Palladium-catalyzed cyclization/heck- and cyclization/conjugate-addition- type sequences in the preparation of polysubstituted furans

Article abstract of DOI:10.1021/jo800211q

(Chemical Equation Presented) Palladium-catalyzed heterocyclization- coupling sequences have been developed starting from buta-1,2,3-trienyl carbinols and electron-deficient alkenes. Polysubstituted furans are formed where the heterocyclic ring originates from the elements of the butatrienyl carbinol while the electron-deficient olefin is incorporated as a C-3 substituent. In most cases, the reaction proceeds via a Heck-type pathway leading to the efficient formation of 3-vinylfurans. However, couplings with methyl vinyl ketone display a divergent behavior to afford selectively either Heck- or hydroarylation-type products depending on reaction conditions.

Full text of DOI:10.1021/jo800211q

SCHEME 1. Oxypalladation/Heck Strategy for 3-Vinylfuran
Synthesis
Palladium-Catalyzed Cyclization/Heck- and
Cyclization/Conjugate-Addition-Type Sequences
in the Preparation of Polysubstituted Furans
José M. Aurrecoechea,* Aritz Durana, and Elena Pérez
Departamento de Química Orgánica II, Facultad de Ciencia
y Tecnología, UniVersidad del País Vasco, Apartado 644,
48080 Bilbao, Spain
organic halides or triflates (R-X) and acyclic unsaturated
substrates bearing an internal nucleophile is a practical method
for the preparation of a variety of substituted heterocyclic
structures incorporating the organic fragment (R).4 While the
preparation of 3-(3-oxopropenyl)furan derivatives by using this
strategy has been described starting from 3-iodoacrylates and
either allenyl carboxylic acids5 or R-allenones,6 this approach
is nevertheless limited by the availability of the required iodo-
derivatives. An attractive alternative would involve the use of
simple R,ꢀ-unsaturated carbonyl derivatives in Pd(II)-catalyzed
intramolecular oxypalladation/Heck-type coupling sequences
(Scheme 1), and this may also allow the general introduction
of other vinyl units. However, in this particular approach Pd(0)
is released in the Heck coupling7 whereas Pd(II) is needed to
activate the unsaturated system toward cyclization. In fact, the
difficulties associated with reoxidation of Pd(0) to the Pd(II)
needed to maintain the catalytic cycle probably explain the
scarcity of literature reports on intramolecular nucleopalladation
followed by Heck reaction.8 In the only reported case utilizing
alcohol nucleophiles, the use of hydroxyalkenes provided an
entry into saturated oxygen heterocycles of the tetrahydrofuran
type,8d but in these examples the new vinyl unit was necessarily
incorporated at the exocyclic carbon located at the furan C-2
rather than directly at C-3, as required for 3-vinylfuran synthesis.
Pd(0)-catalyzed cyclization/couplings of penta-2,3,4-trien-1-
ols 3 with organic halides, on the other hand, have been shown
to incorporate aryl-9a and allylic9b groups at C-3 of the newly
formed furan ring. Notably, alcohols 3 are easily generated in
situ from readily available epoxypropargyl ester substrates 1
and have the appropriate oxidation state needed to lead directly
to the fully aromatic furan system. With these precedents, we
jm.aurrecoechea@ehu.es
ReceiVed January 28, 2008
Palladium-catalyzed heterocyclization-coupling sequences
have been developed starting from buta-1,2,3-trienyl carbinols
and electron-deficient alkenes. Polysubstituted furans are
formed where the heterocyclic ring originates from the
elements of the butatrienyl carbinol while the electron-
deficient olefin is incorporated as a C-3 substituent. In most
cases, the reaction proceeds via a Heck-type pathway leading
to the efficient formation of 3-vinylfurans. However, cou-
plings with methyl vinyl ketone display a divergent behavior
to afford selectively either Heck- or hydroarylation-type
products depending on reaction conditions.
Furans substituted at C-3 with a 3-oxopropenyl unit (ketone,
ester, or amide) have attracted recent attention because of their
applications as active ingredients in pharmaceutical or agro-
chemical formulations, besides being useful synthetic intermedi-
ates.1 The simple 2,4,5-unsubstituted derivatives are readily
available from 3-furfural2 or 3-lithiofuran3 by using conventional
chemistry, but for more substituted derivatives the synthesis is
not as straightforward.1b The Pd(0)-catalyzed coupling between
(4) Recent reviews: (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42–64.
(b) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000,
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12–21. (e) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2002, 56, 613–
632. (f) Ma, S. Acc. Chem. Res. 2003, 36, 701–712. (g) Balme, G.; Bouyssi, D.;
Lomberget, T.; Monteiro, N. Synthesis 2003, 2115–2134.
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(6) Ma, S. M.; Zhang, J. L.; Lu, L. H. Chem. Eur. J. 2003, 9, 2447–2456.
(7) Recent reviews: (a) Beletskaya, I. P.; Cheprakov, A. V Chem. ReV. 2000,
100, 3009–3066. (b) Larhed, M.; Hallberg, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley and Sons: New York,
2002; Vol. 1, pp 1133–1178. (c) Braese, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; Vol. 1, pp 217–315. (d) Knowles, J. P.;
Whiting, A. Org. Biomol. Chem. 2007, 5, 31–44.
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4501. (b) Hamamura, K.; Sasaki, S.; Amano, Y.; Sakamoto, J.; Fukatsu, K. PCT
Int. Appl. WO 2004022551, 2004. Chem. Abstr. 2004, 140, 270727. (c)
Werkheiser, J. L.; Rawls, S. M.; Cowan, A. Neuropharmacology 2007, 52, 925–
930. (d) Ono, M.; Hori, M.; Haratake, M.; Tomiyama, T.; Mori, H.; Nakayama,
M. Bioorg. Med. Chem. 2007, 15, 6388–6396.
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102, 3583–3587. (b) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29,
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Semmelhack, M. F.; Epa, W. R. Tetrahedron Lett. 1993, 34, 7205–7208. (e)
Yasuhara, A.; Kaneko, M.; Sakamoto, T. Heterocycles 1998, 48, 1793–1799.
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2002, 50, 235–238. (g) Huang, Q. H.; Larock, R. C. J. Org. Chem. 2003, 68,
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63, 4489–4493. (c) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade,
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3650 J. Org. Chem. 2008, 73, 3650–3653
10.1021/jo800211q CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

TABLE 2. Preparation of Furans 5–9 from Epoxides 1 and
Electron-Deficient Alkenes 4a
SCHEME 2. Epoxypropargyl Ester Route to
Polysubstituted Furans
1
R1 R2
R3
R4
EWG
t (h)b
5
yieldc
1
2
3
4
5
6
7
8
9
1a Me Me Me
1a Me Me Me
1a Me Me Me
1a Me Me Me
1a Me Me Me
1b Me Me Me
1b Me Me Me
1b Me Me Me
1c iPr iBu Me
(CH2)3CN CO2Et
(CH2)3CN CO2NH2
(CH2)3CN SO2Me
(CH2)3CN CN
17
18
18
28
4
17
20
20
20
16
43
18
24
50
4
5a
6a
7a
8a
9a
5b 83
6b 80
7b 69
5c
6c
7c
5d 73
6d 72
7d 70
5e
6e
7e
5f
6f
7f
74
58
TABLE 1. Survey of Reaction Conditions for the
Palladium-Catalyzed Stepa
54
53d
20e
(CH2)3CN COMe
(CH2)2Ph CO2Et
(CH2)2Ph CONH2
(CH2)2Ph SO2Me
(CH2)2Ph CO2Et
(CH2)2Ph CONH2
(CH2)2Ph SO2Me
(CH2)2Arf CO2Et
(CH2)2Arf CONH2
(CH2)2Arf SO2Me
(CH2)2Ph CO2Et
(CH2)2Ph CONH2
(CH2)2Ph SO2Me
CO2Et
76
72
61
10 1c iPr iBu Me
11 1c iPr iBu Me
12 1d iPr iBu
13 1d iPr iBu
14 1d iPr iBu
15 1e Me Me
16 1e Me Me
17 1e Me Me
H
H
H
H
H
H
Pd
additives (n)b
5ac
11ac
1
2
3
4
5
6
7
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
H2O (1)/LiCl (4)
H2O (1)/LiCl (4)
H2O (1)/LiCl (4)/Et3N (1)
H2O (1)/LiCl (4)/Et3N (5)
H2O (1)/LiCl (4)/Et3N (5)
H2O (1)/Et3N (5)
52 (52)
39
(41)
74
<30
46
8 (5)
29
(2)
45
56
51
80
71
66
20
20
4
5
20
18 1f Me Me (CH2)5
19 1f Me Me (CH2)5
20 1f Me Me (CH2)5
CONH2
SO2Me
LiCl (4)/Et3N (5)
a Amounts of reagents relative to 1: SmI2 (2.25 equiv), Pd(PPh3)4 (5
mol %), H2O (1 equiv), LiCl (4 equiv), Et3N (5 equiv), and alkene (15
equiv). b Reaction time for the Pd-catalyzed step. c Isolated yield (%) of
pure product. d Based on recovered triene 3a (37%). e Also obtained in
39% yield was ketone 10a [R1 ) R2 ) R3 ) Me, R4 ) (CH2)3CN,
Scheme 2]. f Ar ) 3,4-dimethoxyphenyl.
8d
9e
10f
11g
12h
H2O (1)/LiCl (4)/Et3N (5)
H2O (1)/LiCl (4)/Et3N (5)
H2O (1)/LiCl (4)/Et3N (5)
H2O (1)/LiCl (4)/Et3N (5)
LiCl (4)/Et3N (5)
63
61
59
48
21
18
a Unless otherwise indicated, 5 mol % of Pd complex and 15 equiv of
ethyl acrylate. b n ) number of equivalents. c Isolated yield (%) of pure
product. Alternatively, within parentheses, yield calculated by 1H NMR
with 3,4-dimethoxybenzonitrile as internal standard. d Ten equivalents of
ethyl acrylate was used. e Five equivalents of ethyl acrylate was used.
f Two equivalents of ethyl acrylate was used. g Reaction run under Ar.
h Reaction run from isolated 3a.
additional use of Et3N had the effect of decreasing the amount
of 11a relative to 5a (entries 3 and 4). This beneficial effect of
Et3N was particularly noticeable with Pd(PPh3)4 as catalyst
whereupon formation of 11a was completely suppressed and
the yield of 5a increased significantly (entry 4). The presence
of phosphines in this last catalyst appeared to be important too,
as Pd2(dba)3 afforded a poor yield of 5a under otherwise
identical conditions (entry 5). Further control experiments served
to establish the need for both H2O and LiCl under Pd(PPh3)4
catalysis (entries 6 and 7) as well as the convenience of using
a large excess of ethyl acrylate for optimum yields (entries
8–10). A very significant reaction was observed under strict Ar
conditions (entry 11) suggesting the presence of alternative
internal oxidants.8d–h Finally, the need for running the reaction
without isolation of alcohol 3a was shown by the experiment
in entry 12 where the application of the reaction conditions of
entry 1 to a purified sample of 3a (prepared in 85% isolated
yield from 1a)9a resulted in a comparatively much lower yield
of 5a. These observations hint at the involvement of Sm(III)
salts at the Pd-oxidation and/or some other stage of the coupling.
By using the conditions found optimal for formation of 5a
as standard (entry 4, Table 1), a survey of alkenes was conducted
to determine the scope of this reaction (Table 2). Thus,
acrylamide (4b), methyl vinyl sulfone (4c), and acrylonitrile
(4d) were also suitable partners for the cyclization/coupling
sequence, providing good yields of the corresponding products
6a-8a (entries 2–4). However, the reaction with methyl vinyl
ketone (4e) was complicated by competition between Heck- and
hydroarylation-type pathways with the latter predominating
have now studied an alternative cyclization/oxidative Heck-type
sequence between alcohols 3 and electron-deficient alkenes 4
as an entry into 3-vinylfurans 5–9. As will be shown below, in
a particular case the reaction can also be steered to the formation
of products of type 10, the formal result of an alternative
conjugate addition to the electron-deficient alkene (Scheme 2).
Epoxide 1a and ethyl acrylate (4a) were selected as model
substrates for a survey of reaction conditions (Table 1).
Reduction of 1a generated a samarium alkoxide (2a) that was
directly treated with a Pd catalyst and ethyl acrylate under
various conditions. After an initial screening, suitable starting
conditions for formation of the Heck product 5a were found in
the form of Pd(OAc)2 as catalyst, with H2O and LiCl as
additives, in THF at 60 °C under an air atmosphere (entry 1).
In these initial experiments, the desired furan 5a was invariably
accompanied by 11a, the result of cycloisomerization of alcohol
3a.9a For catalyst reoxidation the simple and mild protocol of
allowing air to diffuse through a CaCl2 tube, as in entry 1, was
of comparable efficiency to the use of a pure oxygen atmosphere.
However, other oxidants or cooxidants, such as Cu(OAc)2 or
benzoquinone, gave poorer results. Under the foregoing oxidiz-
ing conditions, a Pd(0) complex also promoted the reaction but
with concomitant substantial formation of 11a (entry 2). The
J. Org. Chem. Vol. 73, No. 9, 2008 3651

TABLE 3. Preparation of Furans 9 and 10 from 1 and Methyl
Vinyl Ketonea
(entry 5). Other alkenes, such as acrylaldehyde, cyclohexenone,
ethyl crotonate, tert-butyl methacrylate, styrene, cyclohexene,
or 3,4-dihydro-2H-pyran, were not successful.
The corresponding reactions with other epoxides 1 and
electron-deficient alkenes 4a-c provided uniformly good yields
of 3-vinylfuran derivatives 5–7 (entries 6–20), which display
structural diversity stemming from the choice of the olefin
activating group as well as from the convergent assembly of
the starting esters.9 Therefore, in common with other Pd-
catalyzed applications of intermediates 3, this cyclization/Heck-
type coupling sequence succeeds in the formation of densely
substituted functionalized furans10 in a highly efficient manner,
with complete regiocontrol, and without interference from the
competing Pd(II)-catalyzed cycloisomerization process.
As noticed above, under the standard cyclization/coupling
conditions, the reaction with methyl vinyl ketone departed from
the general trend in that it provided 10a as major product in
addition to the expected 9a (entry 5, Table 2). The tendency of
R,ꢀ-unsaturated ketones (and aldehydes) to give unwanted
hydroarylation (conjugate addition) products with aryl halides
or triflates, under typical Pd(0)-catalyzed Heck reaction condi-
tions, is well-known.11,12 In fact, that particular reactivity of
methyl vinyl ketone (and related conjugated ketones and
aldehydes) has already been exploited with nucleophile-tethered
(oxygen- or nitrogen-based) unsaturated derivatives in Pd(II)-
catalyzed cyclization/conjugate-addition reactions.8c,13 However,
in the reported cases a relatively high acidity of the nucleophile
(pH e 5) has been found to be a requirement for adequate
reactivity, whereas the use of relatively nonacidic alcohol
nucleophiles has not been described so far.14 Therefore, the
possibility of taking synthetic advantage of this divergent
behavior to perform alternatively Heck- or conjugate-addition-
type coupling sequences in the context of furan synthesis was
explored next. The corresponding results are displayed in Table
3. It was found that performing the reaction with Pd(OAc)2 as
catalyst in the absence of Et3N, under either air or Ar
atmospheres, completely suppressed the formation of Heck
products 9 (entries 1–6). On the other hand, a high Heck
1
conditionsb
t (h)b 9, 10c
yieldd
53
52
65
50
70
52
60
57
1
2
3
4
5
6
7
8
9
1a Pd(OAc)2, LiCl, air
1a Pd(OAc)2, LiCl, Ar
1b Pd(OAc)2, LiCl, Ar
1c Pd(OAc)2, LiCl, Ar
1d Pd(OAc)2, LiCl, Ar
1f Pd(OAc)2, LiCl, Ar
2
5
2
22
2
23
26
52
40
3
10a
10a
10b
10c
10d
10f
9a
1a Pd(PPh3)4, Ag2CO3, Et3N, air
1c Pd(PPh3)4, Ag2CO3, Et3N, air
1f Pd(PPh3)4, Ag2CO3, Et3N, air
9c
9f, 10f 66, 18
10e 1f Pd(OAc)2, LiCl, air
9f, 10f (21), (21)
a Amounts of reagents relative to 1: SmI2 (2.25 equiv), palladium catalyst
(5 mol%), H2O (1 equiv), LiCl (4 equiv), Et3N (5 equiv), Ag2CO3 (2
equiv), methyl vinyl ketone (15 equiv). b Conditions and reaction time for
the Pd-catalyzed step. c Cycloisomerization products 11 were also obtained
(<10% yield) in entries 1–6. d Isolated yield (%) of pure product. Alt-
ernatively, within parentheses, yield calculated by 1H NMR with 3,4-
dimethoxyphenylacetonitrile as internal standard. e Reaction run from
isolated 3f.
SCHEME 3. Catalytic Cycle for Formation of 5-10 from 3
(9) (a) Aurrecoechea, J. M.; Pérez, E. Tetrahedron 2004, 60, 4139–4149.
(b) Aurrecoechea, J. M.; Pérez, E. Tetrahedron Lett. 2003, 44, 3263–3266. (c)
Aurrecoechea, J. M.; Pérez, E.; Solay, M. J. Org. Chem. 2001, 66, 564–569.
(10) Leading references into the synthesis of tetrasubstituted furans: (a) Zhan,
Z. P.; Wang, S. P.; Cai, X. B.; Liu, H. J.; Yu, J. L.; Cui, Y. Y. AdV. Synth.
Catal. 2007, 349, 2097–2102. (b) Dudnik, A. S.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 5195–5197. (c) Sanz, R.; Miguel, D.; Martínez, A.; Alvarez-
Gutiérrez, J. M.; Rodríguez, F. Org. Lett. 2007, 9, 727–730. (d) Shindo, M.;
Yoshimura, Y.; Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto, K.;
Shishido, K Org. Lett. 2007, 9, 1963–1966. (e) Watanabe, S.-I.; Miura, Y.;
Iwamura, T.; Nagasawa, H.; Kataoka, T. Tetrahedron Lett. 2007, 48, 813–816.
(f) Dey, S.; Nandi, D.; Pradhan, P. K.; Giri, V. S.; Jaisankar, P. Tetrahedron
Lett. 2007, 48, 2573–2575. (g) Miyagawa, T.; Satoh, T. Tetrahedron Lett. 2007,
48, 4849–4853, and references cited therein.
selectivity was restored by using Ag2CO3 in place of LiCl under
otherwise standard conditions (entries 7–9). Again, running the
reactions without isolation of alcohols 3 proved advantageous,
as shown by the experiment in entry 10 where an isolated
alcohol 3f was submitted to the conditions of entry 1 (expected
to give 10f selectively), resulting in a mixture of 9f and 10f
with no selectivity. Therefore, a simple switch of reaction
conditions provides access to either series of products 9 or 10
selectively. Furthermore, ethyl acrylate and methyl vinyl ketone
give noticeably different results under identical reaction condi-
tions (compare entry 1 of Table 1 with entry 1 of Table 3).
Thus, the former follows the Heck pathway exclusively whereas
the latter affords only a conjugate-addition product.
(11) Cacchi, S.; Fabrizi, G.; Goggiamani, A. ArkiVoc 2003, 8, 58–66, and
references cited herein.
(12) For geometrically unbiased acyclic systems, conditions have been devised
that provide hydroarylation products predominantly: (a) Cacchi, S.; Palmieri,
G. Synthesis 1984, 575–577. (b) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi,
S.; Cerrini, S.; Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813–828. (c) Cacchi,
S. Pure Appl. Chem. 1990, 62, 713–22. (d) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Pace, P. Tetrahedron 1996, 52, 6983–6996.
(13) (a) Lei, A.; Lu, X. Org. Lett. 2000, 2, 2699–2702. (b) Wang, Z.; Zhang,
Z.; Lu, X. Organometallics 2000, 19, 775–780. (c) Liu, G. S.; Lu, X. Y. Org.
Lett. 2001, 3, 3879–3882. (d) Zhang, Z. G.; Lu, X. Y.; Xu, Z. R.; Zhang, Q. H.;
Han, X. L. Organometallics 2001, 20, 3724–3728. (e) Liu, G. S.; Lu, X. Y.
Tetrahedron Lett. 2003, 44, 127–130. (f) Shen, Z. M.; Lu, X. Y. Tetrahedron
2006, 62, 10896–10899.
A mechanistic rationale for formation of 5–10 is provided in
Scheme 3. Thus, after the initial Pd(II)-promoted cyclization,
intermediate 13 undergoes carbopalladation followed by either
Pd-H elimination (eventually leading to 5–9) or protonation
(14) For a related Ru-catalyzed reaction, see: (a) Trost, B. M.; Pinkerton,
A. B. J. Am. Chem. Soc. 2002, 124, 7376–7389. For a mechanistic variant in a
similarly Ru-catalyzed reaction, see: (b) Trost, B. M.; Pinkerton, A. B. J. Am.
Chem. Soc. 1999, 121, 10842–10843. (c) Trost, B. M.; Pinkerton, A. B.; Seidel,
M. J. Am. Chem. Soc. 2001, 123, 12466–12476.
3652 J. Org. Chem. Vol. 73, No. 9, 2008

throughout the remainder of the procedure. After allowing the
mixture to reach room temperature, H2O (0.14 mL of a 2.8 M
solution in THF, 0.40 mmol) was added, followed by the appropriate
alkene (6.00 mmol), LiCl (68 mg, 1.60 mmol, previously maintained
at 0.5 mmHg and 350 °C for 45 min) [or Ag2CO3 (220 mg, 0.80
mmol) in the case of methyl vinyl ketone], Et3N (0.28 mL, 2.00
mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol). The resulting mixture
was placed in an oil bath at 60 °C and stirred until consumption of
alcohol 3, as judged by TLC. After cooling, the reaction mixture
was poured over saturated K2CO3 (15 mL), and the layers were
separated. The aqueous phase was extracted with EtOAc (3 × 15
mL), and the combined organic layers were washed with H2O (2
× 10 mL) and dried (Na2SO4). For reactions run with acrylamide
and methyl vinyl sulfone, the combined organic layers were washed
with saturated K2CO3 (2 × 10 mL), H2O (2 × 10 mL), and brine
(2 × 10 mL) before drying with Na2SO4. The crude after
evaporation was purified as indicated in the Supporting Information
for the individual cases.
General Procedure for Reduction/Oxypalladation/Conjugate-
Addition Coupling of Epoxides 1 and Methyl Vinyl Ketone. A
solution of SmI2 (0.1 M, 9 mL, 0.9 mmol) was added to a solution
of epoxide 1 (0.40 mmol) in THF (2 mL) at -5 °C under Ar, and
the mixture was stirred for 3 h. Dry air was bubbled through the
solution to destroy excess SmI2, and the mixture was purged with
Ar for 15 min. After the mixture was allowed to reach room
temperature, H2O (0.14 mL of a 2.8 M solution in THF, 0.40 mmol)
was added, followed by methyl vinyl ketone (0.50 mL, 6.0 mmol),
LiCl (0.068 g, 1.60 mmol, previously maintained at 0.5 mmHg and
350 °C for 45 min), and Pd(OAc)2 (4.5 mg, 0.02 mmol). The
resulting mixture was placed in an oil bath at 60 °C and stirred
until TLC indicated total consumption of triene 3. After cooling,
the reaction mixture was poured over saturated K2CO3 (15 mL),
and the layers were separated. The aqueous phase was extracted
with EtOAc (3 × 15 mL), and the combined organic layers were
washed with H2O (2 × 10 mL) and dried (Na2SO4). The crude
after evaporation was purified as indicated in the Supporting
Information for the individual cases.
(to afford 10). In contrast to the Heck-type pathway forming
5–9, formation of 10 directly regenerates the catalytic Pd(II)
species and no oxidation is needed in that case. The formation
of 10 from 3 and methyl vinyl ketone was initially thought to
be also associated to the well-known effect of LiCl to inhibit
ꢀ-H elimination from palladium complexes.8c,13 However, the
formation of equivalent amounts of 9 and 10 when the reaction
was performed from an isolated alcohol 3 under typical
conjugate-addition conditions (entry 10) indicates that Sm(III)
species, usually carried over from the preceding reduction step
but absent in this particular case, are also at least partially
responsible for the formation of 10 in our reaction. It is further
suggested that the oxophilicity of Sm(III) may promote a ligand
exchange with Pd(II) (at the stage of 14) with formation of a
Sm(III) enolate, which then undergoes protonation. On the other
hand, the precise role of Ag2CO3 in these reactions is unclear.15
Nevertheless, it is noted that it may act both as base and
oxidant,16 and that it has been previously used in Heck-type
reactions.16,17
In summary, the sequential one-pot reduction/coupling start-
ing from alkynyloxiranes 1 and electron-deficient olefins
provides an expeditious entry into functionalized furans 5–10.
The formation of either Heck- or conjugate-addition-type
products is in part dictated by the choice of electron-withdrawing
group on the alkene. Thus, ester, amide, nitrile, and sulfone
activating groups cause the reaction to follow exclusively the
Heck pathway, whereas the acetyl group gives alternative access
to both types of products depending on the particular reaction
conditions. This work introduces unsaturated alcohols as new
substrates for Pd-catalyzed cyclization/conjugate additions se-
quences.
Experimental Section
General Procedure for Reduction/Oxypalladation/Heck Cou-
pling of Epoxides 1 and Alkenes. A solution of SmI2 (0.1 M, 9
mL, 0.9 mmol) was added to a solution of epoxide 1 (0.40 mmol)
in THF (2 mL) at -5 °C under Ar, and the mixture was stirred for
3 h. Excess SmI2 was destroyed by allowing air into the system
through a CaCl2 guard tube, which was maintained in place
Acknowledgement. We thank the Spanish Ministerio de
Ciencia y Tecnología (Grant CTQ2004-04901, FEDER), Uni-
versidad del País Vasco (Grant 9/UPV00041.310-14471/2002
and fellowship to E.P.), and Gobierno Vasco (Fellowship to
A.D.) for financial support.
(15) A possible role for Ag+ as Lewis acid cyclization promoter, with
subsequent transmetalation to Pd(II),5 is unlikely because in independent studies
Ag+ was shown not to promote cycloisomerization of 3 to 11. M. Solay, Ph.D.
Thesis, Universidad del País Vasco, Bilbao, Spain, 1997.
(16) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
10323–10333.
Supporting Information Available: Details of preparation
and characterization data for 1c, 1f, and 5–10, and copies of
1H NMR spectra for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(17) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4130–
4133.
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