Palladium catalyzed ring opening of furans as a route to α,β-unsaturated aldehydes

Article abstract of DOI:10.1039/c0cc04164e

Furans may be ring opened via pallado-catalyzed reactions leading to α,β-unsaturated aldehydes and ketones tethered to indole and isoquinoline moieties. Besides their synthetic interest, these fragmentations bring interesting elements into the discussion

Full text of DOI:10.1039/c0cc04164e

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Palladium catalyzed ring opening of furans as a route to a,b-unsaturated
aldehydesw
Laurent El Kaım,* Laurence Grimaud* and Simon Wagschal*
¨
Received 30th September 2010, Accepted 16th November 2010
DOI: 10.1039/c0cc04164e
Furans may be ring opened via pallado-catalyzed reactions
leading to a,b-unsaturated aldehydes and ketones tethered to
indole and isoquinoline moieties. Besides their synthetic interest,
these fragmentations bring interesting elements into the
discussion around the reaction mechanisms involved in palladium
C–H activations of electron-rich heterocycles.
With a Dewar resonance energy of 4.3 kcal molÀ1, furans
represent the least stabilized among the classical five- and
six-membered ring aromatic heterocycles.1 This property may
be illustrated by the different behavior of 5-membered ring
heteroaromatics as dienes in Diels–Alder reactions as well as
various ring opening reactions observed with furans.2 The
cleavage of the furan ring with strong Brønsted acids to form
diketone derivatives has been known for many years.3 In these
reactions, the intermediate protonated furans may be trapped
by internal nucleophiles to afford various heterocyclic
systems.4 The most powerful synthetic routes involving electro-
philic activation of furan towards ring opening are certainly
those involving oxidative conditions (such as the Achmatowicz
reaction).5 Considering all these ring opening reactions
triggered by an electrophilic attack on furans,6 one may be
surprised by the absence of related fragmentations using
electron deficient organometallic derivatives such as palladium(II)
species.7 The formation of aryl–aryl bonds through palladium
catalyzed C–H activation of aromatic derivatives has recently
been the object of tremendous efforts.8 Studies on the C–H
functionalization of furans have shown that both inter
and intramolecular additions could be observed, with the
2-position being the most reactive.9 When substituted at the
2-position, intramolecular couplings of furans usually lead to
adducts functionalized at C-3. Among the various mechanisms
proposed for these reactions,10 we surmised that if an electro-
philic pathway could be operative, reactive palladium inter-
mediates could undergo ring opening of the furan moiety
instead of the C-3 functionalization (Scheme 1).
Scheme
1 Potential C-3 functionalization/furan ring openings
competition.
Scheme 2 Furan ring opening of Ugi–Smiles adduct 5a.
furfurylamine 1, iodopyrimidine 2, isocyanide 3 and aldehyde
4 (Scheme 2). When 5a was treated in acetonitrile with
palladium acetate, triphenylphosphine couple and diisopropyl-
ethylamine (DIPEA), we were delighted to observe the
formation of the pyrrolopyrimidine 6a in a modest 27% yield
(Scheme 2).
The conversion of 5a into 6a was then optimized using
different bases, solvents and catalysts under both thermal
and microwave conditions. The use of PdCl2(PPh3)2 in hot
acetonitrile gave a slightly higher yield of 6a (40%) which
could be improved to 85% by performing the reaction under
microwave irradiation (130 1C, 100 W).
Under these conditions, a set of Ugi–Smiles adducts
obtained from iodopyrimidines (Table 1, entries 1–8) and
iodonitrophenols (Table 1, entries 9 and 10) can be trans-
formed into the expected pyrrolopyrimidines and indoles in
good to moderate yields.12 Furans substituted at the 5 position
afford a,b-unsaturated ketones instead of aldehydes in
comparable yields (Table 1, entries 5–8). More interestingly,
the scope of this reaction can be broadened as shown by
the behavior of model compounds prepared by standard
amination/alkylation procedures (Table 2).
In order to examine such transformations, we decided to
prepare potential substrates using our 4-component Ugi–Smiles
procedure with furfurylamines and o-iodohydroxyaromatic
derivatives.11 Compared with the preparation of model
compounds using standard acylation/alkylation strategies, this
procedure offers suitable starting materials in one step. Thus
furan 5a was prepared in 62% isolated yield from
Considering the various reports on palladium-triggered
cyclizations onto furans, it is surprising that such a behavior
has not been previously observed. This is probably due to the
fact that the substrates examined lack a hydrogen capable of
inducing fragmentation (hydrogen highlighted in intermediate
A, Scheme 1)9a–c or the use of benzofurans, which are reluctant
Laboratoire Chimie et Proce´de´s, UMR 7652, Ecole Nationale
´
´
Superieure des Techniques Avancees, 32 Bd Victor, 75015 Paris,
France. E-mail: laurent.elkaim@ensta.fr, laurence.grimaud@ensta.fr;
Fax: +33 145528322; Tel: +33 145525537
w Electronic supplementary information (ESI) available: Full
characterisation for 5a-j, 6a-j, 7a-i, 8a-I, 9a-d and 10a-d. See DOI:
10.1039/c0cc04164e
c
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Chem. Commun., 2011, 47, 1887–1889 1887

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Table 1 Palladium catalyzed furan fragmentation of Ugi–Smiles
adducts
Beside the synthetic potential of these fragmentations,
the disclosure of this new reactive path reveals interesting
mechanistic elements about palladium catalyzed C–H activation
of heterocycles. Of the various mechanisms proposed for
these reactions, Heck-type reactive pathways are usually
discarded10,13 and there are still discussions between electro-
philic palladations (SEAr path)10a,b and concerted metalation
deprotonation processes (CMD path).10c–e In the case of
2-substituted furans, the fragmentations reported herein are
in strong support of an SEAr process. The mechanism of these
reactions as well as their extension to other 5-membered ring
systems are currently being examined.
Product
(yield, %)
Entry R1
R2
R3 R4 R5
X
Y
1
2
3
4
5
6
7
8
9
10
p-MeOBn
p-ClBn
p-ClBn
i-Bu
Me
H
H
H
H
H
Me i-Pr N
Me i-Pr N
Me i-Pr N
Me i-Pr N
N
N
N
N
N
N
N
N
6a (85)
6b (88)
6c (68)
6d (71)
6e (76)
6f (58)
6g (66)
6h (78)
We thank the French Ministry of Defense for financial
support.
CH2CH2Ara Me
p-MeOBn
Cy
p-ClBn
p-ClBn
p-MeOBn
p-ClBn
i-Bu
i-Bu
Me Me i-Pr N
Me Me i-Pr N
Notes and references
p-ClPh Me Me i-Pr N
i-Bu
Me
Me Me Ph N
H
H
1 A. T. Balaban, D. C. Oniciu and A. R. Katritzky, Chem. Rev.,
2004, 104, 2777–2812.
H
H
H
H
C–Me C–NO2 6i (66)
C–Cl C–NO2 6j (71)
i-Bu
2 (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795–819; (b) B. A. Keay
and P. W. Dibble, in Comprehensive Heterocyclic Chemistry II, ed.
A. R. Katrizky, C. W. Rees, E. F. Schriven and C. W. Bird,
Pergamon, Oxford, U.K., 1996, vol. 2, pp. 395–436; (c) G. W.
H. Cheeseman and C. W. Bird, in Comprehensive Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Uses of
Heterocyclic Compounds, Pergamon Press, Oxford, New York,
1984, vol. 4; (d) M. Shipman, Contemp. Org. Synth., 1995, 2, 1–17.
3 (a) G. Benson, Org. Synth., 1943, Coll. Vol. 2, 220; (b) S. Takano,
S. Otaki and K. Ogasawara, J. Chem. Soc., Chem. Commun., 1983,
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1980, 45, 4584–4586; (d) R. Faragher and T. L. Gilchrist, J. Chem.
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J. Hirai and R. Yoneda, J. Chem. Soc., Perkin Trans. 1, 1987,
1771–1776.
a
Ar = 3,4-MeOC6H3
Table 2 Palladium catalyzed furan fragmentation of model compounds
Product
(yield, %)
Entry
R1
R2
R3
R4
X
Y
Z
4 (a) C. Rivalle, J. Andre-Louisfert and E. Bisagni, Tetrahedron,
1976, 32, 829–834; (b) H. Hikino, K. Agatsuma, C. Konno and
T. Takemoto, Tetrahedron Lett., 1968, 9, 4417–4419;
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(d) A. V. Butin, S. K. Smirnov, T. A. Stroganova, W. Bender
and G. D. Krapivin, Tetrahedron, 2007, 63, 474–491; Furan ring
opening under addition of iminium cations: (e) A. V. Butin,
M. G. Uchuskin, A. S. Pilipenko, F. A. Tsiunchik,
D. A. Cheshkov and I. V. Trushkov, Eur. J. Org. Chem., 2010,
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1998, 63, 6914–6928; Similar opening with tropylium ions:
(g) K. Yamamura, Y. Houda, M. Hashimoto, T. Kimura,
M. Kamezawa and T. Otani, Org. Biomol. Chem., 2004, 2,
1413–1418.
5 (a) N. Clausen-Kaas and Z. Tyle, Acta Chem., Scand., 1952, 6,
667–670; (b) Y. Lefebvre, Tetrahedron Lett., 1972, 13, 133–136;
(c) G. Piancatelli, A. Scettri and S. Barbadoro, Tetrahedron Lett.,
1976, 39, 3555–3558; (d) O. Achmatowicz and R. Bielski,
Carbohydr. Res., 1977, 55, 165–176; (e) K. Yakushijin,
M. Kozuka and H. Furukawa, Chem. Pharm. Bull., 1980, 28,
2178–2184; (f) D. Balachari and G. A. O’Doherty, Org. Lett., 2000,
2, 863–866; (g) M. A. Ciufolini, Y. W. Hermann, Q. Dong,
T. Shimizu, S. Swaminathan and N. Xi, Synlett, 1998, 105–114;
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Soc., 2008, 130, 4097–4104.
1
2
3
4
5
6
7
8
9
i-Pr
i-Pr
Ph
Ph
Ph
i-Pr
H
Me
Me
Me
Me
Me
Me
H
Et
Me
Et
Me
Bn
Me
Et
Bn
Me
H
Me
H
Me
H
H
H
H
H
I
I
I
I
I
Br
I
I
I
N
N
N
N
N
N
C–H
C–H
C–H
N
N
N
N
N
N
C–H
C–H
C–H
8a (72)
8b (77)
8c (76)
8d (81)
8e (75)
8f (59)
8g (83)
8h (78)
8i (77)
H
Cl
H
H
to form highly reactive methylenequinone intermediates
(corresponding to C in Scheme 1).9d
The examples reported in Table 1 and 2 underscore the high
potential of this process for the preparation of indoles. These
compounds are important medicinal scaffolds and the additional
unsaturated carbonyl moiety opens up many opportunities
for further functionalizations. In addition, this process is not
limited to cyclizations forming five membered rings as shown
by the behavior of furans 9. Indeed, under similar treatment
with palladium under microwave irradiation we could
observe an analogous cascade leading to the formation of
isoquinolinones 10 (Scheme 3).
6 For
a furan ring opening after thioisocyanate addition:
(a) A. V. Butin, F. A. Tsiunchik, V. T. Abaev and
V. E. Zavodnik, Synlett, 2008, 1145–1148; For a further radical
triggered furan ring opening: (b) A. Demircan and P. J. Parsons,
Synlett, 1998, 1215–1216.
7 For gold catalyzed ring opening of alkynylfurans see: (a)
A. S. K. Hashmi, T. M. Frost and J. W. Bats, J. Am. Chem.
Soc., 2000, 122, 11553–11554; (b) Y. Chen, Y. Lu, G. Li and
Y. Liu, Org. Lett., 2009, 11, 3838–3841.
Scheme 3 Furan ring openings towards isoquinolines.
1888 Chem. Commun., 2011, 47, 1887–1889
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8 For recent reviews on palladium catalyzed C–H functionalization see:
(a) B. Sezen and D. Sames, in Handbook of C–H Transformations, ed.
G. Dyker, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
Germany, 2005, pp. 3–10; (b) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174–238; (c) F. Bellina and
R. Rossi, Tetrahedron, 2009, 65, 10269–10310; (d) T. W. Lyons and
M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169.
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K. Fagnou, J. Am. Chem. Soc., 2008, 130, 10848–10849;
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M. Tymoschenko, Org. Lett., 2003, 5, 301–304.
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2005, 44, 7165–7169; (b) L. El Kaim, M. Gizolme, L. Grimaud and
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66, 1716–1724; (b) L.-C. Campeau, M. Parisien, A. Jean and
K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581–590; (c) M. Smet,
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10 (a) B. S. Lane, M. A. Brown and D. Sames, J. Am. Chem. Soc.,
2005, 127, 8050–8057; (b) C.-H. Park, V. Ryabova, I. V. Seregin,
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12 To a 0.25 M solution of the aniline 7g (56 mg, 0.17 mmol) in
acetonitrile were successfully added bis(triphenylphosphine)-
palladium chloride (6 mg, 5 mol%) and diisopropylethylamine
(30 mL, 0.17 mmol, 1 equiv.). The resulting mixture was then stirred
under microwave activation for 20 min at 130 1C (power = 100 W,
pressure = 13 bar). The crude mixture was first filtered and rinsed
with methanol. After removal of the volatile materials, purification
by flash chromatography (petroleum ether–diethyl ether, 50 : 50)
gave 8g (28 mg, 83%) as a white solid. Mp 99–100 1C. 1H NMR
(CDCl3, 400 MHz) d 9.60 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 7.4 Hz,
1H), 7.66 (d, J = 15.7 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H),
7.37–7.27 (m, 2H), 6.74 (dd, J = 15.7, 7.9 Hz, 1H), 4.22 (q, J =
7.3 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz)
d 194.1, 146.5, 137.4, 132.4, 126.1, 124.1, 123.3, 121.9, 120.6, 112.5,
110.2, 41.6, 15.2. IR (thin film) 1663, 1611, 1521, 1388 cmÀ1. HRMS
calculated for C13H13NO 199.0997, found 199.0991.
13 Even though Heck type mechanisms are usually discarded, an
alternative reaction pathway may involve, in our case, a carbo-
palladation followed by a fragmentation to a p-allyl species and
final reductive elimination.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1887–1889 1889