The preparation of 2,3,5-tri- and 2,3-disubstituted furans by regioselective palladium(0)-catalyzed coupling reactions: Application to the syntheses of rosefuran and the F5 furan fatty acid

Article abstract of DOI:10.1002/(sici)1099-0690(199909)1999:9<2045::aid-ejoc2045>3.0.co;2-6

The 5-acceptor-substituted 2,3-dibromofurans 1 and 2 underwent a regioselective Pd⁰-catalyzed coupling reaction at the C-2 carbon atom. With alkynes the corresponding 2-alkynylfurans 4 and 5 were accessible (49-97% yield) Alkyl-, aryl-, and alk

Full text of DOI:10.1002/(sici)1099-0690(199909)1999:9<2045::aid-ejoc2045>3.0.co;2-6

FULL PAPER
The Preparation of 2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective
Palladium(0)-Catalyzed Coupling Reactions: Application to the Syntheses of
Rosefuran and the F5 Furan Fatty Acid
Thorsten Bach*[a] and Lars Krüger[a]
Keywords: Homogenous catalysis / Palladium / Cross-coupling / Heterocycles / Synthetic methods
The 5-acceptor-substituted 2,3-dibromofurans
1
and
2
catalyst in THF (reflux) to yield compounds 13–16 and 24
(67–76% ) and with SnMe4 and PdCl2[P(o-Tol)3]2 as the
catalyst in DMA (90 °C) for the 2-allyl-3-bromofuran 8e to
yield 18 (70% ). The more facile reaction of the 2-
alkynylfurans relative to those of furans bearing an sp3-
carbon atom at C-2 appears to be due to steric reasons.
Studies on the 2-alkyl-3-bromofuran 20 supported this
notion. With the regioselective coupling methodology the
terpene rosefuran (22) was prepared in four steps starting
from furan 2 (35% yield overall). The F5 furan fatty acid (26)
was synthesized from furan 1 in five steps (29% yield
overall).
underwent a regioselective Pd0-catalyzed coupling reaction
at the C-2 carbon atom. With alkynes the corresponding 2-
alkynylfurans 4 and 5 were accessible (49–97% yield). Alkyl-,
aryl-, and alkenylzinc reagents gave the 2-substituted furans
8 starting from compound 2 (66–84% yield). The 2-allylfurans
8e and 8f were obtained by a regioselective Stille coupling
in 79% and 73% yield. The latter reaction was also applied to
the parent 2,3-dibromofuran (27) and yielded the substitution
product 28 (60% yield). Subsequent Pd0-catalyzed reactions
to introduce
a
methyl group in 3-position by
a
methyldebromination were successfully conducted for 2-
alkynyl-3-bromofurans with MeZnCl and PdCl2(PPh3)2 as the
Multiply substituted furans[1] have recently attracted in-
creasing attention as synthetic target compounds[2] due to
their widespread occurence in nature and due to the wide
range of biological activities they cover. Some prominent
examples of naturally occurring tri- or tetrasubstituted fu-
rans include the abundant furan fatty acids,[3] the sphingan-
ine-derived calicogorgins[4] and the cytotoxic, diterpenoid
furanocembranes,[5] pseudopteranes,[6] and gersolanes.[7] In
addition, many other terpenes are known to contain a mul-
tiply substituted furan ring, e.g. the monoterpenes rosefu-
ran[8] and α-clausenan,[9] the sesquiterpenes agassizin and
furodysin,[10] and the diterpene mikanifuran.[11]
Our synthetic approach to 2,3-di- and 2,3,5-trisubstituted
furans is depicted in Scheme 1. We speculated that the read-
ily available 5-acceptor-substituted 2,3-dibromofurans 1[12]
and 2[12] (A ϭ acceptor) can be selectively substituted at
the 2-position by Pd0-catalyzed cross-coupling reactions[13]
(step I). In subsequent operations the transformation of the
formyl group (A ϭ CHO) to a carbon side chain with con-
ventional olefination methods (step IIa) and the substi-
tution of the bromine at C-3 in a second Pd0-catalyzed
coupling reaction (step IIIa) was projected to yield 2,3,5-
trisubstituted furans. Alternatively, a furan with the more
robust methoxycarbonyl substituent at the 5-position (A ϭ
COOMe) appeared to be suited for a second Pd0-catalyzed
coupling at C-3 (step IIb) immediately after the first substi-
tution. Straightforward saponification and decarboxylation
was expected to yield 2,3-disubstituted furans.
Scheme 1. General strategy for preparation of 2,3,5-tri- and 2,3-
disubstituted furans from the 2,3-dibromofurans 1 and 2
The notion of a selective coupling in 5-acceptor-substi-
tuted 2,3-dibromofurans (step I, Scheme 1) was based on
the assumption that the oxidative addition of Pd0 was the
regioselectivity-determining step of the reaction. The
known propensity of these furans to undergo nucleophilic
substitution reactions with high preference at C-2[14] and
the analogy between the nucleophilic aromatic substitution
and the oxidative addition of Pd0 into arylϪhalogen bonds
which has been frequently stressed[15] made a preferential
attack at C-2 likely. In general, even on the parent 2,3-di-
bromofuran, reactions that require an electrophilic carbon
atom are known to occur at C-2.[1,16,17] When we started
our work,[18] regioselective Pd0-catalyzed coupling reactions
[a]
Philipps-Universität Marburg, Fachbereich Chemie,
D-35032 Marburg, Germany
Fax: (internat.) ϩ 49(0)6421/288917
E-mail: bach@chemie.uni-marburg.de
Eur. J. Org. Chem. 1999, 2045Ϫ2057
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0909Ϫ2045 $ 17.50ϩ.50/0
2045

T. Bach, L. Krüger
FULL PAPER
had, to the best of our knowledge, not been reported. How-
ever, there was a precedence for regioselective cross-coup-
ling reactions on other polyhalogenated five-membered het-
erocycles, e.g. on thiophenes,[19] thiazoles,[20] and imidaz-
oles,[21] to name some relevant examples. Other strategies
for the synthesis of multiply substituted furans based on
regioselective reactions are known and have been recently
reviewed.[22] In this account we report on our results for the
reactions depicted in Scheme 1 and discussed above.
Table 1. Regioselective Cu- (10 mol-% CuI) and Pd-catalyzed [5
mol-% PdCl2(PPh3)2] coupling of alkynes 3 (2 equiv.) with the di-
bromofurans 1 and 2 in NEt2R1 as solvent at room temperature
according to Equation (a)
1. Regioselective Pd0-Catalyzed Coupling with
Alkynes
Entry Furan Alkyne R1 Time[a] [h] Product Yield[b] (%)
In a first set of experiments we turned towards the cross
coupling of alkynes with the dibromofurans 1 and 2 accord-
ing to the Sonogashira protocol.[23] The reaction is known
to tolerate a plethora of functional groups, which was con-
sidered to be beneficial both for the choice of alkyne sub-
strates and for the somewhat sensitive formyl group in furan
1. Most of the alkynes 3 employed were commercially avail-
able. The benzyl ester 3f was prepared from the correspond-
ing undecynoic acid via the acid chloride [1. (COCl)2 in
CH2Cl2; 2. BnOH, NEt3, DMAP (cat.) in CH2Cl2; 95%].
1
2
1
1
2
1
2
1
2
1
2
2
1
2
1
2
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
3e
3e
3f
Et
H
24
24
24
72
48
96
72
48
48
96
96
168
96
24
4a
4a
5a
4b
5b
4c
5c
4d
5d
5d
4e
5e
4f
84
83
95
81
80
68
73
71
85
97
68
49
61
80
3
Et
H
4
5
H
H
Et
Et
H
6
7
8
9
10
11
12
13
14
Et
Et
Et
H
3g
Et
5g
[a]
[b]
Time required for complete conversion. Ϫ
Yield of isolated
product.
tution indirectly proves the regioselectivity. Direct chemical
proof was obtained by hydrodebromination and concomi-
tant carbonyl reduction of compound 4a with LiAlH4,
which gave the alcohol 7 in low yield. Independent synthesis
of this material starting from 5-bromofurfural (6)[12] as de-
picted in Equation (b)[25] and its comparison with the prod-
uct obtained from furan 4a suppported the regiochemical
assignment. In addition, the product 4f was converted into
a natural product, the constitution of which is known
(vide infra).
In general, the coupling reaction with furan 1 proceeded
smoothly to yield a single substitution product on em-
ploying 2 equivalents of alkyne in the presence of CuI (0.2
equiv.) and PdCl2(PPh3)2 (0.1 equiv.) [Equation (a), Table
1]. The choice of amine base, namely, diethylamine vs. tri-
ethylamine, as solvent proved to have a minor influence on
the reaction course as exemplified by comparison of Entries
1 and 2, and 9 and 10, for which only small differences were
observed. Although most reactions were close to com-
pletion upon stirring overnight it is advisable to extend the
reaction time until no starting material is left in order to
facilitate the separation of the product. Methyl propargyl
ether (3e) did not react well with diethylamine as base. With
triethylamine the yields were higher, but they did not fully
match those obtained with the other alkynes.
The 13C-NMR signals for the C-2 carbon atoms of the
substitution products 4 and 5 exhibit significant chemical
shift differences (∆δ ഠ 10 ppm) from the signals for the
starting materials 1 and 2, whereas the other furan carbon
atoms resonate at similar frequencies (∆δ ഠ ±3 ppm).
2. Regioselective Pd0-Catalyzed Coupling with
Organometallic Compounds
Although the 2-alkynyl-substituted furans 4 and 5 are
Based on APT (attached proton test) experiments and on versatile precursors to 2,3,5-trisubstituted furans, we were
previously reported chemical shift data[1][24] the peaks at also interested in the coupling of other organometallic re-
δ ϭ 131.3 in 1 and at δ ϭ 128.3 in 2 were assigned to the agents in order to extend the scope of the regioselective
C-2 carbon atom. They are significantly deshielded upon coupling reaction. The ester 2 was chosen as the substrate
substitution and their signals are found at δ ϭ 139.8Ϫ141.3 for these experiments. Coupling reactions with organozinc
in 4 and at δ ϭ 138.5Ϫ139.8 in 5. The fact that the signals reagents[26] proceeded smoothly in THF at room tempera-
for the C-3 carbon atoms are not affected by the substi- ture and gave the substitution products 8 in good yields
2046
Eur. J. Org. Chem. 1999, 2045Ϫ2057

2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective Palladium(0)-Catalyzed Coupling Reactions
FULL PAPER
[Equation (c), Table 2]. The zinc reagent was generated from than DMF as the solvent. In the run specified by Entry 9
the corresponding lithium or magnesium reagent by trans- the desired furan 8e was isolated in 79% yield.
metalation with ZnCl2 (1.5Ϫ2 equiv.) in THF. If an excess
of the organozinc reagent was used, a reduction (hydrode-
bromination) at C-3 was observed after longer reaction
times or at elevated temperatures. The reduction could not
be suppressed if organozinc reagents possessing a β-hydro-
gen atom were employed in the reaction. With n-butylzinc
chloride, for example, the reaction proceeded under a vari-
With DMA as solvent it was also possible to prolong the
ety of conditions to a mixture of the desired 3-bromofuran
reaction times significantly without product decomposition.
and its debrominated analogue. The 2-vinylfuran 8d was
This fact allowed the lowering of both the catalyst and the
unstable and decomposed rapidly upon standing even at
stannane quantity to some extent. A 70% yield of furan 8e
Ϫ30°C.
was obtained with 5 mol-% of Pd(PPh3)4 as catalyst and 1.2
equivalents of stannane 9 in DMA at 90°C (72 h). Other
allylstannanes reacted similarly under the reaction con-
ditions optimized for 9, as exemplified by the clean conver-
sion of allyltributylstannane (10) into furan 8f [Equation
(e)] in 73% yield.
The substitution products 8 exhibit similar characteristics
in their 13C-NMR spectra to the alkynyl-substituted deriva-
tives 4 and 5. The deshielding of the C-2 carbon atom in
compounds 8 relative to the starting material 2 is even more
Table 2. Regioselective Pd-catalyzed [5 mol-% PdCl2(PPh3)2] cou-
pling of organozinc reagents with the dibromofuran 2 in THF as
pronounced and a shift difference ∆δ of more than 30 ppm
to lower field was observed. The C-4 and C-5 carbon atom
remained unaffected whereas the C-3 carbon atom was
slightly shielded (∆δ ϭ Ϫ5 ppm).
To summarize sections 1 and 2 briefly, the regioselective
coupling of various carbon fragments to the 2,3-dibromin-
ated furans 1 and 2 was achieved. For the coupling of an
alkynyl group the Sonogashira conditions proved highly
suitable, and allyl fragments were successfully attached to
the C-2 atom of furan 2 with the Stille reaction. Alkenyl,
aryl, and methyl groups could be regioselectively coupled
by using the corresponding zinc reagents.
solvent at room temperature according to Equation (c)
Entry
R
Equiv.
Time[a] [h] Product
Yield[b] (%)
1
2
3
4
Ph
2.0
24
16
24
96
8a
66
76
84
74
2-Furyl 2.0
8b
Me
Vinyl
1.2
2.0
8c
8d[c]
[a]
[b]
Time required for complete conversion. Ϫ
Yield of isolated
product. Ϫ [c] The compound was unstable and decomposed rapidly
upon standing.
It has been reported that the cross coupling of allylzinc
reagents is sluggish[26b] and the Stille coupling[27] with the
corresponding allylstannanes consequently appeared to be
the method of choice to install allyl groups at the 2-position
of multiply substituted furans. The readily available 3-meth-
ylbut-2-enylstannane 9[28][29] was selected for preliminary
studies as its reaction product was considered to be a suit-
3. Pd0-Catalyzed Cross Coupling at Carbon
Atom C-3
It was crucial for the success of our strategy (Scheme 1)
able precursor for the synthesis of rosefuran (vide infra). that a substituent could not only be introduced at the C-2
For the cross-coupling of stannane 9 and furan 2 some but also at the C-3 position of the furan nucleus by Pd0
experimentation was neccessary to find the optimum con- catalysis. Most naturally occurring furans bear a methyl
ditions which guaranteed a complete and clean reaction group at this site and we consequently concentrated our
[Equation (d), Table 3]. A slight excess of stannane 9 (1.5 efforts on the coupling of a methylmetal reagent with the
equiv.) was used in all runs. In toluene and THF as solvent 3-bromofurans obtained by the regioselective reactions de-
the coupling proceeded slowly (Entries 2 and 3) or side re- scribed above. The first experiments were conducted with
actions such as hydrodebromination and decomposition of the 2-alkynyl-substituted furans 4 derived from furfural 1.
the starting material took over (Entry 1). DMF proved to After Wittig olefination to the corresponding alkenes the
be superior in terms of reaction efficiency and conversion methyldebromination could be smoothly achieved with an
(Entries 4Ϫ8). Still, the reaction was somewhat sluggish at excess of methylzinc chloride (3 equiv.) and PdCl2(PPh3)2
a reaction temperature of 100°C with 0.05 equivalents of as the catalyst in refluxing THF. Two examples starting
the catalyst (Entries 4Ϫ6). Raising the amount of catalyst from the 3-bromofurans 11 and 12 are depicted in Equation
to 0.1 equivalents (10 mol-%) was a remedy for this problem (f). The coupling products 13 and 14 were obtained in yields
which allowed us to run the reaction at a slightly lower of 71% and 68%, respectively. This reaction paved the way
temperature (Entry 8). Finally, it turned out that N,N-di- to the synthesis of 2,3,5-trisubstituted furans starting from
methylacetamide (DMA) gave more reproducible results compound 1 and an application is described in section 4.
Eur. J. Org. Chem. 1999, 2045Ϫ2057
2047

T. Bach, L. Krüger
FULL PAPER
Table 3. Attempted coupling reactions of stannane 9 (1.5 equiv.) with the dibromofuran 2 at varying conditions according to Equation (d)
Entry
Catalyst
Equiv.
Solvent
Temperature [°C]
Time[a] [h]
Ratio 8e/2[b]
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
0.1
toluene
toluene
THF
DMF
DMF
DMF
DMF
DMF
DMA
reflux
reflux
reflux
100
16
6
90:10[c]
< 5:95
< 5:95
85:15
0.05[d]
0.1
22
15
15
24
22
18
18
0.05
0.05[d]
0.05
0.1[e]
0.1
100
90:10
100
92:8
90
> 95:5
> 95:5
> 95:5
90
0.1
90
[a]
[b]
Time during which the mixture was kept at the indicated temperature. Ϫ
The ratio was determined by GLC. Ϫ [c] Large amounts
of unidentified side products were observed by GLC and 1H NMR. Ϫ
was used.
PPh3 (0.1 equiv.) was added Ϫ [e] 1.2 equiv. of stannane 9
[d]
aration and solvent purity, the superiority of PdCl2[P(o-
Tol)3]2 becomes quite obvious (Entries 8Ϫ11).
Table 4. Attempted coupling reactions of MeZnCl (3 equiv.) and
the bromofuran 8e in the presence of various catalysts (5 mol-%)
according to Equation (g) in THF at reflux
Entry
Catalyst
Time[a] [h] Ratio 8e/17/18[b]
1
2
NiCl2(PPh3)2
20
72
24
24
15
18
20
20
18
42
18
18
100:0:0
95:5:0
24:38:38
30:23:47
88:9:3
67:8:25
33:29:38
27:12:61
19:17:64
20:13:67
16:16:68
7:24:69
NiCl2(dppp)
3
PdCl2(PPh3)2[c]
4
PdCl2(PPh3)2
5
PdCl2(dppe)
6
Pd(PPh3)4
7
Pd(OAc)2/dppf
Pd(OAc)2/P(o-Tol)3
PdCl2[P(o-Tol)3]2[d]
PdCl2[P(o-Tol)3]2[e]
PdCl2[P(o-Tol)3]2[f]
PdCl2[P(o-Tol)3]2
8
9
10
11
12
[a] Time for which the mixture was kept at reflux in THF. Ϫ [b] The
[c]
ratio was determined by GLC. Ϫ 10 mol-% of the catalyst was
used. Ϫ [d] A 1:1 ratio of THF/DMF (v/v) was used as the solvent.
[e]
Ϫ
A 1:1 ratio of THF/DMA (v/v) was used as the solvent. Ϫ
In an analogous fashion the 3-bromofurancarboxylates
5a and 5d were converted into the 3-methylfurancar-
boxylates 15 and 16 [Equation (g)].
[f] A 1:1 ratio of THF/DMF (v/v) was used as the solvent. The zinc
reagent was added at 50°C.
Disappointingly, the coupling of the 3-bromofurans 8 de-
It was unfortunate that the three compounds 8e, 17, and
rived from furanoic ester 2 proceeded by far less readily. 18 obtained in these reaction could not be separated by
The reaction was sluggish and extensive hydrodebromin- chromatography due to their almost identical polarity. Even
ation at the C-3 position was found to occur. The factors in the best run (Entry 10) the products were isolated as a
influencing the ratio of starting material, hydrodebromin- mixture (61% yield) which contained 8e, 17, and 18 in a
ated product and methylated product were studied more ratio of roughly 1:1:5 as determined by 1H-NMR spec-
closely on furan 8e which was considered to be a precursor troscopy.
for rosefuran. In Table 4 the dependence of this ratio (8e/
Apparently, the oxidative addition into the bromineϪcar-
17/18) on the catalyst chosen [Equation (h)] is given. Al- bon bond of 8e can be fairly well achieved with PdCl2[P(o-
though care is neccessary in evaluating these results, in par- Tol)3]2 as the catalyst. This high reactivity has been attri-
ticular if one considers the importance of catalyst prep- buted to the formation of monoligated “PdP(o-Tol)3” at el-
2048
Eur. J. Org. Chem. 1999, 2045Ϫ2057

2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective Palladium(0)-Catalyzed Coupling Reactions
FULL PAPER
evated temperature.[30] In attempts to speed up the transme-
talation and the reductive elimination we turned towards
the Stille reaction. In DMA as the donor solvent the forma-
tion of R3SnBr should be highly favored[27b] and this fact
might lead to an enhanced velocity of the transmetalation.
Moreover, DMA allows for a higher reaction temperature,
which enabled us to study the influence of temperature on
the reaction course. To our delight we found that the reac-
tion of 3-bromofuran 8e to form the desired compound 18
proceeded cleanly and without the formation of hydrode-
brominated product 17 if an excess of tetramethylstannane
(2 equiv.) was employed as the reagent in DMA at 90°C in
the presence of PdCl2[P(o-Tol)3]2 as the catalyst (5 mol-%).
The reaction is depicted in Equation (i).
Scheme 2. Preparation of furan 20 from the 2-alkynylfuran 4d and
attempted coupling reactions
4. Synthetic Applications
The monoterpene rosefuran (22) [Equation (j)] was selec-
ted as an example for a 2,3-disubstituted furan, which
should be accessible by the route depicted in Scheme 1
along steps I, IIb, and IIIb. Indeed, the direct precursor 18
for rosefuran was prepared from methyl 2,3-dibromfuran-
5-carboxylate (2) in two successive Stille reactions as de-
scribed in sections 2 and 3. The total yield amounted to
55%. The decarboxylation was achieved by conventional
saponification and decarboxylation to yield rosefuran in a
short and efficient way. An alternative approach will be dis-
cussed in section 5.
A comparison of the results we recorded in the coupling
of 2-alkynyl-substituted 3-bromofurans such as 5, 11, and
12 (vide supra) with the observations made on the at-
tempted coupling reactions with furan 8e suggests that the
sp3-carbon atom in 2-position of 8e not only slows down
the oxidative addition but also facilitates hydrodebromin-
ation, possibly by retarding the transmetalation and/or re-
ductive elimination step. In order to study this phenomenon
further and possibly to generalize it we prepared the 3-
bromofuran 20 from alkyne 4d (Scheme 2). Hydrogenation
of the alkyne yielded the 2-alkyl-substituted intermediate
19, which was converted into compound 20 by a Wittig re-
action. The alkynyl analogue 12 of furan 20 was earlier
shown [cf. Equation (f)] to undergo a facile methyldebro-
As an example for a 2,3,5-trisubstituted furan we had
mination with MeZnCl in the presence of PdCl2(PPh3)2. In selected a furan fatty acid, namely the so-called F5 acid (26)
contrast, under the same reaction conditions furan 20 gave that had been previously prepared by Schlenk et al. from
a mixture of starting material 20, hydrodebrominated prod- methyl 3-methylfuran-2-carboxylate in 5 steps (3% yield)[31]
uct, and the desired methyldebrominated product 21 in a and by Marson et al. from cyclodecanone in 6 steps (13%
39:21:40 ratio (GLC). This result parallels our earlier obser- yield).[2b] We started the synthesis (Scheme 3) from the
vations in the attempted coupling of methyl 3-bromo-2-(3- above-mentioned ester 4f which was converted by a Wittig
methylbut-2-enyl)furan-5-carboxylate (8e), which are given reaction into compound 23 and by a subsequent Pd0-cata-
in Table 4. It supports the notion of a sterically encumbered lyzed coupling to the furan 24. The transformation to the
situation retarding attempted coupling reactions at the C-3 free acid can be achieved by treatment with hydrogen at
atom of 2-alkyl-3-bromofurans. The conversion of bromide high pressure effecting both the hydrogenation of the mul-
20 into the 3-methylfuran 21 proceeded without hydrode- tiple bonds and the hydrogenolysis of the benzyl ester.[18a]
bromination with SnMe4 as the reagent and PdCl2[P(o- A two-step procedure, first conducting the rapidly occur-
Tol)3]2 as the catalyst.
ring hydrogenation at atmosperic pressure and then sapon-
The two cross-coupling protocols for methyldebromin- ifying the ester 25, proved to be more efficient and it gave
ation at the C-3 carbon atom of 3-bromofurans with either the desired acid 26 in 76% yield.
MeZnCl/PdCl2(PPh3)2 in THF (for 2-alkynyl-substituted
Overall, the reaction sequence starting from the bulk ma-
furans) or SnMe4/PdCl2(Po-Tol3)2 in DMA (for 2-alkyl- terial 2,3-dibromofurfural (1) proceeded in five steps with a
substituted furans) complete the organometallic part of the total yield of 29%. The substitution pattern at the 2- and
general synthetic strategy outlined in Scheme 1. It remained the 5-position can be varied over a broad range which
to show that an application to the synthesis of target mol- should facilitate the synthesis of additional target com-
ecules is possible.
pounds by this strategy.
Eur. J. Org. Chem. 1999, 2045Ϫ2057
2049

T. Bach, L. Krüger
FULL PAPER
have not looked into this route more closely as it did not
appear to be advantageous for the reasons mentioned
above.
6. Summary and Conclusion
5-Acceptor-substituted 2,3-dibromofurans 1 and 2 un-
dergo a regioselective Pd0-catalyzed cross-coupling reaction
at the C-2 carbon atom with a variety of reagents. The ob-
served regioselectivity is most likely due to the electron de-
ficiency at this position, which renders an oxidative ad-
dition of Pd0 in the CϪBr bond facile. The Stille reaction
of furan 2 and the parent 2,3-dibromofuran (27) with stan-
nane 9 proceeded equally well. Apparently, the acceptor
substituent at C-5 is not required for an activiation of the
2-position. A Pd0-catalyzed coupling at the more electron-
rich C-3 carbon atom is by far more difficult to achieve.
Two methods were devised which facilitate a methyldebro-
mination at this site. The first method is applicable to 2-
alkynyl-3-bromofurans and employs MeZnCl and
PdCl2(PPh3)2 as the catalyst. The desired reaction proceeds
smoothly in refluxing THF. The second method was devel-
oped for 2-alkyl-3-bromofurans, the Pd0-catalyzed cross
coupling of which is hampered by two factors. First, the
oxidative addition is retarded and the reaction rate is conse-
quently much lower than in the case of the 2-alkynyl-3-
bromofurans. Second, a hydrodebromination at C-3 is ob-
served as a side reaction, which point towards an ineffective
transmetalation or reductive elimination. These problems
are overcome by using SnMe4 and the catalyst PdCl2[P(o-
Tol)3]2 in DMA as the solvent (90°C). With these reagents
clean cross-coupling reactions have been achieved at the C-
3 position. Ready access to 2,3-dibsubstituted and 2,3,5-
trisubstituted furans is possible by combining the regiose-
lective cross coupling at C-2 and the subsequent methylde-
bromination at C-3. The two natural products rosefuran
(22) and F5 fatty acid (26) were prepared in short synthetic
sequences following this strategy.
Scheme 3. The synthesis of the F5 furan fatty acid (26) starting
from the product 4f of the regioselective cross coupling at C-2
5. Reasons for the Pronounced Regioselectivity
In the introduction we alluded to the fact that the oxidat-
ive addition of Pd0 in the 2-position of compounds 1 and 2
is a facile process which eventually determines the regiose-
lectivity of the reaction. Although the experimental data
obtained so far undermine this hypothesis, it remained un-
clear why the oxidative addition into the carbonϪbromine
bond is so facile at the 2-position. This phenomenon could
be either due to the inherent higher electrophilicity of C-2
over C-3 or it could be induced by the acceptor substituent
at C-5, which is expected to withdraw electron density from
the 2- and 4-position by its ϪM effect, or it could be due
to the sum of both. In order to clarify this question we
studied the Stille reaction of 2,3-dibromofuran (27), which
was prepared from the ester 2 by saponification and decar-
boxylation[16b] (Scheme 4). This substrate exhibited the
same selectivity observed for the acceptor-substituted ana-
logue 2 [cf. Equation (d)], and it yielded exclusively the 3-
bromofuran 28.
Scheme 4. Preparation[16b] and regioselective Stille reaction of 2,3-
dibromofuran (27)
Experimental Section
General: All reactions involving water-sensitive compounds were
carried out in flame-dried glassware with magnetic stirring under
argon. THF was distilled from K/Na immediately prior to use.
Common solvents [tert-butyl methyl ether (TBME), pentane (P),
diethyl ether, ethyl acetate, and methanol] were distilled prior to
No side reactions at C-3 were observed but the yield was
lower than the one obtained with compound 2. Apparently,
the acceptor substituent is not neccessary for the regioselec-
tivity control but it does have a beneficial influence on the
stability of the furan nucleus. Indeed, it was previously ob- use. Furans 1,[12] 2,[12] 6,[12] 27,[16b] and stannane 9[29] were pre-
pared according to reported procedures. N,N-dimethylformamide
(DMF; Fluka puriss. abs.), N,N-dimethylacetamide (DMA; Fluka
puriss. abs.) and all other reagents were used as received. Ϫ Melting
points (uncorrected): Reichert hot-stage. Ϫ IR: Bruker IFS 88 FT-
IR or Nicolet 510 M FT-IR. Ϫ MS: Varian CH7 (EI) or Finnigan
MAT 95S (HRMS). Ϫ GLC: HewlettϪPackard HP 6890 series GC
system, column HP-1 (cross-linked methylsiloxane, 30 m). Ϫ 1H
and 13C NMR: Bruker ARX-200 and Bruker AC-300. Chemical
shifts are reported relative to tetramethylsilane as internal refer-
ence. CDCl3 was used as solvent unless stated otherwise. The multi-
served that acceptor-substituted furans are less labile than
alkyl-substituted furans under oxidative and acidic con-
ditions,[1] a fact which is in accord with our observations.
For the synthesis of 2,3-disubstituted furans as outlined in
Scheme 1, a possible alternative route is obvious, i.e., the
successive introduction of substituents in the 2- and 3-posi-
tion of 2,3-dibromofuran (27) by Pd0-catalyzed coupling re-
actions. If one considers that 2,3-dibromofuran is prepared
from ester 2 this is, in effect, an interchange of steps con-
ducting the decarboxylation prior to the cross coupling. We plicities of the 13C-NMR signals were determined by attached pro-
2050 Eur. J. Org. Chem. 1999, 2045Ϫ2057

2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective Palladium(0)-Catalyzed Coupling Reactions
ton test (APT) experiments. Ϫ Elementary analysis: Varian Ele-
Br)ϩ], 139 (100), 138 (99). Ϫ C13H7BrO2 (275.097): calcd. C 56.76,
FULL PAPER
mentar vario EL. Ϫ TLC: Merck glass sheets 0.25 mm silica gel H 2.56; found C 56.84, H 2.51.
60-F254). A PE/TBME mixture was used as the eluent; detection
3-Bromo-2-(4-hydroxybut-1-ynyl)furan-5-carbaldehyde (4c): The re-
by UV or by coloration with cerium(IV) ammonium molybdate
(CAM). Ϫ Flash chromatography:[32] Merck silica gel 60 (230Ϫ400
mesh) (ca. 50 g for 1 g of material to be seperated), eluent given
in parentheses.
action was carried out as described in typical procedure A starting
from furan 1[12] and alkyne 3c on a 2-mmol scale. The residue was
purified by flash chromatography (P/TBME ϭ 98:2). A total of
330 mg (68%) of furan 4c was obtained as a red oil. Ϫ Rf ϭ 0.50
(P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 3403 cmϪ1 (br, m, OϪH),
2972 (w, CϪH), 2886 (w, CϪH), 2232 (m, CϵC), 1682 (s, CϭO),
1054 (m, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 1.93 (b, s, 1 H), 2.77
(t, J ϭ 6.3 Hz, 2 H), 3.85 (t, J ϭ 6.3 Hz, 2 H), 7.21 (s, 1 H), 9.53
(s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 24.1 (t), 60.4 (t), 70.2 (s),
99.4 (s), 106.8 (s), 122.7 (d), 140.7 (s), 151.0 (s), 176.8 (d). Ϫ MS
(70 eV); m/z (%): 244 (55) [Mϩ (81Br)], 242 (56) [Mϩ (79Br)], 213
(68) [(M Ϫ CH3O)ϩ (81Br)], 211 (70) [(M Ϫ CH3O)ϩ (79Br)], 75
(100). Ϫ C9H7BrO3 (243.054): calcd. C 44.47, H 2.90; found C
44.44, H 2.83.
Benzyl 10-Undecynoate (3f): To 5 mmol of 10-undecynoic acid
(910 mg), dissolved in 30 mL of CH2Cl2, a catalytic amount of
DMF was added and the mixture was cooled to 0°C. A solution
of 10 mmol of oxalyl chloride (1.27 g, 0.88 mL) in 20 mL of
CH2Cl2 was added dropwise. After complete transformation (2 h),
the solvent was removed in vacuo. The crude product was dissolved
in 20 mL of CH2Cl2 and the solution was added slowly to a mixture
of 5.5 mmol of benzyl alcohol (595 mg), 0.25 mmol of 4-(dimeth-
ylamino)pyridine (31 mg) and 5 mmol of NEt3 (1.01 g, 0.70 mL) in
20 mL of CH2Cl2. After stirring for 2 h at room temperature, the
solvent was removed in vacuo and the residue was purified by flash
chromatography (P/TBME ϭ 90:10). A total of 1.30 g (95%) of
compound 3f was obtained as a colorless liquid. Ϫ Rf ϭ 0.62 (P/
TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 3299 cmϪ1 (m, CϵCϪH), 3035
(w, CArϪH), 2935 (s, CϪH), 2858 (m, CϪH), 2119 (w, CϵC), 1737
3-Bromo-2-(5-chloropent-1-ynyl)furan-5-carbaldehyde (4d): The re-
action was carried out as described in typical procedure A starting
from furan 1[12] and alkyne 3d on a 2-mmol scale. The residue was
purified by flash chromatography (P/TBME ϭ 98:2) to give 391 mg
(71%) of furan 4d as an orange-brown oil. Ϫ Rf ϭ 0.50 (P/TBME ϭ
75:25). Ϫ IR (film): ν˜ ϭ 2962 cmϪ1 (w, CϪH), 2230 (m, CϵC),
1682 (s, CϭO), 1057 (w, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 2.10
(quint, J ϭ 6.5 Hz, 2 H), 2.73 (t, J ϭ 6.5 Hz, 2 H), 3.72 (t, J ϭ
6.5 Hz, 2 H), 7.23 (s, 1 H), 9.55 (s, 1 H). Ϫ 13C NMR (50 MHz):
δ ϭ 17.1 (t), 30.6 (t), 43.2 (t), 69.5 (s), 100.7 (s), 106.6 (s), 122.8
(d), 140.6 (s), 150.9 (s), 176.6 (d). Ϫ MS (70 eV); m/z (%): 278 (6)
[Mϩ (81Br, 37Cl)], 276 (28) [Mϩ (81Br, 35Cl)], 274 (22) [Mϩ (79Br,
35Cl)], 241 (30) [(M Ϫ 35Cl)ϩ (81Br)], 239 (30) [(M Ϫ 35Cl)ϩ (79Br)],
213 (22), 211 (25), 160 (16), 131 (17), 103 (73), 75 (100). Ϫ
C10H8BrClO2 (275.529): calcd. C 43.59, H 2.93; found C 43.57,
H 2.64.
1
(s, CϭO). Ϫ H NMR (200 MHz): δ ϭ 1.10Ϫ1.65 (m, 12 H), 1.86
(t, J ϭ 2.5 Hz, 1 H), 2.10 (dt, J ϭ 7.2 Hz, J ϭ 2.5 Hz, 2 H), 2.27
(t, J ϭ 7.2 Hz, 2 H), 5.04 (s, 2 H), 7.22Ϫ7.32 (m, 5 H). Ϫ 13C
NMR (50 MHz): δ ϭ 18.3 (t), 24.9 (t), 28.4 (t), 28.6 (t) 28.8 (t)
29.0 (t), 29.1 (t), 34.2 (t), 66.0 (t), 68.1 (d), 84.7 (s), 128.1 (d), 128.1
(d), 128.5 (d), 136.1 (s), 173.6 (s). Ϫ MS (70 eV); m/z (%): 272 (0.2)
[Mϩ], 108 (31), 91 (100) [C7H7ϩ]. Ϫ C18H24O2 (272.387): calcd. C
79.37, H 8.88; found C 79.13, H 8.78.
3-Bromo-2-(3,3-dimethylbut-1-ynyl)furan-5-carbaldehyde (4a).
؊
Typical Procedure A: To a stirred solution of 10 mmol of furan 1[12]
(2.54 g), 1 mmol of CuI (190 mg), and 0.5 mmol of PdCl2(PPh3)2
(350 mg) in 50 mL of the amine at room temperature was slowly
added 20 mmol of alkyne 3a (1.64 g). After the period of time indi-
cated in Table 1 (24 h), the amine was removed by distillation. The
solid was filtered off and washed with P/TBME ϭ 50:50. Further
purification was carried out by flash chromatography (P/TBME ϭ
98:2). A total of 2.14 g (84%) of furan 4a was obtained as an orange
solid. Ϫ Rf ϭ 0.60 (P/TBME ϭ 75:25). Ϫ M.p. 60Ϫ64°C. Ϫ IR
(KBr): ν˜ ϭ 2917 cmϪ1 (m, CϪH), 2220 (m, CϵC), 1680 (s, CϭO),
3-Bromo-2-(3-methoxyprop-1-ynyl)furan-5-carbaldehyde (4e): The
reaction was carried out as described in typical procedure A start-
ing from furan 1[12] and alkyne 3e on a 2-mmol scale. The residue
was purified by flash chromatography (P/TBME ϭ 98:2). A total
of 330 mg (68%) of furan 4e was obtained as a yellow-brown solid.
Ϫ Rf ϭ 0.48 (P/TBME ϭ 75:25). Ϫ M.p. 38Ϫ40°C. Ϫ IR (KBr):
ν˜ ϭ 2989 cmϪ1 (m, CϪH), 2938 (m, CϪH), 2825 (m, CϪH), 1687
1
(s, CϭO), 1061 (m, CϪBr). Ϫ H NMR (300 MHz): δ ϭ 3.40 (s, 3
1
H), 4.33 (s, 2 H), 7.20 (s, 1 H), 9.52 (s, 1 H). Ϫ 13C NMR (75 MHz):
δ ϭ 57.9 (t), 60.0 (q), 73.9 (s), 96.6 (s), 107.8 (s), 122.2 (d), 139.8
(s), 151.5 (s), 176.8 (d). Ϫ MS (70 eV); m/z (%): 244 (30) [Mϩ
(81Br)], 242 (31) [Mϩ (79Br)], 215 (99) [(M Ϫ CHO)ϩ (81Br)], 213
(100) [(M Ϫ CHO)ϩ (79Br)], 106 (72), 75 (100). Ϫ C9H7BrO3
(243.054): calcd. C 44.47, H 2.90; found C 44.70, H 2.98.
1040 (w, CϪBr). Ϫ H NMR (300 MHz): δ ϭ 1.35 (s, 9 H), 7.22
(s, 1 H), 9.54 (s, 1 H). Ϫ 13C NMR (75 MHz): δ ϭ 28.5 (s), 30.2
(q), 67.5 (s), 106.2 (s), 110.6 (s), 122.8 (d), 141.3 (s), 150.9 (s), 176.7
(d). Ϫ MS (70 eV); m/z (%): 256 (59) [Mϩ (81Br)], 254 (61) [Mϩ
(79Br)], 241 (73) [(M Ϫ CH3)ϩ (81Br)], 227 (93) [(M Ϫ CHO)ϩ
(81Br)], 225 (100) [(M Ϫ CHO)ϩ (79Br)], 175 (12) [(M Ϫ Br)ϩ], 118
(57), 103 (67), 77 (68), 63 (34), 41 (24). Ϫ C11H11BrO2 (255.108):
calcd. C 51.79, H 4.35; found C 52.20, H 4.64.
Benzyl 11-(3-Bromo-5-formylfuran-2-yl)undec-10-ynoate (4f): The
reaction was carried out as described in typical procedure A start-
ing from furan 1[12] and alkyne 3f on a 2-mmol scale. The residue
was purified by flash chromatography (P/TBME ϭ 90:10). A total
of 543 mg (61%) of furan 4f was obtained as a yellow-brown oil.
Ϫ Rf ϭ 0.34 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 3035 cmϪ1 (w,
3-Bromo-2-(phenylethynyl)furan-5-carbaldehyde (4b): The reaction
was carried out as described in typical procedure A starting from
furan 1[12] and alkyne 3b on a 2-mmol scale. The residue was puri-
fied by flash chromatography (P/TBME ϭ 98:2). A total of 445 mg
(81%) of furan 4b was obtained as an orange solid. Ϫ Rf ϭ 0.54
C
ArϪH), 2932 (s, CϪH), 2857 (m, CϪH), 2231 (m, CϵC), 1737 (s,
1H NMR
(200 MHz): δ ϭ 1.15Ϫ1.65 (m, 12 H), 2.28 (t, J ϭ 7.2 Hz, 2 H),
(P/TBME ϭ 75:25). Ϫ M.p. 75Ϫ78°C. Ϫ IR (KBr): ν˜ ϭ 3094 cmϪ1 OϪCϭO), 1686 (s, CϭO), 1059 (w, CϪBr).
Ϫ
(m, CArϪH), 3051 (m, CArϪH), 2204 (m, CϵC), 1684 (s, CϭO),
1018 (m, CϪBr). Ϫ 1H NMR (300 MHz): δ ϭ 7.23 (s, 1 H),
7.30Ϫ7.40 (m, 3 H), 7.54Ϫ7.58 (m, 2 H), 9.54 (s, 1 H). Ϫ 13C NMR
(75 MHz): δ ϭ 76.9 (s), 100.4 (s), 107.4 (s), 120.9 (s), 122.8 (d),
2.42 (t, J ϭ 7.2 Hz, 2 H), 5.04 (s, 2 H), 7.14 (s, 1 H) 7.22Ϫ7.32 (m,
5 H), 9.46 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 19.7 (t), 24.8 (t),
27.8 (t), 28.6 (t) 28.8 (t) 28.9 (t), 29.0 (t), 34.2 (t), 66.0 (t), 68.8 (s),
128.6 (d), 130.0 (d), 132.0 (d), 141.0 (s), 151.6 (s), 176.8 (d). Ϫ MS 103.1 (s), 106.2 (s), 122.8 (d), 128.1 (d), 128.1 (d), 128.5 (d), 136.0
(70 eV); m/z (%): 276 (92) [Mϩ (81Br)], 274 (94) [Mϩ (79Br)], 219
(s), 141.2 (s), 150.8 (s), 173.6 (s), 176.7 (d). Ϫ MS (70 eV); m/z (%):
(28) [C11H6Brϩ (81Br)], 217 (29) [C11H6Brϩ (79Br)], 195 (7) [(M Ϫ 446 (2) [Mϩ (81Br)], 444 (2) [Mϩ (79Br)], 339 (4), 337 (5), 227 (7),
Eur. J. Org. Chem. 1999, 2045Ϫ2057
2051

T. Bach, L. Krüger
FULL PAPER
225 (6), 91 (100) [C7H7ϩ]. Ϫ C23H25BrO4 (445.353): calcd. C 62.03,
H 5.66; found C 61.97, H 5.66.
43.2 (t), 52.2 (q), 69.5 (s), 99.1 (s) 105.6 (s), 120.8 (d), 139.3 (s),
143.3 (s), 157.5 (s). Ϫ MS (70 eV); m/z (%): 308 (16) [Mϩ (81Br,
37Cl)], 306 (54) [Mϩ (81Br, 35Cl)], 304 (63) [Mϩ (79Br, 35Cl)], 271
(51) [(M Ϫ Cl)ϩ (81Br)], 269 (51) [(M Ϫ Cl)ϩ (79Br)], 249 (4) [(308
Ϫ COOCH3)ϩ], 247 (26) [(306 Ϫ COOCH3)ϩ], 245 (21) [(304 Ϫ
COOCH3ϩ], 243 (60) [(M Ϫ (CH2)2Cl)ϩ (81Br)], 241 (60) [(M Ϫ
(CH2)2Cl)ϩ (79Br)], 190 (4), 103 (66), 75 (100), 59 (48) [COOCH
Methyl
3-Bromo-2-(3,3-dimethylbut-1-ynyl)furan-5-carboxylate
(5a): The reaction was carried out as described in typical procedure
A starting from furan 2[12] and alkyne 3a on a 10-mmol scale. The
residue was purified by flash chromatography (P/TBME ϭ 90:10).
A total of 2.7g (95%) of furan 5a was obtained as a white solid. Ϫ
Rf ϭ 0.62 (P/TBME ϭ 75:25). Ϫ M.p. 53Ϫ57°C. Ϫ IR (KBr): ν˜ ϭ
2970 cmϪ1 (m, CϪH), 2228 (m, CϵC), 1737 (s, CϭO), 1037 (m,
ϩ]. Ϫ C11H10BrClO3 (305.555): calcd. C 43.24, H 3.30; found C
3
43.12, H 3.10.
1
CϪBr). Ϫ H NMR (200 MHz): δ ϭ 1.31 (s, 9 H), 3.87 (s, 3 H),
Methyl 3-Bromo-2-(3-methoxyprop-1-ynyl)furan-5-carboxylate (5e):
7.14 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 28.4 (s), 30.3 (q), 52.2 The reaction was carried out as described in typical procedure A
(q), 67.3 (s), 105.1 (s), 109.0 (s), 121.0 (d), 139.8 (s), 143.0 (s), 157.7 starting from furan 2[12] and alkyne 3e on a 2-mmol scale. The
(s). Ϫ MS (70 eV); m/z (%): 286 (43) [Mϩ (81Br)], 284 (45) [Mϩ
residue was purified by flash chromatography (P/TBME ϭ 98:2).
(79Br)], 271 (100) [(M Ϫ CH3)ϩ (81Br)], 269 (97) [(M Ϫ CH3)ϩ A total of 265 mg (49%) of furan 5e was obtained as a colorless
(79Br)], 255 (8) [(M Ϫ OCH3)ϩ (81Br)], 253 (8) [(M Ϫ OCH3)ϩ oil. Ϫ Rf ϭ 0.45 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2953 cmϪ1
(79Br)], 227 (77) [(M Ϫ COOCH3)ϩ (81Br)], 225 (76) [(M Ϫ
(m, CϪH), 2895 (w, CϪH), 2824 (m, C-H), 2232 (w, CϵC), 1736
COOCH3)ϩ (79Br)], 205 (16) [(M Ϫ Br)ϩ], 118 (38), 103 (38), 59 (s, CϭO), 1055 (m, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 3.40 (s, 3
(20) [COOCH3ϩ]. Ϫ C12H13BrO3 (285.134): calcd. C 50.55, H 4.60; H), 3.85 (s, 3 H), 4.33 (s, 2 H), 7.13 (s, 1 H). Ϫ 13C NMR (50 MHz):
found: C 50.68, H 4.56.
δ ϭ 52.3 (q), 57.8 (q), 60.0 (t), 73.9 (s), 95.4 (s) 106.9 (s), 120.8 (d),
138.5 (s), 144.0 (s), 157.5 (s). Ϫ MS (70 eV); m/z (%): 274 (46) [Mϩ
(81Br)], 272 (26) [Mϩ (79Br)], 243 (53) [(M Ϫ OCH3)ϩ (81Br)], 241
(56) [(M Ϫ OCH3)ϩ (79Br)], 215 (69) [(M Ϫ COOCH3)ϩ (81Br)],
213 (100) [(M Ϫ COOCH3)ϩ (79Br)], 106 (62), 75 (68), 59 (36) [CO-
OCH3ϩ]. Ϫ C10H9BrO4 (273.083): calcd. C 43.98, H 3.32; found C
43.98, H 3.16.
Methyl 3-Bromo-2-(phenylethynyl)furan-5-carboxylate (5b): The re-
action was carried out as described in typical procedure A starting
from furan 2[12] and alkyne 3b on a 2-mmol scale. The residue was
purified by flash chromatography (P/TBME ϭ 98:2). A total of
488 mg (80%) of furan 5b was obtained as a brown solid. Ϫ Rf ϭ
0.60 (P/TBME ϭ 75:25). Ϫ M.p. 108Ϫ110°C. Ϫ IR (KBr): ν˜ ϭ
3054 cmϪ1 (w, CArϪH), 2957 (w, CϪH), 2214 (m, CϵC), 1740 (s,
Methyl 3-Bromo-2-(trimethylsilyl)ethynylfuran-5-carboxylate (5g):
CϭO), 1032 (m, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 3.86 (s, 3 The reaction was carried out as described in typical procedure A
H), 7.20 (s, 1 H), 7.30Ϫ7.40 (m, 3 H), 7.50Ϫ7.59 (m, 2 H). Ϫ 13C
starting from furan 2[12] and alkyne 3g on a 2-mmol scale. The
NMR (50 MHz): δ ϭ 52.3 (q), 76.8 (s), 99.0 (s), 106.4 (s), 121.1 residue was purified by flash chromatography (P/TBME ϭ 98:2).
(d), 121.1 (s), 128.5 (d), 129.6 (d), 131.8 (d), 139.4 (s), 143.9 (s) A total of 483 mg (80%) of furan 5g was obtained as a white solid.
157.6 (s). Ϫ MS (70 eV); m/z (%): 306 (79) [Mϩ (81Br)], 304 (90) Ϫ Rf ϭ 0.70 (P/TBME ϭ 75:25). Ϫ M.p. 71°C. Ϫ IR (KBr): ν˜ ϭ
[Mϩ (79Br)], 275 (9) [(M Ϫ OCH3)ϩ (81Br)], 273 (7) [(M Ϫ OCH3)ϩ 2959 cmϪ1 (m, CϪH), 2900 (m, CϪH), 2161 (m, CϵC), 1729 (s,
(79Br)], 219 (28), 217 (26), 138 (100), 59 (12) [COOCH3ϩ]. Ϫ
C14H9BrO3 (305.128): calcd. C 55.11, H 2.97; found C 54.91, H
2.88.
CϭO), 1033 (m, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 0.25 (s, 9
H), 3.88 (s, 3 H), 7.15 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ Ϫ0.6
(q), 52.4 (q), 90.9 (s) 106.8 (s), 120.1 (s), 120.9 (d), 139.2 (s), 143.7
(s), 157.6 (s). Ϫ MS (70 eV); m/z (%): 302 (39) [Mϩ (81Br)], 300
(58) [Mϩ (79Br)], 287 (86) [(M Ϫ CH3)ϩ (81Br)], 285 (100) [(M Ϫ
CH3)ϩ (79Br)], 221 (7) [(M Ϫ Br)ϩ], 147 (20), 119 (11), 89 (20), 59
(16) [COOCH3ϩ]. Ϫ C11H13BrO3Si (301.209): calcd. C 43.86, H
4.35; found C 43.77, H 4.31.
Methyl 3-Bromo-2-(4-hydroxybut-1-ynyl)furan-5-carboxylate (5c):
The reaction was carried out as described in typical procedure A
starting from furan 2[12] and alkyne 3c on a 2-mmol scale. The
residue was purified by flash chromatography (P/TBME ϭ 98:2).
A total of 399 mg (73%) of furan 5c was obtained as a brown solid.
Ϫ Rf ϭ 0.12 (P/TBME ϭ 75:25). Ϫ M.p. 98°C. Ϫ IR (KBr): ν˜ ϭ 5-(3,3-Dimethylbut-1-ynyl)-2-hydroxymethylfuran (7): The cross-
3242 cmϪ1 (br, m, OϪH), 2948 (w, CϪH), 2844 (w, CϪH), 2232 coupling reaction was carried out as described in typical procedure
(m, CϵC), 1732 (s, CϭO), 1048 (m, CϪBr). Ϫ 1H NMR
(200 MHz): δ ϭ 2.62 (b, s, 1 H), 2.72 (t, J ϭ 6.5 Hz, 2 H), 3.80 (m,
A starting from furan 6[12] and alkyne 3a on a 1-mmol scale. The
crude product was added to a solution of 5 mmol of LiAlH4
2 H), 3.85 (s, 3 H), 7.13 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 23.9 (190 mg) in 10 mL of THF at 0°C by syringe. The mixture was
(t), 52.3 (q), 60.3 (t), 69.9 (s) 98.0 (s) 105.6 (s), 120.8 (d), 139.2 (s),
143.2 (s), 157.6 (s). Ϫ MS (70 eV); m/z (%): 274 (30) [Mϩ (81Br)],
272 (41) [Mϩ (79Br)], 243 (51) [(M Ϫ CH3O)ϩ (81Br)], 241 (45) [(M
Ϫ CH3O)ϩ (79Br)], 215 (3) [(M Ϫ COOCH3)ϩ (81Br)], 213 (5) [(M
Ϫ COOCH3)ϩ (79Br)], 187 (6), 185 (26), 103 (21), 75 (100), 59 (18)
stirred for 10 min at room temperature. After quenching with 5 mL
of water, the product was extracted with diethyl ether (3 ϫ 10 mL).
The combined organic layers were washed with brine (10 mL),
dried with MgSO4, and filtered. After removal of the solvent in
vacuo, the residue was purified by flash chromatography (P/
[COOCH3ϩ]. Ϫ C10H9BrO4 (273.083): calcd. C 43.98, H 3.32; TBME ϭ 90:10). A total of 124 mg (70%) of furan 7 was obtained
found C 43.93, H 3.40.
as a yellow solid. Ϫ Rf ϭ 0.16 (P/TBME ϭ 75:25). Ϫ M.p.
33Ϫ36°C. Ϫ IR (KBr): ν˜ ϭ 3336 cmϪ1 (br, s, OϪH), 2971 (s,
CϪH), 2869 (m, CϪH), 2225 (w, CϵC). Ϫ H NMR (200 MHz):
δ ϭ 1.23 (s, 9 H), 2.50 (b, s, 1 H), 4.46 (s, 2 H), 6.16 (d, J ϭ 3.1 Hz,
1 H), 6.32 (d, J ϭ 3.1 Hz, 1 H). Ϫ 13C NMR (75 MHz): δ ϭ 28.2
(s), 30.7 (q), 57.4 (t), 69.9 (s), 102.7 (s), 108.8 (d), 114.5 (d), 137.5
(s), 154.3 (s). Ϫ MS (70 eV); m/z (%): 178 (82) [Mϩ], 163 (100) [(M
Ϫ CH3)ϩ], 147 (68) [(M Ϫ CH3O)ϩ], 119 (18). Ϫ C11H14O2
(178.228): calcd. C 74.13, H 7.92; found C 74.02, H 7.75.
Methyl 3-Bromo-2-(5-chloropent-1-ynyl)furan-5-carboxylate (5d):
The reaction was carried out as described in typical procedure A
starting from furan 2[12] and alkyne 3d on a 10-mmol scale. The
residue was purified by flash chromatography (P/TBME ϭ 98:2).
A total of 2.97 g (97%) of furan 5d was obtained as a yellow oil.
Ϫ Rf ϭ 0.55 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2957 cmϪ1 (m,
CϪH), 2845 (w, CϪH), 2232 (m, CϵC), 1736 (s, CϭO), 1055 (m,
CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 2.04 (quint, J ϭ 6.5 Hz, 2
1
H), 2.66 (t, J ϭ 6.5 Hz, 2 H), 3.66 (t, J ϭ 6.5 Hz, 2 H), 3.84 (s, 3 Methyl 3-Bromo-2-phenylfuran-5-carboxylate (8a). ؊ Typical Pro-
H), 7.11 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 17.0 (t), 30.6 (t),
cedure B: 2 mmol of ester 2[12] (568 mg) and 0.08 mmol of
2052
Eur. J. Org. Chem. 1999, 2045Ϫ2057

2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective Palladium(0)-Catalyzed Coupling Reactions
FULL PAPER
PdCl2(PPh3)2 (56 mg) were dissolved in 8 mL of THF at room tem-
perature. A solution of 4 mmol of phenylzinc chloride, prepared by
transmetalation of phenyllithium (4 mmol, 2.2 mL of a 1.8  solu-
tion) with ZnCl2 (6 mmol, 818 mg), in 8 mL of THF was added by
syringe. The mixture was stirred at room temperature for 16 h and
it was subsequently quenched with a saturated aqueous NH4Cl
solution (10 mL). After extraction with ether (3 ϫ 15 mL) the or-
ganic layers were collected, washed with brine, and dried with
MgSO4. After removal of the solvent, the residue was purified by
flash chromatography (P/TBME ϭ 98:2). A total of 371 mg (66%)
a 1.9  solution) with zinc chloride (6 mmol, 818 mg). After
workup, the residue was purified by flash chromatography (P/
TBME ϭ 98:2). A total of 342 mg (74%) of furan 8d was obtained
as a yellow oil. The compound decomposed rapidly upon standing
at 0°C and a correct elemental analysis was not obtained. Ϫ Rf ϭ
0.65 (P/TBME ϭ 75:25). Ϫ 1H NMR (200 MHz): δ ϭ 3.85 (s, 3
H), 5.44 (dd, J ϭ 1.0 Hz, J ϭ 11.5 Hz, 1 H), 6.02 (dd, J ϭ 1.0 Hz,
J ϭ 17.8 Hz, 1 H), 6.56 (dd, J ϭ 11.5 Hz, J ϭ 17.8 Hz, 1 H), 7.12
(s, 1 H). Ϫ 13C NMR (75 MHz): δ ϭ 52.0 (q), 95.6 (s), 118.4 (t),
121.6 (d), 121.6 (d), 142.9 (s), 152.7 (s), 158.2 (s). Ϫ MS (70 eV);
of furan 8a was obtained as a white solid. Ϫ Rf ϭ 0.60 (P/TBME ϭ m/z (%): 232 (93) [Mϩ (81Br)], 230 (92) [Mϩ (79Br)], 201 (98) [(M
75:25). Ϫ M.p. 80Ϫ84°C. Ϫ IR (KBr): ν˜ ϭ 3127 cmϪ1 (m, CArϪH),
2952 (s, CϪH), 1726 (s, CϭO), 1072 (w, CϪBr). Ϫ 1H NMR
(200 MHz): δ ϭ 3.75 (s, 3 H), 7.10 (s, 1 H), 7.30Ϫ7.45 (m, 3 H),
7.95Ϫ8.03 (m, 2 H). Ϫ 13C NMR (50 MHz): δ ϭ 52.1 (q), 97.0 (s),
123.2 (d), 126.4 (d), 128.5 (s), 128.6 (d), 129.4 (d), 142.6 (s), 152.4
(s), 158.4 (s). Ϫ MS (70 eV); m/z (%): 282 (91) [Mϩ (81Br)], 280
(100) [Mϩ (79Br)], 251 (33) [(M Ϫ OCH3)ϩ (81Br)], 249 (33) [(M Ϫ
OCH3)ϩ (79Br)], 224 (3) [(M Ϫ COOCH3)ϩ (81Br)], 222 (13) [(M
Ϫ COOCH3)ϩ (79Br)], 195 (30) [(224 Ϫ CO)ϩ (81Br)], 193 (27), 114
(41), 77 (7) [C6H5ϩ], 51 (4), 28 (18). Ϫ C12H9BrO3 (281.106): calcd.
C 51.27, H 3.23; found C 50.94, H 3.21.
Ϫ OCH3)ϩ (81Br)], 199 (100) [(M Ϫ OCH3)ϩ (79Br)], 174 (18) [(M
Ϫ COOCH3)ϩ (81Br)], 172 (20) [(M Ϫ COOCH3)ϩ (79Br)], 92 (19),
64 (71).
Methyl 3-Bromo-2-(3-methylbut-2-enyl)furan-5-carboxylate (8e). ؊
Typical Procedure C: 2 mmol of furan 2[12] (568 mg), 3 mmol of tri-
n-butyl(3-methylbut-2-enyl)stannane (9)[29] (1.08 g) and 0.1 mmol
of Pd(PPh3)4 (116 mg) were dissolved in 10 mL of DMA and the
mixture was heated to 90°C for 16 h. The mixture was cooled to
room temperature and subsequently quenched with a saturated
aqueous NH4Cl solution (10 mL). After extraction with ether (3 ϫ
15 mL), the organic layers were combined, washed with brine
(15 mL), and dried with MgSO4. The solvent was removed in vacuo
and the residue was purified by flash chromatography (P/TBME ϭ
Methyl 3-Bromo-2-(furan-2-yl)furan-5-carboxylate (8b): The reac-
tion was carried out as described in typical procedure B starting
from furan 2[12] on a 2-mmol scale and 4 mmol of furylzinc chlo- 98:2). A total of 432 mg (79%) of furan 8e was obtained as a color-
ride, prepared by metalation of 4 mmol of furan (272 mg) with n-
butyllithium (4 mmol, 2.2 mL of a 1.8  solution) and transmetal-
less oil. Ϫ Rf ϭ 0.80 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2955
cmϪ1 (m, CϪH), 2928 (m, CϪH), 2857 (w, CϪH), 1736 (s, CϭO),
ation with ZnCl2 (6 mmol, 818 mg). After workup, the residue was 1030 (m, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 1.70 (d, J ϭ 1.5 Hz,
purified by flash chromatography (P/TBME ϭ 98:2). A total of 6 H), 3.39 (d, J ϭ 7.0 Hz, 2 H), 3.84 (s, 3 H), 5.23 (t sept, J ϭ
411 mg (76%) of furan 8b was obtained as a white solid. Ϫ Rf ϭ 7.0 Hz, J ϭ 1.5 Hz, 1 H), 7.08 (s, 1 H). Ϫ 13C NMR (50 MHz):
0.60 (P/TBME ϭ 75:25). Ϫ M.p. 82Ϫ84°C. Ϫ IR (KBr): ν˜ ϭ 3118
cmϪ1 (m, CArϪH), 2959 (m, CϪH), 1713 (s, CϭO), 1022 (m,
CϪBr). Ϫ H NMR (200 MHz): δ ϭ 3.85 (s, 3 H), 6.48 (dd, J ϭ
3.5 Hz, J ϭ 1.7 Hz, 1 H), 7.01 (d, J ϭ 3.5 Hz, 1 H), 7.19 (s, 1H),
7.50 (d, J ϭ 1.7 Hz, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 52.2 (q),
96.0 (s), 110.9 (d), 111.8 (d), 122.5 (d), 142.6 (s), 143.4 (s), 143.7 COOCH3)ϩ (81Br)], 213 (33) [(M Ϫ COOCH3)ϩ (79Br)], 193 (15)
(s), 146.0 (s), 158.2 (s). Ϫ MS (70 eV); m/z (%): 272 (81) [Mϩ [(M Ϫ Br)ϩ], 178 (24), 134 (89), 119 (30), 78 (80), 59 (53) [COOCH
(81Br)], 270 (100) [Mϩ (79Br)], 213 (4) [(M Ϫ COOCH3)ϩ (81Br)],
211 (3) [(M Ϫ COOCH3)ϩ (79Br)], 185 (26), 183 (27), 104 (11), 59 C 48.00, H 4.96.
δ ϭ 18.0 (q), 25.6 (q), 25.8 (t), 52.0 (q), 97.4 (s), 117.1 (d), 121.3
(d), 135.2 (s), 142.6 (s), 156.9 (s), 158.4 (s). Ϫ MS (70 eV); m/z (%):
274 (98) [Mϩ (81Br)], 272 (100) [Mϩ (79Br)], 259 (55) [(M Ϫ CH3)ϩ
(81Br)], 257 (58) [(M Ϫ CH3)ϩ (79Br)], 243 (11) [(M Ϫ OCH3)ϩ
1
(81Br)], 241 (10) [(M
Ϫ Ϫ
OCH3)ϩ (79Br)], 215 (23) [(M
ϩ], 41 (83). Ϫ C11H13BrO3 (273.123): calcd. C 48.37, H 4.80; found
3
(10) . Ϫ C10H7BrO4 (271.068): calcd. C 44.31, H 2.60; found C
44.43, H 2.82.
Methyl 2-Allyl-3-bromofuran-5-carboxylate (8f): The reaction was
carried out as described in typical procedure C starting from furan
2[12] and stannane 10 on a 2-mmol scale. After workup, the residue
was purified by flash chromatography (P/TBME ϭ 98:2). A total
of 358 mg (73%) of furan 8f was obtained as a colorless oil. Ϫ Rf ϭ
0.75 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2955 cmϪ1 (m, CϪH),
2924 (m, CϪH), 2853 (w, CϪH), 1738 (s, CϭO), 1024 (m, CϪBr).
Methyl 3-Bromo-2-methylfuran-5-carboxylate (8c): The reaction
was carried out as described in typical procedure B starting from
furan 2[12] on a 2-mmol scale and 2.4 mmol of methylzinc chloride,
prepared by transmetalation of methyllithium (2.4 mmol, 1.33 mL
of a 1.8  solution) with ZnCl2 (3.6 mmol, 491 mg). After workup,
the residue was purified by flash chromatography (P/TBME ϭ
98:2). A total of 368 mg (84%) of furan 8c was obtained as a white
solid. Ϫ Rf ϭ 0.70 (P/TBME ϭ 75:25). Ϫ M.p. 58Ϫ62°C. Ϫ IR
Ϫ
1H NMR (200 MHz): δ ϭ 3.38Ϫ3.50 (m, 2 H), 3.84 (s, 3 H),
5.04Ϫ5.10 (m, 1 H), 5.12Ϫ5.17 (m, 1 H), 5.73Ϫ5.95 (m, 1 H), 7.10
(s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 30.9 (t), 52.0 (q), 98.4 (s),
118.0 (t), 121.2 (d), 131.2 (d), 143.0 (s), 155.1 (s), 158.3 (s). Ϫ MS
(KBr): ν˜ ϭ 2959 cmϪ1 (m, CϪH), 2839 (m, CϪH), 1751 (s, CϭO),
1040 (m, CϪBr). Ϫ H NMR (200 MHz): δ ϭ 2.35 (s, 3 H), 3.86 (70 eV); m/z (%): 246 (63) [Mϩ (81Br)], 244 (64) [Mϩ (79Br)], 215
(s, 3 H), 7.09 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 12.3 (q) 52.0 (28) [(M Ϫ OCH3)ϩ (81Br)], 213 (28) [(M Ϫ OCH3)ϩ (79Br)], 187
(q), 98.3 (s), 121.2 (d), 142.5 (s), 154.4 (s), 158.4 (s). Ϫ MS (70 eV); (41) [(M Ϫ COOCH3)ϩ (81Br)], 185 (40) [(M Ϫ COOCH3)ϩ (79Br)],
1
m/z (%): 220 (55) [Mϩ (81Br)], 218 (52) [Mϩ (79Br)], 189 (57) [(M
Ϫ OCH3)ϩ (81Br)], 187 (100) [(M Ϫ OCH3)ϩ (79Br)], 161 (5) [(M
Ϫ COOCH3)ϩ (81Br)], 159 (6) [(M Ϫ COOCH3)ϩ (79Br)], 133 (8),
131 (12), 80 (7), 52 (22) , 51 (30), 28 (9). Ϫ C7H7BrO3 (219.035):
calcd. C 38.39, H 3.22; found C 38.23, H 3.31.
160 (60), 158 (100), 138 (78), 106 (30), 78 (80), 51 (63), 28 (27).
Ϫ C9H9BrO3 (245.070): calcd. C 44.11, H 3.70; found C 44.46,
H 3.93.
3-Bromo-2-(3,3-dimethylbut-1-ynyl)-5-pent-1-enylfuran (11).
؊
Typical Procedure D: To a suspension of 2 mmol of n-butyltri-
Methyl 3-Bromo-2-vinylfuran-5-carboxylate (8d): The reaction was phenylphosphonium bromide (0.80 g) in 15 mL of THF 2 mmol of
carried out as described in typical procedure B starting from furan
2[12] on a 2-mmol scale and 4 mmol of vinylzinc chloride, prepared
by transmetalation of vinylmagnesium chloride (4 mmol, 2.1 mL of
n-butyllithium (1.36 mL of a 1.47  solution in hexane) was slowly
added at 0°C. The mixture was stirred for 10 min. A solution of
2 mmol of furan 4a in 5 mL of THF was added by syringe over a
Eur. J. Org. Chem. 1999, 2045Ϫ2057
2053

T. Bach, L. Krüger
FULL PAPER
period of 20 min. The mixture was refluxed for 2 h and sub-
sequently quenched with 5 mL of water. The product was extracted
with ether (3 ϫ 10 mL), the combined organic layers were washed
2-(5-Chloropent-1-ynyl)-3-methyl-5-pent-1-enylfuran (14): The typi-
cal procedure B was slightly modified to the extent that the reaction
mixture was kept at reflux for 18 h. The reaction was carried out
with brine (10 mL), dried with MgSO4, and filtered. After removal starting from furan 12 on a 1.5-mmol scale and 4.5 mmol of meth-
of the solvent in vacuo, the residue was purified by flash chroma-
tography (P/TBME ϭ 90:10). A total of 360 mg (61%) of furan 11
was obtained as a yellow oil. Analytical data are provided for the
predominant (Z) isomer [(Z)/(E) ratio: 86:14]. Ϫ Rf ϭ 0.70 (P/
TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2971 cmϪ1 (s, CϪH), 2931 (m,
CϪH), 2873 (m, CϪH), 2225 (w, CϵC), 1038 (w, CϪBr). Ϫ 1H
ylzinc chloride, prepared by transmetalation of methyllithium
(4.5 mmol, 2.5 mL of a 1.8  solution) with ZnCl2 (6 mmol,
818 mg). After workup, the residue was purified by flash chroma-
tography (P/TBME ϭ 98:2). A total of 253 mg (68%) of furan 14
was obtained as a yellow oil. Analytical data are provided for the
predominant (Z) isomer [(Z)/(E) ratio: 82:18]. Ϫ Rf ϭ 0.76 (P/
NMR (200 MHz): δ ϭ 0.88 (t, J ϭ 7.4 Hz, 3 H), 1.27 (s, 9 H), 1.40 TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2959 cmϪ1 (s, CϪH), 2928 (s,
(sext, J ϭ 7.4 Hz, 2 H), 2.28 (dq, J ϭ 7.4 Hz, J ϭ 1.8 Hz, 2 H),
5.56 (dt, J ϭ 11.8 Hz, J ϭ 7.4 Hz, 1 H), 6.01 (dt, J ϭ 11.8 Hz, J ϭ
1.8 Hz, 1 H), 6.21 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 13.7 (q),
22.9 (t), 28.3 (s), 30.5 (q), 31.3 (t), 68.0 (s), 105.7 (s), 109.8 (s),
CϪH), 2872 (s, CϪH), 2226 (w, CϵC). Ϫ 1H NMR (200 MHz):
δ ϭ 0.96 (t, J ϭ 7.3 Hz, 3 H), 1.48 (sext, J ϭ 7.3 Hz, 2 H), 2.04 (s,
3 H), 1.97Ϫ2.13 (m, 2 H), 2.37 (dq, J ϭ 7.3 Hz, J ϭ 1.8 Hz, 2 H),
2.66 (t, J ϭ 6.5 Hz, 2 H), 3.69 (t, J ϭ 6.5 Hz, 2 H), 5.55 (dt, J ϭ
112.5 (d), 116.7 (d), 132.9 (s), 134.2 (d), 152.9 (s). Ϫ MS (70 eV); 11.8 Hz, J ϭ 7.3 Hz, 1 H), 6.07 (dt, J ϭ 11.8 Hz, J ϭ 1.8 Hz, 1
m/z (%): 296 (84) [Mϩ (81Br)], 294 (87) [Mϩ (79Br)], 281 (99) [(M H), 6.09 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 10.5 (q), 13.8 (q),
Ϫ CH3)ϩ (81Br)], 279 (100) [(M Ϫ CH3)ϩ (79Br)], 267 (30) [(M Ϫ 17.2 (t), 22.6 (t), 31.3 (t), 31.4 (t), 43.6 (t), 71.7 (s), 95.1 (s), 111.9
C2H5)ϩ (81Br)], 265 (100) [(M Ϫ C2H5)ϩ (79Br)], 239 (14) [(M Ϫ
C4H9)ϩ (81Br)], 237 (15) [(M Ϫ C4H9)ϩ (79Br)], 158 (17), 55 (90),
41 (45). Ϫ C15H19BrO (295.215): calcd. C 61.03, H 6.49; found C
61.24, H 6.49.
(d), 117.1 (d), 126.3 (s), 132.4 (s), 133.0 (d), 153.0 (s). Ϫ MS
(70 eV); m/z (%): 252 (47) [Mϩ (37Cl)], 250 (100) [Mϩ (35Cl)], 235
(19) [(M Ϫ CH3)ϩ (35Cl)], 221 (95) [(M Ϫ C2H5)ϩ (35Cl)], 214 (31),
115 (68), 41 (41), 28 (79). C15H19ClO (HRMS): calcd. 250.1124;
found 250.1126.
3-Bromo-2-(5-chloropent-1-ynyl)-5-pent-1-enylfuran (12): The reac-
tion was carried out as described in typical procedure D starting
from furan 4d on a 3-mmol scale. After workup, the residue was
purified by flash chromatography (P/TBME ϭ 95:5). A total of
825 mg (87%) of furan 12 was obtained as an orange-yellow oil.
Analytical data are provided for the predominant (Z) isomer [(Z)/
(E) ratio: 81:19]. Ϫ Rf ϭ 0.80 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ
2961 cmϪ1 (s, CϪH), 2228 (w, CϵC), 1055 (w, CϪBr). Ϫ 1H NMR
(200 MHz): δ ϭ 0.94 (t, J ϭ 7.3 Hz, 3 H), 1.48 (sext, J ϭ 7.3 Hz,
2 H), 2.05 (quint, J ϭ 6.5 Hz, 2 H), 2.35 (dq, J ϭ 7.3 Hz, J ϭ
1.8 Hz, 2 H), 2.68 (t, J ϭ 6.5 Hz, 2 H), 3.70 (t, J ϭ 6.5 Hz, 2 H),
5.64 (dt, J ϭ 11.8 Hz, J ϭ 7.3 Hz, 1 H), 6.06 (dt, J ϭ 11.8 Hz, J ϭ
1.8 Hz, 1 H), 6.27 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 13.6 (q),
17.2 (t), 22.5 (t), 31.0 (t), 31.6 (t), 43.5 (t), 70.5 (s), 97.2 (s), 106.3
(s), 112.5 (d), 116.4 (d), 133.3 (s), 134.5 (d), 153.2 (s). Ϫ MS
(70 eV); m/z (%): 318 (45) [Mϩ (81Br, 37Cl)], 316 (100) [Mϩ (81Br,
35Cl)], 314 (88) [Mϩ (79Br, 35Cl)], 287 (99) [(M Ϫ C2H5)ϩ (81Br,
35Cl)], 171 (49), 55 (72), 41 (42). Ϫ C14H16BrClO (315.633): calcd.
C 53.27, H 5.11; found C 53.09, H 5.07.
Methyl
2-(3,3-Dimethylbut-1-ynyl)-3-methylfuran-5-carboxylate
(15): The typical procedure B was slightly modified to the extent
that the reaction mixture was kept at reflux for 18 h. The reaction
was carried out starting from furan 5a on a 1.5-mmol scale and
4.5 mmol of methylzinc chloride, prepared by transmetalation of
methyllithium (4.5 mmol, 2.5 mL of a 1.8  solution) with ZnCl2
(6 mmol, 818 mg). After workup, the residue was purified by flash
chromatography (P/TBME ϭ 98:2). A total of 231 mg (70%) of
furan 15 was obtained as a colorless oil. Ϫ Rf ϭ 0.60 (P/TBME ϭ
75:25). Ϫ IR (film): ν˜ ϭ 2970 cmϪ1 (s, CϪH), 2930 (m, CϪH),
2868 (w, CϪH), 2230 (w, CϵC), 1736 (s, CϭO). Ϫ 1H NMR
(200 MHz): δ ϭ 1.28 (s, 9 H), 2.04 (s, 3 H), 3.83 (s, 3 H), 6.97 (s,
1 H). Ϫ 13C NMR (50 MHz): δ ϭ 10.3 (q), 28.2 (s), 30.6 (q), 51.9
(q), 68.3 (s), 106.8 (s), 120.4 (d), 125.6 (s), 138.5 (s), 142.5 (s), 158.6
(s). Ϫ MS (70 eV); m/z (%): 220 (44) [Mϩ], 205 (100) [(M Ϫ CH3)ϩ],
161 (58) [(M Ϫ COOCH3)ϩ], 91 (16) [C7H7ϩ], 41 (7). Ϫ C13H16O3
(220.264): calcd. C 70.89, H 7.32; found C 70.49, H 7.37.
Methyl 2-(5-Chloropent-1-ynyl)-3-methylfuran-5-carboxylate (16):
The typical procedure B was slightly modified to the extent that
the reaction mixture was kept at reflux for 18 h. The reaction was
carried out starting from furan 5d on a 2-mmol scale and 6 mmol
of methyl zinc chloride, prepared by transmetalation of methyl lith-
ium (6 mmol, 3.3 mL of a 1.8  solution) with ZnCl2 (9 mmol,
1228 mg). After workup, the residue was purified by flash chroma-
tography (P/TBME ϭ 98:2). A total of 321 mg (67%) of furan 16
was obtained as a colorless oil. Ϫ Rf ϭ 0.50 (P/TBME ϭ 75:25).
Ϫ IR (film): ν˜ ϭ 2957 cmϪ1 (m, CϪH), 2928 (m, CϪH), 2845 (w,
CϪH), 2232 (w, CϵC), 1732 (s, CϭO). Ϫ 1H NMR (200 MHz):
δ ϭ 2.03 (quint, J ϭ 6.6 Hz, 2 H), 2.05 (s, 3 H), 2.64 (t, J ϭ 6.6 Hz,
2 H), 3.66 (t, J ϭ 6.6 Hz, 2 H), 3.84 (s, 3 H), 6.96 (s, 1 H). Ϫ 13C
NMR (50 MHz): δ ϭ 10.3 (q), 17.0 (t), 30.9 (t), 43.4 (t), 51.9 (q),
70.6 (s), 96.8 (s) 120.3 (d), 126.2 (s), 138.0 (s), 142.8 (s), 158.5 (s).
Ϫ MS (70 eV); m/z (%): 242 (35) [Mϩ (37Cl)], 240 (76) [Mϩ (35Cl)],
205 (51) [(M Ϫ Cl)ϩ], 183 (8) [(242 Ϫ COOCH3)ϩ], 181 (28) [(240
Ϫ COOCH3)ϩ], 177 (100) [(M Ϫ (CH2)2Cl)ϩ], 145 (28), 117 (52),
91 (31) [C7H7ϩ], 77 (28), 28 (26). Ϫ C12H13ClO3 (240.683): calcd.
C 59.88, H 5.44; found C 59.80, H 5.30.
2-(3,3-Dimethylbut-1-ynyl)-3-methyl-5-pent-1-enylfuran (13): The
typical procedure B was slightly modified to the extent that the
reaction mixture was kept at reflux for 18 h. The reaction was car-
ried out on a 1-mmol scale starting from furan 11 using 3 mmol of
methylzinc chloride, prepared by transmetalation of methyllithium
(1.67 mL of a 1.8  solution) with ZnCl2 (4.5 mmol, 610 mg). After
workup, the residue was purified by flash chromatography (P/
TBME ϭ 98:2). A total of 164 mg (71%) of furan 13 was obtained
as a yellow oil. Analytical data are provided for the predominant
(Z) isomer [(Z)/(E) ratio: 85:15]. Ϫ Rf ϭ 0.75 (P/TBME ϭ 75:25).
Ϫ IR (film): ν˜ ϭ 2969 cmϪ1 (s, CϪH), 2928 (m, CϪH), 2870 (m,
1
CϪH), 2226 (w, CϵC). Ϫ H NMR (200 MHz): δ ϭ 0.95 (t, J ϭ
7.5 Hz, 3 H), 1.31 (s, 9 H), 1.48 (sext, J ϭ 7.5 Hz, 2 H), 2.03 (s, 3
H), 2.36 (dq, J ϭ 7.5 Hz, J ϭ 1.8 Hz, 2 H), 5.53 (dt, J ϭ 11.8 Hz,
J ϭ 7.5 Hz, 1 H), 6.09 (dt, J ϭ 11.8 Hz, J ϭ 1.8 Hz, 1 H), 6.09 (s,
1 H). Ϫ 13C NMR (50 MHz): δ ϭ 10.5 (q), 13.8 (q), 22.6 (t), 28.3
(s), 30.9 (q), 31.4 (t), 69.2 (s), 105.3 (s), 111.9 (d), 117.3 (d), 125.9
(s) 132.1 (d), 133.3 (s), 152.2 (s). Ϫ MS (70 eV); m/z (%): 230 (100)
[Mϩ], 215 (96) [(M Ϫ CH3)ϩ], 201 (75) [(M Ϫ C2H5)ϩ], 173 (18)
[(M Ϫ C4H9)ϩ], 28 (34). Ϫ C16H22O (230.345): calcd. C 83.43, H
9.63; found C 83.14, H 9.70.
Methyl 3-Methyl-2-(3-methylbut-2-enyl)furan-5-carboxylate (18). ؊
Typical Procedure E: 2 mmol of furan 8e (546 mg), 4 mmol of tetra-
2054
Eur. J. Org. Chem. 1999, 2045Ϫ2057

2,3,5-Tri- and 2,3-Disubstituted Furans by Regioselective Palladium(0)-Catalyzed Coupling Reactions
FULL PAPER
methylstannane (720 mg, 0.55 mL) and 0.1 mmol of Pd(Po-
Tol3)2Cl2 (70 mg) were dissolved in 10 mL of DMA and the mix-
ture was heated to 90°C for 20 h. Ϫ CAUTION: Tetramethylstan-
nane is very toxic on inhalation, in contact with skin and if swal-
lowed! Appropriate safety protection and utmost care is required
when handling this compound! Ϫ The mixture was cooled to room
temperature and subsequently quenched with a saturated aqueous
NH4Cl solution (10 mL). After extraction with ether (3 ϫ 15 mL),
the organic layers were combined, washed with brine (15 mL), and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due was purified by flash chromatography (P/TBME ϭ 98:2). A
total of 280 mg (70%) of furan 18 was obtained as a colorless oil.
Ϫ Rf ϭ 0.70 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2951 cmϪ1 (m,
CϪH), 2930 (m, CϪH), 2874 (w, CϪH), 1732 (s, CϭO). Ϫ 1H
NMR (200 MHz): δ ϭ 1.69 (d, J ϭ 1.5 Hz, 6 H), 1.96 (s, 3 H),
3.32 (d, J ϭ 7.2 Hz, 2 H), 3.83 (s, 3 H), 5.23 (t sept, J ϭ 7.2 Hz,
J ϭ 1.5 Hz, 1 H), 6.94 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 9.6
(q), 17.8 (q), 25.6 (q), 25.7 (t), 51.6 (q), 116.6 (s), 118.7 (d), 121.6
(d), 133.9 (s), 141.5 (s), 155.7 (s), 159.4 (s). Ϫ MS (70 eV); m/z (%):
208 (87) [Mϩ], 193 (100) [(M Ϫ CH3)ϩ], 153 (30) [(M Ϫ C4H7ϩ],
149 (42) [(M Ϫ COOCH3)ϩ], 121 (14), 91 (34) [C7H7ϩ], 41 (29). Ϫ
C12H16O3 (208.254): calcd. C 69.21, H 7.74; found C 69.21, H 8.00.
41 (22), 28 (31). Ϫ C14H20BrClO (319.665): calcd. C 52.60, H 6.31;
found C 52.58, H 6.20.
2-(5-Chloropentyl)-3-methyl-5-pent-1-enylfuran (21): The reaction
was carried out as described in typical procedure E starting from
furan 20 on a 0.4-mmol scale. After workup, the residue was puri-
fied by flash chromatography (P/TBME ϭ 98:2). No hydrodebrom-
inated product was observed. The product (50 mg) was, however,
contaminated with the corresponding 2-(5-bromopentyl)furan (ca.
10% according to GLC) which is presumably formed by a Fink-
elstein reaction and which could not be separated by chromatogra-
phy. The yield was consequently not determined and a correct el-
emental analysis was not obtained. Analytical data are provided
for the predominant (Z) isomer [(Z)/(E) ratio: 80:20]. Ϫ Rf ϭ 0.82
(P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2957 cmϪ1 (s, CϪH), 2930
(s, CϪH), 2870 (s, CϪH). Ϫ 1H NMR (200 MHz): δ ϭ 0.95 (t, J ϭ
7.3 Hz, 3 H), 1.36Ϫ1.86 (m, 8 H), 1.92 (s, 3 H), 2.37 (dq, J ϭ
7.3 Hz, J ϭ 1.8 Hz, 2 H), 2.55 (t, J ϭ 7.3 Hz, 2 H), 3.51 (t, J ϭ
6.6 Hz, 2 H), 5.43 (dt, J ϭ 11.8 Hz, J ϭ 7.3 Hz, 1 H), 6.02 (s, 1
H), 6.07 (dt, J ϭ 11.8 Hz, J ϭ 1.8 Hz, 1 H). Ϫ 13C NMR
(50 MHz): δ ϭ 9.8 (q), 13.9 (q), 22.7 (t), 25.7 (t), 26.4 (t), 27.7 (t),
31.3 (t), 32.4 (t), 44.9 (t), 112.2 (d), 115.5 (s), 117.5 (d), 129.5 (d),
149.9 (s), 150.6 (s). Ϫ MS (70 eV); m/z (%): 256 (22) [Mϩ (37Cl)],
254 (57) [Mϩ (35Cl)], 227 (17) [(M Ϫ C2H5)ϩ (37Cl)], 225 (46) [(M
Ϫ C2H5)ϩ (35Cl)], 219 (22), 213 (10) [(M Ϫ C3H7)ϩ (37Cl)], 211 (34)
[(M Ϫ C3H7)ϩ (35Cl)], 163 (100), 121 (54), 107 (38), 91 (30)
[C4H8Clϩ (35Cl)], 55 (31), 41 (21), 28 (37). Ϫ C15H23ClO (HRMS):
calcd. 254.1437; found 254.1436.
3-Bromo-2-(5-chloropentyl)furan-5-carbaldehyde (19).
؊ Typical
Procedure F: 2 mmol of furan 4d (551 mg) was dissolved in 15 mL
of ethyl acetate and 0.2 mmol of the catalyst Pd/C [10% w/w]
(213 mg) was added to the solution. The hydrogenolysis was carried
out in a conventional hydrogenation apparatus at ambient tempera-
ture and atmospheric pressure. The progress of the reaction was
indicated by the volume of consumed hydrogen and was further
monitored by GLC. Upon complete transformation (150 min), the
mixture was filtered and the solvent was removed in vacuo. The
residue was purified by flash chromatography (P/TBME ϭ 90:10).
A total of 360 mg (65%) of furan 19 was obtained as a yellow oil.
Ϫ Rf ϭ 0.58 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2940 cmϪ1 (m,
CϪH), 2864 (m, CϪH), 1685 (s, CϭO), 1022 (m, CϪBr). Ϫ 1H
NMR (200 MHz): δ ϭ 1.44Ϫ1.58 (m, 2 H), 1.65Ϫ1.86 (m, 4 H),
2.78 (t, J ϭ 6.4 Hz, 2 H), 3.55 (t, J ϭ 6.4 Hz, 2 H), 7.20 (s, 1 H),
9.52 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 26.2 (t), 26.4 (t), 26.5
(t), 32.0 (t), 44.6 (t), 99.3 (s), 124.2 (d), 150.9 (s), 159.7 (s), 176.6
(d). Ϫ MS (70 eV); m/z (%): 282 (9) [Mϩ (81Br, 37Cl)], 280 (41) [Mϩ
3-Methyl-2-(3-methylbut-2-enyl)furan (Rosefuran, 22): 1 mmol of
compound 18 (208 mg) was dissolved in 5 mL of an aqueous
NaOH solution [20% w/w] and the mixture was refluxed for 4 h.
After acidification with 5  HCl to pH ϭ 1, the mixture was ex-
tracted with ethyl acetate (3 ϫ 10 mL), washed with brine (10 mL),
and dried with MgSO4. The solvent was removed in vacuo and the
crude product was dissolved in 6 mL of quinoline. 3 mmol of Cu
powder (212 mg) was added and the mixture heated to 180°C.
After complete transformation, 20 mL of diethyl ether was added
and the mixture was washed with 1  HCl (4 ϫ 25 mL) to remove
the quinoline. The organic layer was washed with brine, dried with
MgSO4, and the solvent was removed in vacuo. The residue was
purified by flash chromatography (P/TBME ϭ 95:5). A total of
105 mg (70%) of furan 22 was obtained as a colorless oil. Ϫ Rf ϭ
0.80 (P/TBME ϭ 75:25). Ϫ 1H NMR (200 MHz): δ ϭ 1.70 (s, 6
H), 1.94 (s, 3 H), 3.26 (d, J ϭ 7.2 Hz, 2 H), 5.24 (t sept, J ϭ 7.2 Hz,
J ϭ 1.2 Hz, 1 H), 6.14 (d, J ϭ 1.8 Hz, 1 H), 7.20 (d, J ϭ 1.8 Hz,
1 H). Ϫ All other analytical data are in agreement with those given
in the literature.[2e,33]
ϩ
(81Br, 35Cl)], 278 (23) [Mϩ (79Br, 35Cl)], 189 (100) [C6H4BrO2
(81Br)], 109 (39), 91 (50) [C4H8Clϩ (35Cl)], 55 (67).
Ϫ
C
10H12BrClO2 (279.558): calcd. C 42.96, H 4.33; found C 43.06,
H 4.33.
3-Bromo-2-(5-chloropentyl)-5-pent-1-enylfuran (20): The reaction
was carried out as described in typical procedure D starting from
furan 19 on a 1.8-mmol scale. After workup, the residue was puri-
fied by flash chromatography (P/TBME ϭ 98:2). A total of 466 mg
Benzyl 11-[(3-Bromo-5-pent-1-enylfuran)-2-yl]undec-10-ynoate (23):
(81%) of furan 20 was obtained as a yellow oil. Analytical data are The reaction was carried out as described in typical procedure D
provided for the predominant (Z) isomer [(Z)/(E) ratio: 84:16]. Ϫ
Rf ϭ 0.80 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2957 cmϪ1 (s,
CϪH), 2932 (s, CϪH), 2868 (s, CϪH), 1020 (w, CϪBr). Ϫ 1H
NMR (200 MHz): δ ϭ 0.94 (t, J ϭ 7.3 Hz, 3 H), 1.40Ϫ1.55 (m, 4
H), 1.56Ϫ1.86 (m, 4 H), 2.33 (dq, J ϭ 7.3 Hz, J ϭ 1.8 Hz, 2 H),
starting from furan 4f on a 2-mmol scale. After quenching and
usual workup, the residue was purified by flash chromatography
(P/TBME ϭ 90:10). A total of 815 mg (84%) of furan 23 was ob-
tained as a brown oil. Analytical data are provided for the predomi-
nant (Z) isomer [(Z)/(E) ratio: 82:18]. Ϫ Rf ϭ 0.60 (P/TBME ϭ
2.64 (t, J ϭ 6.5 Hz, 2 H), 3.51 (t, J ϭ 6.5 Hz, 2 H), 5.53 (dt, J ϭ 75:25). Ϫ IR (film): ν˜ ϭ 3032 cmϪ1 (w, CArϪH), 2932 (s, CϪH),
11.8 Hz, J ϭ 7.3 Hz, 1 H), 6.05 (dt, J ϭ 11.8 Hz, J ϭ 1.8 Hz, 1
H), 6.19 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 13.9 (q), 22.6 (t),
25.6 (t), 26.2 (t), 27.0 (t), 31.3 (t), 32.2 (t), 44.8 (t), 97.5 (s), 112.0
2859 (m, CϪH), 2228 (w, CϵC), 1737 (s, OϪCϭO), 1059 (w,
CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 0.93 (t, J ϭ 7.2 Hz, 3 H),
1.15Ϫ1.65 (m, 16 H), 2.33 (t, J ϭ 7.2 Hz, 2 H), 2.46 (t, J ϭ 7.2 Hz,
(d), 116.8 (d), 131.8 (d), 151.1 (s), 151.7 (s). Ϫ MS (70 eV); m/z 2 H), 5.09 (s, 2 H), 5.62 (dt, J ϭ 11.8 Hz, J ϭ 7.2 Hz, 1 H), 6.06
(%): 322 (14) [Mϩ (81Br, 37Cl)], 320 (61) [Mϩ (81Br, 35Cl)], 318 (44)
(dt, J ϭ 11.8 Hz, J ϭ 1.6 Hz, 1 H), 6.26 (s, 1 H), 7.30Ϫ7.40 (m, 5
[Mϩ (79Br, 35Cl)], 291 (53) [(M Ϫ C2H5)ϩ (81Br, 35Cl)], 229 (99) H). Ϫ 13C NMR (50 MHz): δ ϭ 13.8 (q), 19.7 (t), 22.4 (t), 24.9 (t),
[C10H12BrOϩ (81Br)], 227 (100) [C10H12BrOϩ (79Br)], 187 (61) 28.1 (t), 28.6 (t) 28.8 (t) 29.0 (t), 29.1 (t), 31.3 (t), 34.3 (t), 66.0 (t),
[C7H6BrOϩ (81Br)], 185 (66) [C7H6BrOϩ (79Br)], 91 (37), 55 (49),
69.5 (s), 99.4 (s), 105.7 (s), 112.5 (d), 116.5 (d), 128.1 (d), 128.1 (d),
2055
Eur. J. Org. Chem. 1999, 2045Ϫ2057

T. Bach, L. Krüger
128.5 (d), 134.2 (d), 134.8 (s), 136.0 (s), 153.0 (s), 173.7 (s). Ϫ MS 3-Bromo-2-(3-methylbut-2-enyl)furan (28): The reaction was carried
FULL PAPER
(70 eV); m/z (%): 486 (11) [Mϩ (81Br)], 484 (11) [Mϩ (79Br)], 395
out as described in typical procedure C starting from 2,3-dibromo-
(26) [(M Ϫ C7H7)ϩ (81Br)], 393 (24) [(M Ϫ C7H7)ϩ (79Br)], 314 (6) furan (27) and stannane 9 on a 2-mmol scale. After workup, the
[(393 Ϫ Br)], 91 (100) [C7H7ϩ], 41 (25), 28 (48). Ϫ C27H33BrO3 residue was purified by flash chromatography (P) and kugelrohr
(485.488): calcd. C 66.80, H 6.85; found C 66.61, H 6.93.
distillation (10 mbar, 80Ϫ90°C). A total of 490 mg (60%) of furan
28[33] was obtained as a colorless oil. Ϫ Rf ϭ 0.85 (PE/TBME ϭ
75:25). Ϫ IR (film): ν˜ ϭ 2982 cmϪ1 (m, CϪH), 2930 (m, CϪH),
2915 (m, CϪH), 1055 (s, CϪBr). Ϫ 1H NMR (200 MHz): δ ϭ 1.73
(d, J ϭ 1.1 Hz, 6 H), 3.35 (d, J ϭ 7.2 Hz, 2 H), 5.25 (t sept, J ϭ
7.2 Hz, J ϭ 1.1 Hz, 1 H), 6.34 (d, J ϭ 2.0 Hz, 1 H), 7.26 (d, J ϭ
2.0 Hz, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 17.8 (q), 25.3 (q), 25.6
(t), 95.4 (s), 113.6 (d), 118.4 (d), 134.3 (s), 141.1 (d), 152.0 (s). Ϫ
MS (70 eV); m/z (%): 216 (58) [Mϩ (81Br)], 214 (65) [Mϩ (79Br)],
201 (45) [(M Ϫ CH3)ϩ (81Br)], 199 (58) [(M Ϫ CH3)ϩ (79Br)], 161
(25) [(M Ϫ C4H7)ϩ (81Br)], 159 (22) [(M Ϫ C4H7)ϩ (79Br)], 135 (19)
[(M Ϫ Brϩ], 120 (100) [(135 Ϫ CH3)ϩ], 51 (51) [C4H3ϩ], 41 (83)
[C3H5ϩ].
Benzyl 11-[(3-Methyl-5-pent-1-enylfuran)-2-yl]undec-10-ynoate (24):
The reaction was carried out as described in typical procedure B
starting from furan 23 on a 2-mmol scale and 6 mmol of methylzinc
chloride, prepared by transmetalation of methyl lithium (6 mmol,
3.33 mL of a 1.8  solution) with ZnCl2 (9 mmol, 1228 mg). After
workup, the residue was purified by flash chromatography (P/
TBME ϭ 98:2). A total of 655 mg (76%) of furan 24 was obtained
as a brown oil. Analytical data are provided for the predominant
(Z) isomer [(Z)/(E) ratio: 82:18]. Ϫ Rf ϭ 0.80 (P/TBME ϭ 75:25).
Ϫ IR (film): ν˜ ϭ 3067 cmϪ1 (w, CArϪH), 2930 (s, CϪH), 2857 (s,
CϪH), 2228 (w, CϵC), 1738 (s, OϪCϭO). Ϫ 1H NMR (200 MHz):
δ ϭ 0.94 (t, J ϭ 7.4 Hz, 3 H), 1.13Ϫ1.68 (m, 16 H), 2.27Ϫ2.48 (m,
4 H), 2.09 (s, 3 H), 5.09 (s, 2 H), 5.54 (dt, J ϭ 11.7 Hz, J ϭ 7.4 Hz,
1 H), 6.07 (dt, J ϭ 11.7 Hz, J ϭ 1.8 Hz, 1 H), 6.09 (s, 1 H),
7.30Ϫ7.36 (m, 5 H). Ϫ 13C NMR (50 MHz): δ ϭ 10.5 (q), 13.8 (q),
19.7 (t), 22.6 (t), 24.9 (t), 28.5 (t), 28.7 (t) 28.9 (t) 29.0 (t), 29.1 (t),
31.3 (t), 34.2 (t), 66.0 (t), 70.8 (s), 97.3 (s), 111.9 (d), 117.2 (d),
125.8 (s), 128.1 (d), 128.1 (d), 128.5 (d), 132.1 (d), 133.4 (s), 136.1
(s), 152.3 (s), 173.6 (s). Ϫ MS (70 eV); m/z (%): 420 (43) [Mϩ], 329
(27) [(M Ϫ C7H7)ϩ], 91 (100) [C7H7ϩ], 41 (24), 28 (40). Ϫ C28H36O3
(420.584): calcd. C 79.96, H 8.63; found C 79.70, H 8.86.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Ba 1372/5Ϫ1), the Fonds der Chemischen Industrie and by the
Graduiertenkolleg ”Metallorganische Chemie”. The skillful assist-
ance of Tobias Aechtner (undergraduate research participant) is
gratefully acknowledged. We thank the Degussa AG for a gift of
chemicals.
Benzyl 11-[(3-Methyl-5-pentylfuran)-2-yl]undecanoate (25): The re-
action was carried out as described in typical procedure F starting
from furan 24 (2 mmol, 821 mg). 0.03 mmol of Pd(OH)2/C [20%
w/w] (120 mg) was used as catalyst. After workup, the residue was
purified by flash chromatography (P/TBME ϭ 98:2). A total of
358 mg (84%) of furan 25 was obtained as a colorless oil. Ϫ Rf ϭ
0.70 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2928 cmϪ1 (s, CϪH),
2857 (s, CϪH), 1740 (s, OϪCϭO). Ϫ 1H NMR (200 MHz): δ ϭ
0.88 (t, J ϭ 7.4 Hz, 3 H), 1.10Ϫ1.70 (m, 22 H), 1.88 (s, 3 H), 2.33
(t, J ϭ 7.3 Hz, 2 H), 2.47 (t, J ϭ 7.3 Hz, 2 H), 2.50 (t, J ϭ 7.3 Hz,
2 H), 5.09 (s, 2 H), 5.72 (s, 1 H), 7.28Ϫ7.38 (m, 5 H). Ϫ 13C NMR
(50 MHz): δ ϭ 9.8 (q), 14.0 (q), 22.4 (t), 25.0 (t), 25.9 (t), 27.8 (t),
28.0 (t), 28.7 (t) 29.1 (t) 29.2 (t), 29.2 (t), 29.3 (t), 29.4 (t), 29.5 (t),
31.4 (t), 34.3 (t), 66.0 (t), 107.6 (d), 113.8 (s), 128.1 (d), 128.1 (d),
128.5 (d), 136.1 (s), 149.4 (s), 153.5 (s), 173.7 (s). Ϫ MS (70 eV);
m/z (%): 426 (10) [Mϩ], 335 (18) [(M Ϫ C7H7)ϩ], 165 (100), 91 (27)
[C7H7ϩ]. Ϫ C28H42O3 (HRMS): calcd. 426.3134; found 426.3132.
[1]
[1a]
Reviews:
W. Eberbach, Methoden Org. Chem. ( Houben-
[1b]
Weyl) , 4th ed. 1994, vol. E6a, part 1, pp. 16Ϫ185d. Ϫ
M.
V. Sargent, F. M. Dean in: Compr. Heterocycl. Chem., vol. 4
(Ed.: A. R. Katritzky), Pergamon, Oxford, 1984, pp. 599Ϫ656.
[1c]
Ϫ
F. M. Dean, Adv. Heterocycl. Chem. 1982, 30, 167Ϫ238;
1982, 31, 237Ϫ344.
[2]
Selected recent publications: [2a] J. A. Marshall, J. Liao, J. Org.
[2b]
Chem. 1998, 63, 5962Ϫ5970. Ϫ
C. M. Marson, S. Harper,
[2c]
Tetrahedron Lett. 1998, 39, 333Ϫ334. Ϫ
Y. R. Lee, N. S.
[2d]
Kim, B. S. Kim, Tetrahedron Lett. 1997, 38, 5671Ϫ5674. Ϫ
J. A. Marshall, C. A. Sehon, J. Org. Chem. 1997, 62,
[2e]
4313Ϫ4320. Ϫ
M. K. Wong, C. Y. Leung, H. N. C. Wong,
Tetrahedron 1997, 53, 3497Ϫ3512. Ϫ [2f] D. I. MaGee, J. D. Le-
ach, T. C. Mallais, Tetrahedron Lett. 1997, 38, 1289Ϫ1292. Ϫ
[2g]
L. A. Paquette, P. C. Astles, J. Org. Chem. 1993, 58,
165Ϫ169.
[3] [3a]
R. L. Glass, T. P. Krick, D. M. Sand, C. H. Rahn, H.
Schlenk, Lipids 1975, 10, 695Ϫ702. Ϫ [3b] A. Batna, G. Spiteller,
Lipids 1994, 29, 397Ϫ403 and refs. cited therein.
[4]
[5]
[6]
M. Ochi, K. Yamada, H. Kawakami, A. Tatsukawa, H. Kot-
suki, K. Shibata, Tetrahedron Lett. 1992, 33, 7531Ϫ7534.
D. Williams, R. J. Andersen, G. D. Van Duyne, J. Clardy, J.
Org. Chem. 1987, 52, 332Ϫ335 and refs. cited therein.
11-[(3-Methyl-5-pentylfuran)-2-yl)]undecanoic Acid (26): 1 mmol of
furan 25 (427 mg) and 3 mmol of KOH (176 mg) were dissolved in
9 mL of THF/MeOH/water (1:1:1) and the solution was refluxed
for 2 h. After complete transformation, the mixture was extracted
with diethyl ether (3 ϫ 15 mL), washed with brine, and dried with
MgSO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography (P/TBME ϭ 80:20). A total of
302 mg (90%) of furan 26 was obtained as a colorless oil. Ϫ Rf ϭ
0.30 (P/TBME ϭ 75:25). Ϫ IR (film): ν˜ ϭ 2928 cmϪ1 (s, CϪH),
2857 (s, CϪH), 1709 (s, OϪCϭO). Ϫ 1H NMR (200 MHz): δ ϭ
0.84Ϫ0.92 (m, 3 H), 1.14Ϫ1.70 (m, 22 H), 1.87 (s, 3 H), 2.32 (t,
J ϭ 7.3 Hz, 2 H), 2.45 (t, J ϭ 7.3 Hz, 2 H), 2.49 (t, J ϭ 7.3 Hz, 2
H), 5.71 (s, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ 9.9 (q), 14.0 (q),
22.4 (t), 24.7 (t), 25.9 (t), 27.8 (t), 27.9 (t), 28.7 (t) 29.0 (t) 29.1 (t),
29.2 (t), 29.3 (t), 29.4 (t), 29.5 (t), 31.4 (t), 34.0 (t), 107.6 (d), 113.7
(s), 149.4 (s), 153.5 (s), 179.5 (s). Ϫ MS (70 eV); m/z (%): 336 (36)
[Mϩ], 279 (20) [(M Ϫ C4H9)ϩ], 165 (100), 108 (7), 28 (30). Ϫ
C21H36O3 (336.509): calcd. C 74.95, H 10.78; found C 74.80, H
10.71.
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