Synthesis of trisubstituted furans from epoxypropargyl esters by sequential SmI2-promoted reduction - Elimination and Pd(II)-catalyzed cycloisomerization

Article abstract of DOI:10.1021/jo0014257

A two-step one-pot synthesis of 2,3,5-trisubstituted furans 8 from 4,5-epoxyalk-2-ynyl esters 6 is described. The sequence is initiated by a SmI₂-promoted reduction that takes advantage of the ability of the alkynyloxirane moiety present in 6 to accept electrons from SmI₂. The resulting organosamarium species then eliminates an adjacent acetate or benzoate leaving group, leading to the formation of unstable 2,3,4-trien-1-ols 7. Without isolation, these are cycloisomerized to furans 8 by treatment with a catalytic amount of a Pd(II) complex and a proton source. The whole sequence takes place under mild reaction conditions. Some useful functional groups such as cyano and α, βunsaturated esters are tolerated, but benzyl- and silyl-protected hydroxyl groups are deprotected to some extent. Starting materials can be easily assembled using reliable reactions from acetylene, an aldehyde or ketone, and a vinyl halide fragment. This offers the possibility of introducing branched substituents at C-5 of the furan ring.

Full text of DOI:10.1021/jo0014257

564
J . Org. Chem. 2001, 66, 564-569
Syn th esis of Tr isu bstitu ted F u r a n s fr om Ep oxyp r op a r gyl Ester s
by Sequ en tia l Sm I2-P r om oted Red u ction -Elim in a tion a n d
P d (II)-Ca ta lyzed Cycloisom er iza tion
J ose´ M. Aurrecoechea,* Elena Pe´rez, and Mo´nica Solay
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apartado 644, 48080 Bilbao, Spain
qopaufem@lg.ehu.es
Received October 2, 2000
A two-step one-pot synthesis of 2,3,5-trisubstituted furans 8 from 4,5-epoxyalk-2-ynyl esters 6 is
described. The sequence is initiated by a SmI2-promoted reduction that takes advantage of the
ability of the alkynyloxirane moiety present in 6 to accept electrons from SmI2. The resulting
organosamarium species then eliminates an adjacent acetate or benzoate leaving group, leading to
the formation of unstable 2,3,4-trien-1-ols 7. Without isolation, these are cycloisomerized to furans
8 by treatment with a catalytic amount of a Pd(II) complex and a proton source. The whole sequence
takes place under mild reaction conditions. Some useful functional groups such as cyano and R,â-
unsaturated esters are tolerated, but benzyl- and silyl-protected hydroxyl groups are deprotected
to some extent. Starting materials can be easily assembled using reliable reactions from acetylene,
an aldehyde or ketone, and a vinyl halide fragment. This offers the possibility of introducing
branched substituents at C-5 of the furan ring.
In tr od u ction
in the introduction of carbon substituents at a given
position of the furan ring have been important consid-
erations that have dictated in many cases a preference
for the latter strategy.3
Furans are an important class of heteroaromatic
compounds that can be found as components in numerous
natural products and substances with useful industrial
applications.1 They are also extensively utilized as useful
synthetic intermediates in the preparation of acyclic,
carbocyclic, and heterocyclic compounds.2 Not surpris-
ingly, considerable effort has been devoted in recent years
to the development of synthetic methodology directed at
the efficient preparation of polysubstituted furans.3 In
this regard, two general strategies have been commonly
utilized that rely on either the structural modification
of a preformed furan nucleus3-5 or the cyclization of
acyclic precursors. Regiochemical control and flexibility
Among the methods employing acyclic precursors,
those that generate the furan nucleus by intramolecular
cyclization of oxygen nucleophiles onto a tethered carbon-
carbon multiple bond have received particular attention.
Thus, the synthesis of furans has been effected from
alkynediols,6 â- or γ-ketoalkynes,7 â- or γ-alkynyl allylic
alcohols,8 allenyl ketones,9 propargylic ketones,10 and
1-alkynyl-2, 3-epoxy alcohols,11 mainly under either
metal- or base-promoted conditions. We have reported
the synthesis of furan derivatives III from epoxypro-
pargyl esters I by SmI2/Pd(0)-promoted reduction-
elimination followed by in situ cycloisomerization of the
* To whom correspondence should be addressed. Phone: 34-94 601
2578. Fax: 34-94 464 8500.
(6) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. Tetrahedron 1985, 41, 3655-3661. (b) J i, J . G.; Lu, X. Y.
J . Chem. Soc., Chem. Commun. 1993, 764-765. (c) Bew, S. P.; Knight,
D. W. J . Chem. Soc., Chem. Commun. 1996, 1007-1008.
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10.1021/jo0014257 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/30/2000

Synthesis of Trisubstituted Furans
J . Org. Chem., Vol. 66, No. 2, 2001 565
Sch em e 1
Sch em e 3a
a
(a) t-BuOK, t-BuOH, 18-C-6, 60 °C.
organosamariums VII or VIII would be formed and
subsequently expel an adjacent leaving group15c-f,h to
eventually afford a hydroxymethyl-1,2,3-triene VI. Trienes
related to VI have been suggested as key intermediates
in the base-promoted cycloisomerization of alkynyl-
oxiranes IX to furans X (Scheme 3).16a This paper reports
the reactions of epoxyalkynol esters of type IV with SmI2
to generate 1,2,3-trienes of type VI, and the subsequent
in situ Pd-catalyzed cycloisomerization of VI to yield
2,3,5-trisubstituted furans of type X in a one-pot reduc-
tion-elimination-cycloisomerization sequence.17
Sch em e 2
Resu lts a n d Discu ssion
Representative substrates 6 (see Table 1 for descrip-
tion) were prepared by epoxidation of enyne esters 5, that
were prepared following either one of the two synthetic
routes depicted in Scheme 4. For esters 5a -i, the lithium
anions of readily available enynes 1 were reacted with
appropriate aldehydes or ketones, and the resulting
alkoxide was trapped in situ with benzoyl chloride
(5a ,b,d -f,h ,i) or, alternatively, the corresponding alco-
hols (4c, 4g) were isolated and acetylated under standard
conditions. For the preparation of esters 5j-m , the
required alcohols 4j-m were prepared by Sonogashira
coupling18 between vinyl bromide 3 and propargyl alco-
hols 2.
so-formed γ-alkynyl allylic alcohols II (Scheme 1).12 One
serious limitation of this strategy for furan synthesis is
that intermediates II are obtained as E/ Z mixtures
where only the minor (Z)-isomers cyclize to the corre-
sponding furans while the major (E)-isomers remain
unchanged.13 It was reasoned that regioisomeric ep-
oxypropargyl esters IV could also lead to furans via a
different mechanism (Scheme 2). In substrates IV ad-
vantage could be taken of the reactivity of their alkynyl-
oxirane14 and propargylic ester12,15 moieties toward SmI2
and SmI2/Pd(0), respectively. It was then conceivable that
In preliminary experiments, treatment of 6a (Scheme
5) with 2.1 equiv of SmI2 and a catalytic amount (5 mol
%) of Pd(PPh3)4 at room temperature led to the rapid
consumption of the starting material with formation of
two products of higher polarity. Aqueous workup afforded
1
a material with a H NMR spectrum compatible with a
(9) (a) Marshall, J . A.; Bartley, G. S. J . Org. Chem. 1994, 59, 7169-
7171. (b) ref 8b. (c) Hashmi, A. S. K.; Schwarz, L. Chem. Ber. 1997,
130, 1449-1456. (d) Hashmi, A. S. K.; Ruppert, T. L.; Knofel, T.; Bats,
J . W. J . Org. Chem. 1997, 62, 7295-7304. (e) Hashmi, A. S. K.; Choi,
J . H.; Bats, J . W. J . Prakt. Chem. 1999, 341, 342-357. (f) Luo, F. T.;
J eevanandam, A.; Bajji, A. C. Tetrahedron Lett. 1999, 40, 121-122.
(g) Ma, S. M.; Zhang, J . L. Chem. Commun. 2000, 117-118. (h) Ma, S.
M.; Li, L. T. Org. Lett. 2000, 2, 941-944.
diastereomeric mixture of alcohols 7a . Characteristic
features of this material were the absence of the benzoyl
group aromatic protons and the presence of multiplets
at δ ∼4.1 and δ ∼5.5 assigned to the carbinolic and allenic
protons of 7a , respectively. This material proved to be
unstable, in agreement with previous reports on 1,2,3-
trienes,19,20 and further characterization was not feasible.
It was also found that the initial reduction-elimination
step could be performed with the same efficiency in the
(10) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27,
4893-4894. (b) J eevanandam, A.; Narkunan, K.; Cartwright, C.; Ling,
Y. C. Tetrahedron Lett. 1999, 40, 4841-4844.
(11) Marson, C. M.; Harper, S. J . Org. Chem. 1998, 63, 9223-9231.
(12) Aurrecoechea, J . M.; Solay-Ispizua, M. Heterocycles 1994, 37,
223-226. This paper also reports a preliminary result on the present
work.
(16) (a) Marshall, J . A.; DuBay, W. J . J . Am. Chem. Soc. 1992, 114,
1450-1456. (b) Katritzky, A. R.; Li, J . Q. J . Org. Chem. 1995, 60, 638-
643. Other syntheses of furans from alkynyloxiranes: Minami, I.;
Yuhara, M.; Watanabe, H.; Tsuji, J . J . Organom. Chem. 1987, 334,
225-242. Mcdonald, F. E.; Schultz, C. C. J . Am. Chem. Soc. 1994, 116,
9363-9364.
(17) For other Pd-catalyzed syntheses of furans, that employ pro-
pargylic alcohol derivatives as substrates see: (a) Tsuji, J .; Mandai,
T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589-2612. (b) Trost, B.
M.; McIntosh, M. C. J . Am. Chem. Soc. 1995, 117, 7255-7256.
(18) Sonogashira, K. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 521-
549.
(13) This is also a limitation in the direct Ru-8c and Pd-catalyzed8e
cycloisomerizations of 2-en-4-yn-1-ols.
(14) Aurrecoechea, J . M.; Alonso, E.; Solay, M. Tetrahedron 1998,
54, 3833-3850.
(15) (a) Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 5237-5240. (b) Tabuchi, T.; Inanaga, J .; Yamaguchi, M.
Chem. Lett. 1987, 2275-2278. (c) Okamura, W. H.; Aurrecoechea, J .
M.; Gibbs, R. A.; Norman, A. W. J . Org. Chem. 1989, 54, 4072-4083.
(d) Enas, J . D.; Palenzuela, J . A.; Okamura, W. H. J . Am. Chem. Soc.
1991, 113, 1355-1363. (e) Enas, J . D.; Shen, G. Y.; Okamura, W. H.
J . Am. Chem. Soc. 1991, 113, 3873-3881. (f) Vanalstyne, E. M.;
Norman, A. W.; Okamura, W. H. J . Am. Chem. Soc. 1994, 116, 6207-
6216. (g) Sugimoto, Y.; Hanamoto, T.; Inanaga, J . Appl. Organomet.
Chem. 1995, 9, 369-375. (h) Marco-Contelles, J .; Destabel, C.; Chiara,
J . L. Tetrahedron Asymmetry 1996, 7, 105-108. (i) Aurrecoechea, J .
M.; Fan˜ana´s, R.; Arrate, M.; Gorgojo, J . M.; Aurrekoetxea, N. J . Org.
Chem. 1999, 64, 1893-1901.
(19) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J . F. Tetra-
hedron 1991, 47, 1677-1696.
(20) Chow, H. F.; Cao, X. P.; Leung, M. K. J . Chem. Soc., Perkin
Trans. 1 1995, 193-196. Wang, K. K.; Liu, B.; Lu, Y. D. J . Org. Chem.
1995, 60, 1885-1887.

566 J . Org. Chem., Vol. 66, No. 2, 2001
Ta ble 1. Syn th esis of F u r a n s 8 fr om Ep oxyp r op a r gyl Ester sa
Aurrecoechea et al.
6
6
R1
R2
R3
R4
R
Pd(II)
8
yield (%)
1
2
3
4
5
6
7
6a
6a
6a
6b
6c
6d
6e
6e
6e
6f
6g
6h
6h
6i
6i
6j
6k
6k
6l
6l
6l
6m
6m
6m
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
Me
CHMe2
Et
Et
H
H
H
Bz
Bz
Bz
Bz
Ac
Bz
Bz
Bz
Bz
Bz
Ac
Bz
Bz
Bz
Bz
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Pd(OAc)2(PPh3)2
Pd(OAc)2
Pd(OAc)2/PPh3
8a
8a
8a
8b
8c
8d
8e
8e
8e
8f
8g
8h
8h
8i
8i
8j
8k
8k
8l
8l
8l
8m
8m
8m
80
51
32
74
73
76
c
79
70
54
52
31
69e
g
b
Me
Me
H
Et
Et
Et
Me
H
H
H
H
H
Me
H
H
Me
Me
Me
H
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
PdCl2(MeCN)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
PdCl2(MeCN)2
Pd(OAc)2
8d
9d
10
11
12
13d
14
15d
16
17
18d
19
20
21
22
23
24
Et
(CH2)3CN
(E)-(CH2)3CHdCHCO2Et
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
CH2OBn
CH2OBn
(CH2)3CN
(CH2)3CN
(CH2)3CN
(E)-(CH2)3CHdCHCO2Et
(E)-(CH2)3CHdCHCO2Et
(E)-(CH2)3CHdCHCO2Et
CH2-OBn
CH2-OBn
CH2-OPf
CH2-OPf
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
35h
63
g
31
78
77
69
70
65
60
Me
Me
Me
Me
Me
Me
Me
Me
Pd(OAc)2(PPh3)2
PdCl2(MeCN)2
PdCl2(PPh3)2
H
H
a
Unless otherwise indicated, substrate 6 was treated with SmI2 (2.1 equiv) at -5 °C, followed by H2O (2 equiv), AcOH (2 equiv), and
a Pd(II) complex (5 mol %) at room temperature. 10 mol % of PPh3, relative to 6, was used. c Furan 8e was obtained in trace amounts.
b
AcOH was omitted, and 20 equiv of H2O were used. e Benzyl alcohol was isolated in 30% yield. f P ) SiPh2t-Bu. Triene intermediate
d
g
h
underwent degradation. No furan was obtained. t-BuPh2SiOH isolated in 39% yield.
Sch em e 4a
Sch em e 5
Sch em e 6
a
(a) (i) n-BuLi, -78 °C; (ii) R3COR4, -78 °C f rt; (b) BzCl, 0
°C f rt. (c) 2, PdCl2(PPh3)2, CuI, Et2NH, rt. (d) Ac2O, Et3N, DMAP,
rt. (e) MCPBA, CH2Cl2, 0 °C f rt.
resonances at δ ∼200, assigned to the allenic-type sp-
hybridized carbons of 7h .
absence of Pd(0), indicating that reduction of the alky-
nyloxirane14 moiety takes place first to give VII (Scheme
2), followed by expulsion of the benzoate leaving group
and formation of the alkoxide V. Similarly, starting from
epoxypropargyl ester 6h , treatment with SmI2 at -5 °C
afforded two products, assigned as the diastereomeric
pair of alcohols 7h (Scheme 5). In contrast to 7a , the
alcohols 7h were sufficiently stable to allow quick puri-
fication by chromatography in silica gel, eventually
When 7a was exposed to the basic conditions previ-
ously reported for isomerization of alkynyloxiranes to
furans,16 a process which is thought to proceed in part
through trienes VI, a very low yield (7%) of furan 8a was
realized (Scheme 6). The similar treatment of 7h also
resulted in a low yield (25%) of furan 8h (Scheme 6).
Alternatively, the samarium alkoxide (i.e., V) obtained
by treatment of 6a with SmI2 and catalytic Pd(PPh3)4 was
protonated in situ with water (2 equiv) and then treated
with an acidic resin. This resulted in a substantial
improvement, with 8a being isolated in 50% overall yield
in a one-pot procedure starting from 6a . However, these
acidic conditions failed to promote the corresponding
1
leading to the isolation of 7h in 71% yield. The H and
13C NMR spectra of these products were consistent with
the proposed structures. Thus, 1H NMR showed the
expected carbinolic and allenic proton resonances, whereas
the 13C NMR spectrum displayed two characteristic

Synthesis of Trisubstituted Furans
J . Org. Chem., Vol. 66, No. 2, 2001 567
Sch em e 7
Sch em e 8
cyclization of 7h to 8h , as only degradation of 7h was
observed. For formation of 8a , the acidic resin could be
replaced by acetic acid (30 equiv) with similar efficiency
(47% yield from 6a ). Significantly, no furan 8a was
obtained in the absence of resin or acetic acid, even under
refluxing conditions; neither was cyclization effective if
the initial reduction step was performed in the absence
of Pd(0). These experiments appear to indicate that
conversion of 7 to 8 requires both the presence of
palladium and a proton source. On mechanistic grounds
(vide infra) it is therefore likely that the actual promoter
of cyclization is probably a Pd(II) species formed adventi-
tiously from the Pd(0) catalyst when this is used in the
initial reduction-elimination step. In fact, a number of
examples have been described in recent years of Pd(II)-
mediated cycloisomerization of a variety of unsaturated
alcohols leading to substituted furans.21 As shown below,
this was also found to be case for 2,3,4-triene-1-ols 7,
generated from epoxypropargyl esters 6, that cyclo-
isomerize to 2,3,5-trisubstituted furans 8 (Scheme 7)
under Pd(II)-catalyzed conditions.
After some experimentation, we found that appropriate
conditions for formation of furans 8 involved initial
treatment of 6 with SmI2 (ca. 2.1 equiv) at -5 °C,
followed, after consumption of the starting material
(formation of 7 could be monitored by TLC), by addition
at room temperature of a proton source and a Pd(II)
complex (5 mol %). In this way, furans 8 were generally
obtained in good yields under mild reaction conditions
in a one-pot procedure starting from 6 (Scheme 7). The
formation of 8 is readily interpreted in terms of intramo-
lecular oxypalladation of an activated double bond of 7
to give a palladium σ-complex 9, followed by tautomer-
ization and protonolysis of the C-Pd bond (Scheme 8).
The reverse order in the last two steps is also possible.
Results of the application of this procedure to the
synthesis of trisubstituted furans 8 are collected in Table
1. The combined use of water and acetic acid (2 equiv
each) as proton source gave conveniently short reaction
times (usually 1-6 h) for the cyclization step. However,
for acid-sensitive substrates and/or products (see forma-
tion of 8e, 8h , 8i, 8k in Table 1 and discussion below)
this led to low yields or even no formation of furans 8.
In these cases, it was found that replacing the acetic acid
by water (total 20 equiv)7b led to better results in still
reasonable reaction times (∼20 h). It is likely that, under
the former conditions, the role of acetic acid is to enhance
the C-Pd bond protonolysis rate in the final step leading
to 8 (Scheme 8). As Pd(II) source, Pd(OAc)2(PPh3)2 was
used in most cases with good results, but other palladium
catalysts were also useful. For example, similar results
were obtained with PdCl2(MeCN)2 as cyclization pro-
moter (entries 9, 20, 23), while Pd(OAc)2 and PdCl2-
(PPh3)2 gave inferior results (entries 2, 3, 21, 24).
From inspection of Table 1, it appears that the se-
quence 6-to-8 can be useful for formation of both mono-
cyclic and bicyclic systems. The possibility of introducing
R-branched alkyl chains at C-5 also appears feasible (as
exemplified by R4 ) Me in entries 4, 5, 10, 16, 19) if
ketones rather than aldehydes are employed in the
preparation of intermediate precursors 4 or 5 (Scheme
4). Also practical from the strategic point of view is the
flexibility possible in the assembly of the starting materi-
als by using appropriate combinations of building blocks
1-3 and carbonyl derivatives R3COR.4 A number of
functional groups are tolerated by the mild reaction
conditions used throughout the synthesis of 8, including
substrate preparation, reduction, and cyclization steps.
However, the method appears to be limited to aliphatic
R3, R4 groups, as a substrate 6 derived from 1a and
benzaldehyde led to no furan formation. Some other
limitations are also apparent from the results presented
in Table 1. For example, hydroxyl groups protected as
benzyl or TBDPS ethers undergo deprotection to some
extent, as evidenced by the isolation of benzyl alcohol
(30%) and t-BuPh2SiOH (39%) in entries 13 and 15,
respectively. Since these protecting groups are stable
under the typical SmI2 reduction conditions,14 it would
appear that deprotection takes place during the cycliza-
tion step. It is remarkable that this was the case even in
the absence of acetic acid (entries 13, 15). Therefore, it
is likely that the combination of water and Lewis-acidic
Sm(III) species (originated in the reduction step), with
or without the intervention of Pd(II),22 is capable of
promoting alcohol deprotection in these cases.23
In conclusion, we have shown that 4,5-epoxyalk-2-ynyl
esters are practical and convenient precursors of 2,3,5-
trisubstituted furans. This transformation is readily
(22) TBDMS ethers undergo hydrolysis with Pd(II)/H2O, but the
corresponding deprotection of TBDPS ethers under similar conditions
has not been described. See: Wilson, N. S.; Keay, B. A. J . Org. Chem.
1996, 61, 2918-2919.
(21) See refs 6a, 8c, 8e, 8f, 8g. See also: Igarashi, S.; Haruta, Y.;
Ozawa, M.; Nishide, Y.; Kinoshita, H.; Inomata, K. Chem. Lett. 1989,
737-740. Larock, R. C.; Doty, M. J .; Han, X. J . Tetrahedron Lett. 1998,
39, 5143-5146.
(23) The corresponding furans with unprotected hydroxymethyl
(entries 12-15) or 2-hydroxyethyl (entries 17, 18) groups were not
isolated. Besides the products indicated in Table 1, only complex
uncharacterized mixtures were obtained in these reactions.

568 J . Org. Chem., Vol. 66, No. 2, 2001
Aurrecoechea et al.
organic layers were dried (Na2SO4), and the solvent was
evaporated. The crude was purified by flash chromatography
as indicated in the Supporting Information for the individual
cases.
achieved, under mild reaction conditions, in a one-pot
sequence comprising SmI2-promoted reduction and Pd(II)-
mediated cycloisomerization of intermediate 2,3,4-trien-
1-ols. In retrosynthetic terms, this strategy allows the
generation of the carbocyclic framework of the hetero-
cyclic ring from one acetylene molecule (C-4 and C-5) and
a disubstituted vinylic fragment (C-2 and C-3). The third
substituent at C-5 is derived from aldehyde or ketone
building blocks, and this also effectively introduces the
possibility of R-branching at that position of the furan
ring.
Gen er a l Ep oxid a tion P r oced u r e. P r ep a r a tion of 4,5-
Ep oxya lk -2-yn yl Ester s 6. In a typical experiment, to a
solution of the appropriate acetate or benzoate 5 (8.2 mmol)
in CH2Cl2 (14 mL) at 0 °C was added MCPBA (57%, 6.54 g,
21.6 mmol). The solution was stirred for 30 min and allowed
to warm to room temperature. After stirring the solution for
2 h at room temperature, 1 M NaOH (100 mL) was added,
and the layers were separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
washed with 1 M NaOH. The residue after evaporation was
purified by flash chromatography as indicated in the Support-
ing Information for the individual cases.
Exp er im en ta l Section
Gen er a l. All reactions involving air- and moisture-sensitive
materials were performed using standard benchtop tech-
niques.24 Tetrahydrofuran (THF) was freshly distilled from
sodium/benzophenone and, for reactions with SmI2, it was
deoxygenated prior to use. Acetic anhydride, acetone, benzyl-
acetone, 5-oxohexanenitrile, 3-pentanone, CH2Cl2, and triethyl-
amine were distilled from CaH2. Solutions of SmI2 in THF were
prepared from Sm and either diiodoethane, diiodomethane, or
iodine using literature procedures.25 Flash column chroma-
tography26 was performed on silica gel (230-400 mesh). HPLC
purifications were carried out with either LiChrosorb Si60 (7
µm, 25 × 2.5 cm, column 1) or µPorasil (10 µm, 19 × 1.5 cm,
column 2) columns using a refraction index detector. Routine
1H and 13C NMR spectra were obtained at 250 and 62.9 MHz,
respectively, using CDCl3 as solvent and internal reference (δ
7.26 for 1H and δ 77.0 for 13C). IR data include only charac-
teristic absorptions. Mass spectra were obtained at 70 eV.
Gen er a l P r oced u r e for Dir ect P r ep a r a tion of Ben -
zoa tes 5a ,b,d -f,h ,i fr om En yn es 1. In a typical experiment,
n-BuLi (1.4 M, 10.5 mL, 15.0 mmol) was added dropwise to a
solution of enyne 1 (19.0 mmol) in THF (62 mL) at -78 °C
under Ar, and the resulting solution was stirred at the same
temperature for 45 min. A solution of an appropriate aldehyde
or ketone (13.8 mmol) in THF (25 mL) was added, and the
reaction mixture was allowed to reach rt and stirred further
1 h. It was then cooled to 0 °C, and neat benzoyl chloride (2.90
g, 20.7 mmol) was added in one portion. After stirring the
mixture 1 h at room temperature, it was quenched with water
(20 mL) and extracted with EtOAc. The combined organic
extracts were dried (Na2SO4), and the crude product was
purified by flash chromatography as indicated in the Support-
ing Information for the individual cases.
Gen er a l P r oced u r e for P r ep a r a tion of En yn ols 4 fr om
Vin yl Br om id e 3 a n d P r op a r gylic Alcoh ols 2 (Son oga sh -
ir a Cou p lin g). In a typical experiment, a solution of 2 (21.0
mmol) in Et2NH (16 mL) was added to a solution of trans-2-
bromobut-2-ene (3) (2.13 mL, 21.0 mmol), Pd(PPh3)2Cl2 (0.35
g, 0.5 mmol), and CuI (0.38 g, 2.0 mmol) in Et2NH (105 mL)
under Ar. The resulting solution was stirred for 16 h at room
temperature. Then a solution of NH4Cl (100 mL) was added,
and the layers were separated. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were
washed with brine. The residue after evaporation was purified
by flash chromatography as indicated in the Supporting
Information for the individual cases.
P r ep a r a tion of F u r a n s 8 fr om Ester s 6 w ith Sm I2/
P d (II). Gen er a l P r oced u r e. In a typical experiment, to a
solution of SmI2 (ca. 0.1 M, 0.58 mmol) in THF (5.8 mL) was
added via cannula a solution of the ester 6 (0.27 mmol) in THF
(3 mL) at -5 °C under Ar. The solution was stirred until
consumption of the starting material as judged by TLC (2-5
h). The cooling bath was removed, and the reaction mixture
was allowed to reach rt. If at that point excess SmI2 remained
(blue-tinted solution), dry air and Ar were successively bubbled
for 5 min each upon which the color changed from blue to
brown-green. To the resulting mixture were successively added
H2O (10.0 µL, 0.54 mmol), AcOH (31.0 mL, 0.54 mmol), and a
Pd(II) complex (0.014 mmol) (see Table 1). In entries 8, 9, 13,
15, 18 (Table 1), this procedure was modified as follows. AcOH
was not used, and the amount of H2O was increased to 10 mL
(5.4 mmol). The reaction mixture was stirred until complete
dissappearance of the presumed trienol intermediate (3-20
h). Saturated K2CO3 (5 mL) was then added, and the layers
were separated. The aqueous layer was extracted with EtOAc,
and the combined organic extracts were washed with brine
and dried (Na2SO4). The residue after evaporation was purified
by flash chromatography as specified below for the individual
cases.
2-(3-P h en ylp r op yl)-4,5,6,7-tetr a h yd r oben zofu r a n (8a ).
Prepared in 80% yield from benzoate 6a after elution with
hexanes. Colorless oil: 1H NMR δ 1.73-1.93 (m, 4H), 2.04 (q,
J ) 7.5 Hz, 2H), 2.45 (apparent t, 2H), 2.62 (t, J ) 6.0 Hz,
2H), 2.67 (t, J ) 7.6 Hz, 2H), 2.75 (t, J ) 7.6 Hz, 2H), 5.87 (s,
1H), 7.2-7.3 (m, 5H); 13C NMR δ 22.1, 23.1, 23.2, 27.6, 29.8,
35.3, 105.8, 117.1, 125.7, 128.2, 128.4, 142.1, 148.7, 153.5; IR
(neat) υ 3060, 2930, 2850, 1600, 1250, 700 cm-1. Anal. Calcd
for C17H20O: C, 84.94; H, 8.39. Found: C, 84.59; H, 8.34.
2-(3-P h en yl-1-m eth ylp r op yl)-4,5,6,7-tetr a h yd r oben zo-
fu r a n (8b). Prepared in 74% yield from benzoate 6b after
elution with hexanes. Colorless oil: 1H NMR δ 1.30 (d, J )
6.9 Hz, 3H), 1.78-1.99 (m, 5H), 2.04-2.21 (m, 1H), 2.49-2.50
(m, 2H), 2.51-2.65 (m, 3H), 2.68 (t, J ) 8.0 Hz, 1H), 2.84-
2.98 (hexaplet, J ) 6.9 Hz, 1H), 5.93 (s, 1H), 7.11-7.35 (m,
5H); 13C NMR δ 19.4, 22.1, 23.1, 32.8, 33.5, 37.5, 104.5, 116.8,
125.6, 128.2, 128.4, 142.5, 148.6, 157.9; IR (CHCl3) υ 2940,
2880, 1610, 1460, 705 cm-1. Anal. Calcd for C18H22O: C, 84.98;
H, 8.72. Found: C, 84.98; H, 8.75.
2-(1-Meth yleth yl)-4,5,6,7-tetr a h yd r oben zofu r a n (8c).
Prepared in 73% yield from acetate 6c after elution with
1
Gen er a l P r oced u r e for Acetyla tion of En yn ols 4. In a
typical experiment, a mixture of 4 (22.0 mmol), DMAP (0.81
g, 6.5 mmol), Et3N (9.2 mL, 66.0 mmol), and Ac2O (4.7 mL,
50.0 mmol) was stirred for 16 h at room temperature. The
residue was poured over a mixture of H2O/ice (20 mL). After
separation of the layers, the organic layer was washed suc-
cessively with 1 M HCl, 1 M NaOH, and brine. The combined
hexanes: H NMR δ 1.23 (d, J ) 6.8 Hz, 6H), 1.67-1.87 (m,
4H), 2.37-2.42 (m, 2H), 2.54-2.59 (m, 2H), 2.84-2.92 (hep-
tuplet, J ) 6.8 Hz, 1H), 5.79 (s, 1H); 13C NMR δ 21.3, 22.2,
23.1, 23.2, 27.8, 103.4, 116.9, 148.6, 159.7; IR (CHCl3) υ 2980,
2960, 2860, 1650, 1450, 1230, 960, 920, 800, 740 cm-1; HRMS
calcd for C11H16O 164.1201, found 164.1197.
2-(2-Meth ylp r op yl)-4,5,6,7-tetr a h yd r oben zofu r a n (8d ).
Prepared in 76% yield from benzoate 6d after elution with
hexanes: 1H NMR δ 0.94 (d, J ) 6.6 Hz, 6H), 1.68-1.87 (m,
4H), 1.94 (heptuplet, J ) 6.7 Hz, 1H), 2.38 (tt, J ) 6.0, 1.9
Hz, 2H), 2.43 (d, J ) 7.1 Hz, 2H), 2.55 (tt, J ) 6.1, 1.9 Hz,
2H), 5.79 (s, 1H); 13C NMR δ 22.1, 22.4, 23.1, 23.2, 27.9, 37.4,
106.5, 117.0, 148.7, 153.2; IR (neat) υ 2920, 2840, 1470, 1120
cm-1; HRMS calcd for C12H18O 178.1358, found 178.1355.
(24) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis Via Boranes; J ohn Wiley & Sons: New York, 1975;
pp 191-261.
(25) Molander, G. A. In Organic Reactions; Paquette, L. A., Ed.; J ohn
Wiley & Sons: New York, 1994; Vol. 46; pp 211-367.
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

Synthesis of Trisubstituted Furans
J . Org. Chem., Vol. 66, No. 2, 2001 569
2-(1-E t h ylp r op yl)-4,5,6,7-t et r a h yd r ob en zofu r a n (8e).
Prepared in 79% yield from benzoate 6e after elution with
hexanes. Colorless oil: 1H NMR δ 0.86 (t, J ) 7.3 Hz, 6H),
1.54-1.86 (m, 8H), 2.36-2.45 (m, 3H), 2.53-2.55 (m, 2H), 5.77
(s, 1H); 13C NMR δ 11.8, 22.2, 23.2, 26.4, 42.3, 105.6, 116.7,
δ 1.05 (s, 9H), 1.77 (s, 3H), 1.90 (quint, J ) 7.5 Hz, 2H), 2.58
(t, J ) 7.4 Hz, 2H), 2.68 (t, J ) 7.6 Hz, 2H), 4.58 (s, 2H), 5.77
(s, 1H), 7.23-7.46 (m, 11H), 7.72 (m, 4H); 13C NMR δ 9.7, 19.3,
26.8, 27.5, 29.6, 35.2, 56.7, 108.3, 117.8, 125.7, 127.5, 128.3,
128.5, 129.5, 133.7, 135.7, 142.1, 147.2, 154.5; IR (neat) υ 2860,
1450, 1430, 1110, 1050, 700 cm-1. Anal. Calcd for C31H36O2Si:
C, 79.44; H, 7.75. Found: C, 79.01; H, 7.77.
148.4, 156.6; IR (CHCl3) υ 2960, 2940, 1760, 1220, 790 cm-1
.
Anal. Calcd for C13H20O: C, 81.18; H, 10.49. Found: C, 80.82;
H, 10.59.
5-(3-P h en yl-1-m eth ylpr opyl)-2,3-dim eth ylfu r an (8j). Pre-
pared in 63% yield from acetate 6j after elution with hexanes.
Colorless oil: 1H NMR δ 1.31 (d, J ) 7.0 Hz, 3H), 1.80-1.92
(m, 1H), 1.99 (s, 3H), 2.02-2.13 (m, 1H), 2.25 (s, 3H), 2.68 (t,
J ) 8.0 Hz, 2H), 2.78-2.86 (m, 1H), 5.85 (s, 1H), 7.21-7.37
(m, 5H); 13C NMR δ 9.9, 11.2, 19.3, 32.6, 33.4, 37.5, 106.8,
113.9, 125.6, 128.2, 128.4, 142.5, 145.1, 157.2; IR (neat) υ
2-(4-Cya n o-1-m et h ylb u t yl)-4,5,6,7-t et r a h yd r ob en zo-
fu r a n (8f). Prepared in 54% yield from benzoate 6f. Elution
with 3% EtOAc/hexanes, yielded 8f as a colorless oil: 1H NMR
δ 1.21 (d, J ) 6.7 Hz, 3H), 1.60-1.80 (m, 8H), 2.20-2.50 (m,
4H), 2.50-2.54 (m, 2H), 2.70-2.80 (m, 1H), 5.80 (s, 1H); 13C
NMR δ 17.0, 19.2, 22.0, 23.0, 32.5, 34.8, 104.8, 116.8, 119.7,
148.8, 156.7; IR (neat) υ 2930, 2220, 1235 cm-1; HRMS calcd
for C14H19NO 217.1467, found 217.1476.
3080-3020, 2950, 1230, 950 cm-1; HRMS calcd for C16H20
228.1514, found 228.1515.
O
5-(2-Ben zyloxyeth yl)-2,3-d im eth ylfu r a n (8k ). Prepared
in 31% yield from acetate 6k . After flash chromatography (2%
EtOAc/hexanes), the product was further purified by HPLC
(Column 1, 5% EtOAc/hexanes, 8 mL/min), yielding 8k as an
2-[(E)-6-E t h oxyca r b on ylh e x-5-e n yl]-4,5,6,7-t e t r a h y-
d r oben zofu r a n (8g). Prepared in 52% yield from acetate 6g
after elution with 2% EtOAc/hexanes. Colorless oil: 1H NMR
δ 1.28 (t, J ) 7.1 Hz, 3H), 1.51-1.81 (m, 8H), 2.18-2.26 (m,
2H), 2.36-2.38 (m, 2H), 2.53-2.60 (m, 4H), 4.18 (q, J ) 7.1
Hz, 2H), 5.78 (s, 1H), 5.81 (dt, J ) 15.5, 1.6 Hz, 1H), 6.96 (dt,
J ) 15.5, 7.1 Hz, 1H); 13C NMR δ 14.2, 22.0, 23.1, 27.4, 27.8,
31.8, 60.1, 105.7, 117.0, 121.3, 148.7, 149.0, 153.3, 166.6; IR
(neat) υ 2930, 1730, 1655, 1260 cm-1; HRMS calcd for C17H24O3
276.1725, found 276.1719.
1
oil: tR ) 33 min; H NMR δ 1.89 (s, 3H), 2.16 (s, 3H), 2.87 (t,
J ) 7.0 Hz, 2H), 3.69 (t, J ) 7.0 Hz, 2H), 4.54 (s, 2H), 5.84 (s,
1H), 7.26-7.38 (m, 5H); 13C NMR δ 9.9, 11.2, 28.8, 68.5, 72.9,
109.1, 114.3, 127.5, 127.6, 128.3, 138.3, 145.6, 149.7; IR (neat)
υ 3080, 3020, 2920, 2850, 1100 cm-1; HRMS calcd for C14H15O2
(M-CH3) 215.1072, found 215.1075.
5-(4-Cya n o-1-m eth ylbu tyl)-2,3-d im eth ylfu r a n (8l). Pre-
pared in 77% yield from acetate 6l. After flash chromatography
(5% EtOAc/hexanes), the product was further purified by
HPLC (Column 1, 5% EtOAc/hexanes, 9 mL/min) yielding 8l
1-Ben zyloxy-3-m eth yl-8-ph en ylocta-3,4,5-tr ien -2-ol (7h ).
To a solution of SmI (ca. 0.1 M, 1.22 mmol) was added a
2
solution of benzoate 6h (0.20 g, 0.44 mmol) at -5 °C under
Ar. The reaction mixture was stirred for 1h and quenched with
sat K2CO3 (10 mL). The layers were separated, the organic
layer was extracted with EtOAc, and the combined organic
extracts were washed with brine and dried (Na2SO4). The
crude product was purified by flash chromatography (15%
EtOAc/hexanes) to afford 7h (71%, diastereomeric mixture) as
a yellowish oil that decomposed slowly upon standing: 1H
NMR δ 1.71-1.83 (m) and 1.93-2.09 (m) (total 3H), 2.47-
2.88 (m, 4H), 3.46-3.71 (m, 2H), 4.26 (br s, minor isomer) and
4.37 (br s, major isomer) (total 1H), 4.59-4.61 (m, 2H), 5.25-
5.31 (m, minor isomer) and 5.52-5.61 (m,major isomer) (total
1H), 7.18-7.36 (m, 10H); 13C NMR δ 15.6, 15.8, 19.1, 19.5,
28.3, 30.7, 34.0, 34.2, 34.9, 35.2 71.2, 71.3, 72.8, 72.9, 73.0,
73.1 73.3, 73.4, 92.9, 93.0, 99.9, 105.9, 106.0, 115.6, 125.6,
125.9, 127.7, 128.3, 128.4, 137.8, 137.9, 141.3, 141.4, 142.3,
1
as an oil: tR ) 30 min; H NMR δ 1.21 (d, J ) 6.9 Hz, 3H),
1.25-1.84 (m, 4H), 1.89 (d, J ) 0.5 Hz, 3H), 2.15 (s, 3H), 2.22-
2.32 (m, 1H), 2.70-2.75 (m, 1H), 5.75 (s, 1H); 13C NMR δ 9.8,
11.2, 17.1, 19.2, 23.1, 32.4, 34.7, 107.1, 113.9, 119.7, 145.4,
156.1; IR (neat) υ 3000-2850, 2240, 1460, 1230 cm-1; HRMS
calc for C12H17O 191.1310, found: 191.1306.
5-[(E )-6-E t h o x y c a r b o n y lh e x -5-e n y l]-2,3-d im e t h y l-
fu r a n (8m ). Prepared in 70% yield from acetate 6m . After
flash chromatography (hexanes), the product was further
purified by HPLC (Column 1, 1% EtOAc/hexanes, 9 mL/min)
yielding 8m as an oil: tR ) 19 min; 1H NMR δ 1.27 (t, J ) 7.1
Hz, 3H), 1.43-1.68 (m, 4H), 1.88 (s, 3H), 2.14 (s, 3H), 2.16-
2.25 (m, 2H), 2.52 (t, J ) 7.2 Hz, 2H), 4.17 (7.1, 2H), 5.73 (s,
1H), 5.80 (dt, J ) 15.6, 1.4 Hz, 1H), 6.95 (dt, J ) 15.6, 1.4 Hz,
1H); 13C NMR δ 9.7, 11.1, 14.1, 27.3, 27.6, 31.7, 60.0, 107.9,
114.0, 121.3, 145.1, 148.9, 152.5, 166.5; IR (neat) υ 2990-2860,
1750, 1660, 1450, 1040 cm-1; HRMS calcd for C15H22O3
250.1569, found 250.1561.
156.5, 160.6, 200.5, 200.6; IR (neat) υ 3400, 1100, cm-1
.
2-B e n zy lo x y m e t h y l-3-m e t h y l-5-(3-p h e n y lp r o p y l)-
fu r a n (8h ). Prepared from benzoate 6h . Elution with 2.5%
EtOAc/hexanes afforded furan 8h (69%) as a yellowish oil: 1H
NMR δ 1.89-2.07 (m, 5H), 1.97 (s, included in m at 1.89-
2.07), 2.58-2.70 (quint, J ) 7.5 Hz, 4H), 4.41 (s, 2H), 4.53 (s,
2H), 5.85(s, 1H), 7.18-7.38 (m, 10H); 13C NMR δ 9.9, 27.5,
29.6, 35.3, 61.8, 71.5, 108.5, 119.8, 125.8, 127.6, 127.8, 128.3,
128.5, 138.3, 142.0, 145.4, 155.3; IR (CHCl3) υ 3025, 2930,
2860, 1600, 1450, 1060, 740, 700 cm-1. Anal. Calcd for
Ack n ow led gm en t. Financial support by Ministerio
de Educacio´n y Cultura (PB92-0449 and PB95-0344)
and by Universidad del Pa´ıs Vasco (UPV 170.310-
EC021/92, 170.310-EC201/94 and 170.310-EB001/99) is
gratefully acknowledged. We also thank Ministerio de
Educacio´n y Cultura and Universidad del Pa´ıs Vasco
for Fellowships to M.S. and E.P., respectively.
C
22H24O2: C, 82.45; H, 7.55. Found: C, 82.46; H, 7.63.
2-(ter t-Bu t yld ip h en ylsilyloxym et h yl)-3-m et h yl-5-(3-
p h en ylp r op yl)fu r a n (8i). Prepared from benzoate 6i. Elution
with 2.5% EtOAc/hexanes afforded furan 8i (35%) as a
yellowish oil. Further elution with 10% EtOAc/hexanes af-
forded tert-butyldiphenylsilanol27 (39%). Data for 8i: 1H NMR
Su p p or t in g In for m a t ion Ava ila b le: Preparation of 2.
Characterization data for 2, 5, 6, 7h . Copies of 1H NMR spectra
for 6, 7h , 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) Mullen, D. G.; Barany, G. J . Org. Chem. 1988, 53, 5240-5248.
J O0014257