dos
Santos, A. A. Tetrahedron Lett. 2005, 46, 4423–4425. (b) Zhou, X.; Wu,
W.; Liu, X.; Lee, C.-S. Org. Lett. 2008, 10, 5525–5528.
(18) (a) Scherrmann, M.-C. Top. Curr. Chem. 2010, 295 (Carbohy-
drates in Sustainable Development II), 1–18. (b) Nagarapu, L.; Chary,
M. V.; Satyender, A.; Supriya, B.; Bantu, R. Synthesis 2009, 2278–2282.
ꢀ
~
(c) Bartoli, G.; Fernandez-Bolanos, J. G.; Di Antonio, G.; Foglia, G.;
Giuli, S.; Gunnella, R.; Mancinelli, M.; Marcantoni, E.; Paoletti, M.
J. Org. Chem. 2007, 72, 6029–6036.
(19) Fournier, J.; Arseniyadis, S.; Cossy, J. Angew. Chem., Int. Ed.
2012, 51, 7562–7566.
(20) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084–3213. (b) Kirsch, S. F. Org. Biomol. Chem.
2006, 4, 2076 and references therein.
(21) Marshall, J. A.; Bennett, C. E. J. Org. Chem. 1994, 59, 6110–
6113.
(22) (a) Du, X.; Chen, H.; Liu, Y. Chem.;Eur. J. 2008, 14, 9495–
9498. (b) Du, X.; Chen, H.; Chen, Y.; Chen, J.; Liu, Y. Synlett 2011,
1010–1014.
(23) (a) Iriye, R.; Uno, T.; Ohwa, I.; Konishi, A. Agric. Biol. Chem.
1990, 54, 1841–1843. (b) Lee, P. H.; Kim, H. S.; Kim, S. Chem. Lett.
1994, 2401–2402. (c) Sammond, D. M.; Sammakia, T. Tetrahedron Lett.
1996, 37, 6065–6068. (d) Donohoe, T. J.; Bower, J. F. Proc. Natl. Acad.
Sci. U.S.A. 2010, 107, 3373–3376.
(24) Butkevich, A. N.; Corbu, A.; Meerpoel, L.; Stansfield, I.;
Angibaud, P.; Bonnet, P.; Cossy, J. Org. Lett. 2012, 14, 4998–5001.
B
Org. Lett., Vol. XX, No. XX, XXXX

entries 5À7) and fused furans (Table 1, entries 8À11) have
been prepared by this one-pot procedure.
derivatives but required prolonged heating (8À16 h in
hexane at 80 °C). However, under microwave irradiation,
in the presence of an inert microwave absorber (graphite
powder) the reaction temperature was increased to 120 °C
and the borylation was complete within 15 min, attaining
80À90% conversion of the starting glycal to the corre-
sponding C6-boronate (GC control). The crude boronates
thus obtained were used directly in the cross-coupling/
cyclization sequence upon filtration through a short pad of
silica and concentration of the filtrate.
The Suzuki-Miyaura coupling intermediates containing
1-aryl- or 1-alkynyl-2-propen-1-ol fragments proved par-
ticularly acid sensitive and required the use of the weaker
trifluoroacetic acid26 instead of pTsOH to increase the
yield of furans (Table 2). Under these conditions, several
2,5-disubstituted and 2,3,5-trisubstituted furans were
prepared.
The dihydropyranyl pinacol boronates, prepared from
tri-O-methyl-D-glucal 38 and tri-O-methyl-D-galactal 39
were involved in the cross-coupling/cyclization process to
form furans 41À43 with polysubstituted side chains in
40À91% yields (Table 3, entries 1À3). As benzyl protect-
ing groups were found incompatible with the borylation
conditions (due to competing borylation of the aromatic
ring), the transformation was instead performed on glycal
Table 2. Preparation of Furans 15 and 31À37
Table 3. Preparation of Polysubstituted Furans by Tandem
Borylation/Cross-coupling/Cyclization of Glycals
The reaction is regioselective as only the disubstituted
furan 35 was obtained from allylic diol 28 and diol 29 was
converted to the trisubstituted furan 36 (Table 2, entries 6
and 7), suggesting that only (Z)-allylic alcohols cyclize to
the corresponding furans. Indeed, the (E)-allylic alcohol 30
produced the corresponding R,β-unsaturated ketone 37 as
the only major product in 43% yield (Table 2, entry 8).
This result indicates that the cyclization of (Z)-allylic
alcohols to furans proceeds much faster than the possible
acid-catalyzed E/Z-isomerization of the double bond.27
The preparation of furans possessing a polysubstituted
side chain was next investigated. The starting glycal bo-
ronates were prepared by Ir-catalyzed CÀH borylation
of glycals 38À40 described by Miyaura et al. {B2pin2 (1.2
equiv), [Ir(cod)(OMe)]2 (1.5 mol %), dtbpy (3 mol %)
in hexane}.28 The reaction was regioselective for glucose
(25) See Supporting Information.
(26) Guthrie, J. P. Can. J. Chem. 1977, 2342–2354.
(27) (a) Nokami, J.; Nishimura, A.; Sunami, M.; Wakabayashi, S.
a The intermediate vinyl dihydropyran cross-coupling product could
be isolated in 65% yield, see Supporting Information for details.
DMB = 3,5-dimethylbenzyl.
ꢀ
Tetrahedron Lett. 1987, 28, 649–650. (b) Boto, A.; Hernandez, D.;
ꢀ
Hernandez, R. Org. Lett. 2007, 9, 1721–1724.
Org. Lett., Vol. XX, No. XX, XXXX
C

ether 40 protected as a tris-3,5-dimethylbenzyl (DMB)
ether.29 The corresponding trisubstituted furan 44 was
obtained in 91% yield (Table 3, entry 4).
Once the cross-coupling intermediate B is protonated, the
resulting carbocation C has three possible pathways (aÀc)
dictated by its structural constraints. Path a leads, by
a kinetically favored 5-endo-trig spiroacetalization fol-
lowed by a protonation/aromatization cascade, to the
target polysubstituted furans E. To prove that the forma-
tion of furans proceeds through a spiroacetal inter-
mediate D, 1,1-disubstituted 3-iodoallylic alcohol 45
was prepared and subjected to the same cross-coupling/
cyclization sequence. The expected 2,5-dihydrofuran
spiroacetal 4630 was isolated as a minor product along
with the diastereomeric products of the double bond
hydration (47a,b). This result can be explained if
an alternative Path b is followed when the aromatiza-
tion step is not possible. Finally, if the starting allylic
alcohol possesses an (E)-configuration, the ring-
opening at the C6ÀO bond with the formation of an
R,β-unsaturated ketone G is thermodynamically pre-
ferred (Path c).
Scheme 2. Tandem Suzuki-Miyaura Coupling/Acid-catalyzed
Cyclization: A Mechanistic View
In summary, we have developed a microwave-assisted
synthesis of polysubstituted furans with a 2-(ω-hydroxyalkyl)
side chain by a tandem one-pot Suzuki-Miyaura coupling/
acid-catalyzed cyclization sequence. The scope and limita-
tions of the process have been evaluated. The proposed
method provides rapid access to a variety of alkyl- and
aryl-substituted furans and may be applied to the synthesis
of complex molecules, such as pharmaceuticals and
natural products.
Acknowledgment. Janssen Pharmaceutica is gratefully
acknowledged for financial support.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR and HRMS) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
The proposed overall reaction mechanism of the de-
scribed preparation of furans is presented in Scheme 2.
ꢀ
(30) (a) Whitby, R.; Kocienski, P. Tetrahedron Lett. 1987, 28, 3619–
(28) Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N.
Chem.ÀAsian J. 2008, 3, 2082–2090.
ꢀ
3622. (b) Kocienski, P.; Whitby, R. Synthesis 1991, 1029–1038.
(29) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172–
4173.
The authors declare no competing financial interest.
D
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