Pd0-catalyzed coupling cyclization reaction of aryl or 1-alkenyl halides with 1,2-allenyl ketones: Scope and mechanism. An efficient assembly of 2,3,4-, 2,3,5-tri- and 2,3,4,5-tetrasubstituted furans

Article abstract of DOI:10.1002/chem.200204664

Described herein is the Pd⁰-catalyzed coupling cyclization reaction of 1,2-allenyl ketones with organic halides leading efficiently and conveniently to not only 2,3,4- and 2,3,5-trisubstituted furans but also 2,3,4,5-tetrasubstituted furans. Fu

Full text of DOI:10.1002/chem.200204664

FULL PAPER
Pd0-Catalyzed Coupling Cyclization Reaction of Aryl or 1-Alkenyl Halides
with 1,2-Allenyl Ketones:Scope and Mechanism. An Efficient Assembly of
2,3,4-, 2,3,5-Tri- and 2,3,4,5-Tetrasubstituted Furans
Shengming Ma,* Junliang Zhang, and Lianghua Lu[a]
Abstract: Described herein is the Pd0-catalyzed coupling cyclization reaction of 1,2-
allenyl ketones with organic halides leading efficiently and conveniently to not only
2,3,4- and 2,3,5-trisubstituted furans but also 2,3,4,5-tetrasubstituted furans. Fur-
thermore, this method showed high substituent-loading capability and tolerance of
various substituents. The reactions of 1,2-allenyl ketones 1e, 1p, 1q, and deuterated
[D]1c were performed for a mechanistic study, which demonstrated that instead of an
À
Keywords: allenes ¥ C C coupling
¥ cyclization ¥ ketones ¥ palladium
enolization pathway, the reaction may proceed via the intermediacy of dienolate
palladium and intramolecular nucleophilic attack on the p-allyl palladium inter-
mediate by the carbonyl oxygen.
2,4-disubstituted furans [Eq. (2)][13] and the AuIII-catalyzed
reaction of terminal 1,2-allenyl ketones with a,b-unsaturated
ketones to afford 2,5-disubstituted furans [Eq. (3)].[14]
Introduction
Furans, one of the most prominent classes of heterocyclic
compounds, can be found in many naturally occurring
products,[1] commercially important pharmaceuticals, and
compounds with flavor and fragrance.[2] They are also
considered as important synthetic intermediates for the
preparation of numerous cyclic and acyclic compounds.[3]
Usually, 2,3,4-, 2,3,5-trisubstituted and 2,3,4,5-tetrasubstituted
furans were synthesized from either derivatization of simple
furans[4] or cyclization of acyclic precursors.[5 10] Due to furans×
potentials and diversity, it is desirable to develop a general
methodology for their synthesis from acyclic precursors.
Marshall and co-workers reported the RhI- or AgI-cata-
lyzed cycloisomerization of 1,2-dienyl ketones to afford
substituted furans [Eq. (1)].[11] They also demonstrated the
application of this reaction to the synthesis of the enantiomers
of natural products such as furanocembrane rubifolide[12a] and
kallolide B.[12b]
O
R1
PdII
R1
R1
R1
(2)
(3)
+
O
CH3CN
O
O
minor
major
R2
R2
AuIII
R1
R3
O
R1
+
R3
O
O
O
Quite recently, we developed a PdII-catalyzed cross-cou-
pling reaction of terminal 1,2-alleny ketones with 1,2-allenic
acids to afford 2,4-disubstituted furans [Eq. (4)].[15]
Recently, Hashmi and co-workers reported the PdII-cata-
lyzed dimerization of terminal 1,2-allenyl ketones to afford
O
R2
O
R2
R3
PdII
R2
H
R1
+
(4)
R3
R4
R2
OH
CH3CN
RhI or AgI
O
R1
(1)
O
R4
R1
O
R1
O
O
[a] Prof. S. Ma, Dr. J. Zhang, L. Lu
State Key Laboratory of Organometallic Chemistry
In spite of the excellence of Marshall×s, Hashmi×s, and our
reactions in terms of efficiency, there is still an obvious
limitation in terms of the introduction of four substituents to
furans. To our knowledge, the introduction of substituents at
the 3- and/or 4-position of the corresponding unsubstituted
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P. R. China)
Fax : ( ‡ 86) 21-6416-6128
E-mail: masm@pub.sioc.ac.cn
Chem. Eur. J. 2003, 9, 2447 2456
DOI:10.1002/chem.200204664
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2447

S.-m. Ma et al.
FULL PAPER
furans is difficult; thus, efficient and general methodologies
for the synthesis of furans with substituents at some or all of
the four positions are still of current interest.
Ph
i)
PhCH2COCl
R1
O
During the course of our study on the cross-coupling
cyclization reaction of functionalized allenes,[16] we noted that,
due to the high substituent-loading capability and easy
availability of 1,2-allenyl ketones, it would be possible to
develop a general methodology for the synthesis of differently
substituted furans from their coupling reaction with organic
compounds containing an appropriate leaving group
(Scheme 1).[17]
1f: R1 = CH3, 30%
1g: R1 = nC3H7, 35%
1
ˆ
Scheme 3. Synthesis of 1,2-allenyl ketones 1 f and g. i) Ph3P CHCOR ,
Et3N, 0 58C, CH2Cl2.
The a-substituted 1,2-allenyl ketones 1h j were prepared
by the treatment of 3-substituted 2,4-pentadione with Ph3PBr2
followed by elimination of HBr in the presence of Et3N
(Scheme 4).[19]
R3
R3
R4
R2
R1
R4
R4
R2
R2
R1
Pd0
R3-LG
+
LG Pd
R1
O
R2
O
O
O
O
i), ii)
Me
Me
Scheme 1. Retrosynthetic analysis of polysubstituted furans.
Me
R2
O
In a previous communication,[18] we reported a palladium-
catalyzed cyclization of 1,2-allenyl ketone with an organic
halide to provide an efficient, general, and versatile route to
polysubstituted furans with a unique assembly of substituents
at the different positions of furans depending on the
substitution style of both reactants. In this paper, we wish to
discuss in detail the scope and mechanism of this reaction.
1h: R2 = CH3, 50%
1i: R2 = nC4H9, 76%
1j: R2 = allyl, 60%
Scheme 4. Synthesis of 1,2-allenyl ketones 1h j. i) Ph3PBr2, CH2Cl2,
reflux; ii) Et3N, CH3CN, 808C.
The a,g-disubstituted 1,2-allenyl ketones 1k p were pre-
pared by a one-pot stepwise reaction of an enyne with an alkyl
lithium reagent followed by the addition of an N,N-dimethyl
organic amide (Scheme 5).
Results and Discussion
Synthesis of the starting 1,2-allenyl ketones: g-Substituted 1,2-
allenyl ketones 1a e were prepared by the treatment of 1,2-
allenyl lithium (prepared by the reaction of 1,2-allene and
nBuLi at À508C for 2 h) with N,N-dimethyl organic amide at
À788C in THF (Scheme 2).[19] 1,2-Allenyl ketones 1 f g were
prepared by the reaction of phenyl acetyl chloride with the
corresponding ylide (Scheme 3).[20]
R4
R2
R2
i), ii)
R1
R4 =R5CH2
O
1k: R1 = CH3, R2 = nC4H9, R4 = nC5H11, 51%
1l: R1 = CH3, R2 = nC5H11, R4 = nC4H9, 66%
R4
R4
i), ii)
1m: R1 = CH3, R2 = nC5H11, R4 = nC5H11, 57%
1n: R1 = iC3H7, R2 = nC5H11, R4 = nC4H9, 70%
1o: R1 = CH3, R2 = nC5H11, R4 = CH3CH2CH(CH3)CH2, 61%
1p: R1 = p-MeC6H4, R2 = nC4H9, R4 = nC5H11, 74%
1q: R1 = p-CF3C6H4, R2 = nC4H9, R4 = nC5H11, 75%
R1
O
1a: R1 = CH3, R4 = nC12H25, 40%
1b: R1 = CH3, R4 = nC4H9, 50%
1c: R1 = CH3, R4 = nC7H15, 44%
1d: R1 = cyclohexyl, R4 = nC7H15, 37%
1e: R1 = tC4H9, R4 = nC7H15, 35%
Scheme 5. Synthesis of a,g-disubstituted 1,2-allenyl ketones 1k p.
i) R5Li, À40 to 158C; ii) R1CONMe2, À788C.
Scheme 2. Synthesis of 1,2-allenyl ketones 1a e. i) nBuLi, À508C, THF,
2 h; ii) R1CONMe2, À788C, THF.
Coupling cyclization of 1,2-allenyl ketones and organic
halides
Synthesis of 2,3,5-trisubstituted furans: As a starting point, we
studied the Pd0-catalyzed cyclization reaction of heptadeca-
3,4-dien-2-one 1a with iodobenzene 2a under different
reaction conditions, the results are summarized in Table 1.
From Table 1, it is clear that the major side reaction is the
cycloisomerization of 1a to afford 2-methyl-5-dodecanylfuran
4a. Fortunately, after some screening, we found that the
Pd(PPh3)4-catalyzed cyclization reaction of 1a with PhI could
afford the expected two-component coupling cyclization
product 3aa in 88% yield together with the formation of 4a
in only 8% yield by using toluene as the solvent, Et3N-
Abstract in Chinese:
2448
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2447 2456

Substituted Furans
2447 2456
Table 1. Pd(PPh3)4-catalyzed cyclization of heptadeca-3,4-dien-2-one with iodobenzene.
These results show that
i) both aryl halides and methyl
(Z)-3-iodopropenoate afforded
the expected 2,3,5-trisubstitut-
ed furans 3 in moderate to
excellent yields and ii) different
substituents such as aryl and
alkyl group could be introduced
to the 2,3,5-positions of furans,
depending on the structures of
the 1,2-alleny ketones and or-
ganic halides.
Ph
H
C12H25
n
PhI (2a)
C
12H25
Me
n
C12H25
n
Me
+
Me
5 mol%
[Pd(PPh3)4]
O
O
O
1a
3aa
4a
PhI
(equiv.)
Solvent
Base
(equiv)
T
[8C]
t
3aa
4a
[%]
[h]
[%][a]
1
2
3
4
52.0
6
7
8
9[c]
1.5MeCN
1.5THF
1.2
Et
Et
THF
PhMe
3N (1.5)[b]
3N (1.5)
60
15(29)
10
11
12
12
1533
1539
12
(9)
reflux
reflux
100
100
80
80
reflux
80
54
38
53
30
15
33
42
67
K2CO3 (1)
Et3N (1.5)
iPr2NEt (1.5)
K2CO3 (1)[b]
Et3N (2.0)[b]
Et3N (2.0)
Et3N (2.0)[b]
2.0
PhMe
2.0
2.0
2.0
2.0
MeCN
DMF
THF
28
35
Synthesis of 2,3,4-trisubstituted
furans: After studying the Pd0-
catalyzed cyclization reaction
of g-substituted 1,2-allenyl ke-
tones, we tried the cyclization
reaction of a-substituted 1,2-
allenyl ketones. As expected,
83
15
9
PhMe
12
88(75)
[a] NMR yield determined by using CH2Br2 as the internal standard. The numbers in the parenthesis are isolated
yield. [b] 0.1 equivalent of Ag2CO3 was added. [c] Conditions A.
Ag2CO3 (2.0 equiv, 10 mol%) as the base (conditions A;
entry 9, Table 1). By using the standard conditions A, the
cyclization reaction of various 1,2-allenyl ketones bearing
different R1 and R4 substituents with different kinds of
organic halides 2 were studied. The results are summarized in
Table 2.
the reaction occurred smoothly under conditions A giving air-
sensitive[21] 2,3,4-trisubstituted furans in moderate to excellent
yields (entries 1 4, Table 2). One thing that should be noted
is that the allyl group in the a-position of allenyl ketones has
no influence on the reaction; this showed that the reaction is
highly chemoselective (entry 4, Table 3).
Table 2. Efficient synthesis of 2,3,5-trisubstituted furans.[a]
Table 3. Efficient synthesis of 2,3,4-trisubstituted furans.[a]
R3
R2
R1
R3
5 mol% [Pd(PPh3)4]
Ag2CO3 (0.1 equiv)
R2
R3X
(2)
R4
5 mol% [ Pd(Ph3P)4]
R1
R4
R1
R1
R3X
+
Et3N (2.0 equiv)
toluene,100oC
Ag2CO3 (0.1 equiv)
Et3N (2.0 equiv)
toluene, 80 oC
O
O
O
O
1
3
3
1
2
1
R2
2
t
3
[%]
R1
[h]
1
R4
2
t
3
[%]
R1
[h]
1
2
3
4
Me
Me (1h)
1h
nC4H9 (1i)
allyl (1j)
2b
2c
2d
2b
11
14
17
12
3hb (79)[b]
3hc (68)
3id (97)
3jb (79)
1
2
3
4
5
6
CH3
nC12H25 (1a)
1a
1a
nC4H9 (1b)
1b
1b
PhI (2a)
p-O2NC6H4I (2b)
p-MeO2CC6H4I (2c)
2a
2b
2c
12
13
14
12
9
3aa (75)[b]
3ab (90)
3ac (94)[c]
3ba (73)[b]
3bb (92)
3bc (85)
Me
Me
CH3
[a] Unless otherwise specified, the reaction was carried out by using allenyl
ketone (1.5equiv) and organic halide (1.0 equiv) under conditions A.
[b] Two equivalents of 1,2-allenyl ketone were used.
9
N
7
1b
1b
Br 2d
11
3bd (71)
N
Synthesis of 2,3,4,5-tetrasubstituted furans: With the encour-
agement of the above results, we were very interested in the
cyclization reaction of a,g-disubstituted 1,2-allenyl ketones,
since 2,3,4,5-tetrasubstituted furans[22] would be provided if
the reaction succeeded. Under conditions A, we found the
reaction did occur to afford the corresponding product 3ka in
70% yield. However, the cycloisomerization product 4k was
also formed in 30% yield; this indicates that conditions A for
the cross-coupling cyclization reaction of a or g-substituted
1,2-allenyl ketones are not yet efficient enough for the highly
selective coupling cyclization of a,g-disubstituted 1,2-allenyl
ketones (entry 1, Table 4). Fortunately, after several trials, we
found that the Pd0-catalyzed cyclization reaction of 1,2-allenyl
ketone 1k with PhI (2a) afforded the cross-coupling cycliza-
tion product 3ka in 92% yield and the cycloisomerization
product 4k in only 8% yield using K2CO3 as the base and
8
2e
11
3be (61)[d]
I
CO2Me
9
10
11
12
13
14
15
16
17
1b
p-MeOC6H4I (2 f)
10
10
12
13
16
10
10
12
12
3bf (64)
3cc (98)[c]
3cf (63)
3da (74)
3dc (76)
3 fb (51)
3 fc (51)
3gb (77)
3gc (73)
CH3
nC7H15 (1c)
1c
nC7H15 (1d)
1d
Ph (1 f)
1 f
2c
2 f
2a
2c
2b
2c
2b
2c
cC6H11
CH3
nC3H7
Ph (1g)
1g
[a] Unless otherwise specified, the reaction was carried out by using 1,2-
allenyl ketone (1.5equiv), organic halide (1.0 equiv) under conditions A.
[b] Two equivalents of organic halides were used. [c] Two equivalents of
ˆ
1,2-allenyl ketone were used. [d] The conformation of the C C bond was E
as determined by the coupling constant between the olefinic protons (J ˆ
15.6 Hz).
Chem. Eur. J. 2003, 9, 2447 2456
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S.-m. Ma et al.
FULL PAPER
Table 4. Pd(PPh3)4-catalyzed cyclization of 1,2-allenyl ketone 1k with iodobenzene.
product 3kf (51%). The possible rational of
formation of 3ka is shown as Scheme 7. The first
oxidative addition of 2 f generates the PdII inter-
mediate 5. Then the reductive elimination of
intermediate 5 and subsequent reoxidative addition
regenerates a new PdII intermediate 6,[23] which
subsequently treated with 1,2-allenyl ketone 1k
affords the unexpected product 3ka.
H
nC4H9
Ph
nC4H9
nC4H9
5 mol%
[Pd(PPh3)4]
C H
n
+
5
CH3
nC5H11
1k
CH3
C H
CH3
n
11
5
11
PhI (2.0 equiv)
O
O
O
4k
3ka
Solvent
Base
T
t
3ka[a]
4k[a]
(equiv)
[8C]
[h]
[%]
[%]
1[b]
2
3
toluene
DME
dioxane
DMF
Et3N(2.0)
as above
as above
as above
as above
as above
K2CO3(2)
K2CO3(2)
K2CO3(2)
100
reflux
100
100
reflux
100
100
100
100
18
70 (57)
30 (11)
Mechanism: A plausible mechanism of this cross-
coupling cyclization reaction is depicted in
Scheme 8. The oxidative addition of R3X with Pd0
generates intermediate R3PdX 7. Then, carbopalla-
dation of 7 with 1,2-allenyl ketone 1 affords the p-
allyl palladium intermediate 8, which may generate
a new p-allyl palladium intermediate 9 in the
presence of a base (path a). The subsequent intra-
molecular nucleophile attack of the intermediate
9[16] will regenerate palladium(0) and afford the
intermediate 10, which would furnish furan 3 upon
10.587
10.577
10.590
14
14
14
13
8
4
9
5CH
6
7
8[c]
9[d]
3CN
88
80
92
90 (72)
29
11
10
8
0
1.3
DMA
DMA
DMA
DMA
10
19
[a] NMR yield determined by using CH2Br2 as the internal standard. The numbers in
parenthesis are isolated yields. [b] The reaction was carried out under conditions A.
[c] nBu4N BrÀ (0.2 equiv) was added (conditions B). [d] PhBr was used instead of PhI.
‡
DMA as the solvent (entry 7, Table 4). A better result was
obtained when 20 mol% of nBu4NBr (TBAB) was added, and
the reaction afforded the corresponding product 3ka as the
only product in 90% yield (isolated yield: 72%; conditions B;
entry 8, Table 4). The reaction of 1k with phenyl bromide is
R3
R2
R1
R5
R2
R3X
i), ii)
R5
Conditions B
R1
O
R2
O
slow (Compare entries 8 and 9, Table 4).
Scheme 6. Efficient and versatile route to 2,3,4,5-tetrasubstituted furans.
i) R5Li, À40 to 158C; ii) R1CONMe2, À788C.
By using conditions B, the reaction of various a,g-disub-
stituted allenyl ketones with different organic halides afford-
ed the corresponding 2,3,4,5-tetrasubstituted furans with
different substitution patterns in moderate to excellent yields
(Table 5). Considering the easy available of a,g-disubstituted
1,2-allenyl ketones with different substituents, it is a very
general, convenient, and versatile route to synthesize 2,3,4,5-
tetrasubstituted furans (Scheme 6).
To our surprise, when p-methoxyphenyl iodide (2 f) was
used as the organic halide, the reaction afforded an unex-
pected furan 3ka in 27% yield together with the normal
Table 5. Efficient synthesis of 2,3,4,5-tetrasubstituted furans.[a]
R3
R2
R1
R4
R2
5 mol% [Pd(PPh3)4]
R3X
+
R4
R1
K2CO3 (2.0 equiv)
TBAB (0.2 equiv)
DMA, 100 oC
O
O
3
1
2
11
R4
2
t
3
[%]
R1
R2
[h]
1
2
3
4
CH3
nC4H9
1k
1k
nC5H11 (1k)
2a
2c
2e
2 f
2a
2a
2a
2a
14
12
13
9
10
10
10
10
3ka (72)
3kc (94)[b]
3ke (64)[c]
3kf (51)[b,d]
3la (69)
3ma (59)
3na (60)
3oa (67)
1k
5CH
nC5H11
nC5H11
nC5H11
nC5H11
nC4H9 (1l)
nC5H11 (1m)
nC4H9 (1n)
3
Scheme 7. The cyclization reaction of 1k with 2 f and its plausible
mechanism.
6
7
8
CH3
iC3H7
CH3
2-methylbutyl (1o)
[a] Unless otherwise specified, the reaction was carried out by using allenyl
ketone (1.0 equiv) and organic halide (2.0 equiv) under conditions B.
[b] Two equivalents of allenyl ketone were used. [c] 1.6 equivalents of 1,2-
allenyl ketone were used. [d] 0.4 equivalents of TBAB were used,
unexpectedly 3ka was also isolated in 27% yield (based on the organic
halide used).
aromatization. An alternative reaction pathway of intermedi-
ate 8 is formation of palladium dienolate 11[24] and the
ˆ
subsequent insertion of the C C double bond into the oxo-
palladium bond to afford intermediate 12 (path b). b-H
elimination from intermediate 12 would afford the furan 3
2450
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, 2447 2456

Substituted Furans
2447 2456
Conclusion
R3
R3
R2
R4
R2
+Pd
O-
We have developed a palladi-
um(0)-catalyzed coupling cycli-
zation reaction of 1,2-allenyl
ketones with organic halides.
The advantages of this method
are its generality, versatility,
and efficiency not only for the
synthesis of 2,3,4- and 2,3,5-
trisubstituted furans but also
for the synthesis of 2,3,4,5-tet-
rasubstituted furans. Further-
more, this methodology shows
high substituent-loading capa-
bility and tolerance of various
substituents. Some control re-
actions for mechanistic studies
R4
3
R6
O
R6
9
10
base
Path a
R3
R3
R2
R1
R2
R4
R3X
1
Path c
Pd0
R3PdX
7
Pd0
R4
XPd
R1
+
O
O
8
R2
R1
R3
13
base
Path b
R4
H+
R3
X
Pd
O
3
R3
2
R
R4
R2
R1
3
R4
R1
XPdO
O
11
12
Scheme 8. Plausible mechanisms of the Pd0-catalyzed coupling cyclization.
and HPdX, which would regenerate palladium(0) in the
presence of a base. In addition, direct intramolecular nucle-
ophile attack on intermediate 8 by the carbonyl oxygen atom
will generate intermediate 13 and regenerate Pd0 (path c).[25]
Intermediate 13 will be deprotonated to afford 3 in the
presence of a base.
showed that instead of an enolization pathway, the reaction
may proceed by the intermediacy of dienolate palladium and
intramolecular nucleophilic attack on the p-allyl palladium
intermediate by the carbonyl oxygen. Synthetic application
for target molecules with potential activities is currently being
carried out in our laboratory.
In order to verify the mechanism, some control reac-
tions were performed. The coupling cyclization of deuterated
1,2-allenyl ketone [D]1c with p-methoxycarbonylphenyl
iodide (2c) produced non-deuterated 3cc [Eq. (5)],
MeO2C
n
C5H11
nC4H9
nC4H9
2c (0.5 equiv)
Me
Conditions B
90%
O
n
C5H11
Me
MeO2C
O
1p (1.0 equiv)
3pc
I
CO2Me
(2c)
nC7H15
(5)
MeO2C
D
CH3
Conditions A
89%
C H
CH3
n
7
15
O
[D]1c
87% D
n
C5H11
nC4H9
O
nC4H9
3cc
2c (0.5 equiv)
CF3
Conditions B
21%
0% D
O
n
C5H11
CF3
O
1q (1.0 equiv)
3qc
which was confirmed by 13C NMR and 1H NMR analysis. This
rules out the possibility of path a. The cyclization results of 1e
and 1p affording furans 3ea and 3pc in the absence of a'-H
further support that this palladium(0)-catalyzed coupling
cyclization reaction may occur via paths b or c [Eq. (6)].
2c (0.5 equiv)
1p (1.0 equiv) + 1q (1.0 equiv)
3pc (81%) + 3qc (11%)
Conditions B
Scheme 9. The cyclization reactions of 1p and 1q with 2c.
Ph
C H
n
7
15
Experimental Section
PhI (4.0 equiv.)
(6)
C H
n
7
15
Conditions A
74%
O
O
The starting 1,2-alleny ketones 1b c,[19b] 1 f[20] and 1h [19b] were prepared
j
according to literature procedures.
1e
3ea
Typical procedure for preparation of 1,2-allenyl ketones 1a e:Heptadeca-
3,4-dien-2-one (1a): Pentadeca-1,2-diene[26] (5.0 g, 24 mmol) was treated
with nBuLi (2.0m in cyclohexane, 20 mmol) in THF at À508C for 2 h
followed by the dropwise addition of N,N-dimethylacetamide (1.7 g,
20 mmol) at À788C. After being stirred for 2 h at À788C, the resulting
solution was slowly transferred into an ice-cooled aqueous HCl solution
(0.1n, 400 mL) and extracted with ether. Drying over MgSO4, rotary
evaporation, and column chromatography on silica gel (hexanes/etherˆ
Furthermore, it is interesting to note that the cyclization of 1p
with an electron-donating methyl group on the phenyl ring
afforded 3pc in 90% yield, while the cyclization of 1q with the
electron-withdrawing trifluoromethyl group afforded 3qc in
only 21% yield. The cyclization of a 1:1 mixture of 1p and 1q
with 2c in a one-pot manner afforded the corresponding
furans 3pc and 3qc in 81% and 11% yields, respectively
(Scheme 9). These results further support the possibility of
path c.
1
100:1) afforded 1a (2.0 g, 40%) as a liquid. H NMR (CDCl3, 300 MHz):
d ˆ 5.75 5.64 (m, 1H; C C CHCO), 5.58 (q, 3J(H,H) ˆ 6.4 Hz, 1H;
ˆ ˆ
ˆ ˆ
HC C C), 2.30 (s, 3H; CH3), 2.30 2.04 (m, 2H; CH2), 1.70 1.50 (m, 2H;
CH2), 1.44 1.18 (m, 18H; 9CH2), 0.85(t, 3J(H,H) ˆ 7.1 Hz, 3H; CH3); IR
(neat): nÄ ˆ 2926, 2856, 1947 (C C C), 1686 cmÀ1(CO); MS (70 eV): m/z
ˆ ˆ
Chem. Eur. J. 2003, 9, 2447 2456
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2451

S.-m. Ma et al.
FULL PAPER
‡
‡
(%): 251 (6.29) [M ‡H], 43 (100) [CH3CO ]; HRMS: calcd for C17H30O:
0.90 0.75(m, 6H; 2CH 3); 13C NMR (75.4 MHz, CDCl3): d ˆ 212.71,
250.2297; found: 250.2285.
199.37, 109.70, 95.37, 31.38, 31.31, 28.67, 28.21, 27.59, 26.84, 26.40, 22.42,
À1
ˆ ˆ
ˆ
22.34, 13.95, 13.91; IR (neat): nÄ ˆ 1944 (C C C), 1679 cm (C O); MS
1-Cyclohexylundeca-2,3-dien-1-one (1d): The reaction of deca-1,2-diene
(2.76 g, 20.0 mmol) with nBuLi (2.0m in cyclohexane, 20 mmol) and
cyclohexanecarboxylic acid N,N-dimethylamide (3.10 g, 20.0 mmol) af-
forded 1d (1.84 g, 37%) as a liquid. 1H NMR (CDCl3, 300 MHz): d ˆ 5.70
‡
‡
(70 eV): m/z (%): 222 (1.69) [M ], 43 (100) [C3H7 ]; HRMS: calcd for
C15H26O: 222.1984; found: 222.1949.
2-Methyl-4-pentyldeca-4,5-dien-3-one (1n): The reaction of nona-1-en-3-
yne (1.34 g, 11.0 mmol) with nPrLi (1.6m in Et2O, 10.0 mmol) and N,N-
dimethyl isobutyramide (1.72 g, 15.0 mmol) afforded 1n (1.65g, 70%) as a
ˆ ˆ
ˆ ˆ
5.60 (m, 1H; C C CHCO), 5.60 5.50 (m, 1H; CH C C), 2.90 2.75(m,
1H; COCH), 2.20 2.05(m, 2H; CH 2), 1.90 1.60 (m, 5H; 2CH2 and CH),
liquid. 1H NMR (300 MHz, CDCl3): d ˆ 5.56 5.40 (m, 1H; HC C C),
3
ˆ ˆ
1.60 1.00 (m, 15H; 7CH2 and CH), 0.86 (t, J(H,H) ˆ 7.2 Hz, 3H; CH3);
13C NMR (75.4 MHz, CDCl3): d ˆ 212.27, 204.76, 96.01, 95.15, 46.67, 31.69,
29.42, 29.00, 28.98, 27.83, 25.79, 25.68, 25.61, 22.56, 14.00; IR (neat): nÄ ˆ
3.30 2.20 (m, 1H, CH), 2.20 2.00 (m, 4H, 2CH2), 1.50 1.10 (m, 10H;
5CH2), 1.10 0.90 (m, 6H; 2CH3), 0.90 0.70 (m, 6H; 2CH3); IR (neat):
À1
À1
‡
ˆ ˆ
ˆ
ˆ ˆ
ˆ
nÄ ˆ 1944 (C C C), 1678 cm (C O); MS (70 eV): m/z (%): 237 (23.54)
1947 (C C C), 1676 cm (C O); MS (70 eV): m/z (%): 248 (4.75) [M ],
‡
‡
‡
[M ‡H], 43 (100) [C3H7 ]; HRMS: calcd for C16H28O: 236.2140; found:
83 (100) [C6H11 ]; HRMS: calcd for C17H28O: 248.2140; found: 248.2143.
236.2093.
2,2-Dimethyltrideca-4,5-dien-3-one (1e): The reaction of deca-1,2-diene
(3.4 g, 24.6 mmol) with nBuLi (10 mL, 2.0m in cyclohexane, 20.0 mmol)
and N,N-dimethylpivalamide (2.5g, 19.3 mmol) afforded 1e (1.5g, 35%).
7-Methyl-3-pentylnona-3,4-dien-2-one (1o): The reaction of nona-1-en-3-
yne (1.34 g, 11 mmol) with secBuLi (1.1 M in Et2O, 10 mmol) and N,N-
dimethylacetamide (1.04 g, 12 mmol) afforded 1o (1.34 g, 61%) as a liquid.
1H NMR (CDCl3, 300 MHz): d ˆ 6.08 6.00 (m, 1H; C C CHCO), 5.55
ˆ ˆ
ˆ ˆ
1H NMR (300 MHz, CDCl3): d ˆ 5.56 5.40 (m, 1H; HC C C), 2.20 (s,
3
5
ˆ ˆ
(q, J(H,H) ˆ J(H,H) ˆ 7.0 Hz, 1H; CH C C), 2.40 2.20 (m, 2H; CH2),
3H; CH3), 2.12 1.80 (m, 4H; 2CH2), 1.45 1.08 (m, 9H, 4CH 2 and CH),
1.50 1.35 (m, 2H; CH2), 1.35 1.10 (m, 8H; 4CH 2), 1.20 (s, 9H; 3CH3),
‡
3
0.90 0.75(m, 9H, 3CH 3); MS (70 eV): m/z (%): 222 (4.80) [M ], 43 (100)
ˆ ˆ
0.88 (t, J(H,H) ˆ 6.6 Hz, 3H; CH3); IR (neat): nÄ ˆ 1951 (C C C), 1722
‡
À1
(C O), 1683 (C C), 1670 cmÀ1; MS (70 eV): m/z (%): 222 (13.23) [M ], 207
‡
ˆ ˆ
ˆ
ˆ
ˆ
[C3H7 ]; IR (neat): nÄ ˆ 1944 (C C C), 1680 cm (C O); HRMS: calcd for
‡
C15H26O: 222.1984; found: 222.1961.
(100) [M À CH3]; HRMS: calcd for C15H26O: 222.1984; found: 222.1975.
1-(4'-Methylphenyl)-2-butylnona-2,3-dien-1-one (1p): The reaction of oct-
1-en-3-yne (2.16 g, 20 mmol) with nBuLi (2.0m in cyclohexane, 20 mmol)
and 4-methylbenzoic acid N,N-dimethylamide (4.08 g, 25mmol) afforded
1p (4.20 g, 74%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.65(d,
3J(H,H) ˆ 7.8 Hz, 2H; 2ArH), 7.16 (d, 3J(H,H) ˆ 7.8 Hz, 2H; 2ArH), 5.40
1-Phenylhepta-1,2-dien-4-one (1g): A solution of phenylacetyl chloride
(3.70 g, 24 mmol) in CH2Cl2 was added dropwise to an ice-cooled (08C)
solution of 1-(triphenylphosphoranylidene)pentan-2-one (6.92 g, 20 mmol)
and Et3N (3.03 g, 30 mmol) in dry CH2Cl2 stirred under Ar. The reaction
mixture turned yellow when the reaction was complete as monitored by
TLC. The reaction mixture was concentrated, and Et2O was added to
remove Ph3PO by precipitation. Filtration, evaporation, and purification by
column chromatography on silica gel (hexanes/etherˆ 100:1) afforded 1g
(1.30 g, 35%) as a yellow liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.40 7.20
ˆ ˆ
5.30 (m, 1H; HC C C), 2.44 2.30 (m, 2H; CH2), 2.36 (s, 3H; CH3), 2.16
2.00 (m, 2H; CH2), 1.54 1.30 (m, 6H; 3CH2), 1.30 1.10 (m, 4H; 2CH2),
0.95(t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3), 0.86 (t, J ˆ 6.9 Hz, 3H; CH3); 13C NMR
(CDCl3): d ˆ 212.69, 195.08, 142.04, 136.01, 128.91, 128.24, 107.05, 94.63,
31.03, 30.10, 28.56, 28.39, 27.85, 22.27(2C), 21.36, 13.84, 13.81; IR (neat):
(m, 5H; C6H5), 6.63 (d, 5J(H,H) ˆ 6.6 Hz, 1H; CH C C), 6.14 (d,
ˆ ˆ
nÄ ˆ 1944 (C C C), 1651 (C O), 1609, 1275cm À1; MS (70 eV): m/z (%): 284
5
ˆ ˆ
ˆ
ˆ ˆ
J(H,H) ˆ 6.6 Hz, 1H; C C CHCO), 2.65 2.50 (m, 2H; CH ), 1.68 1.55
2
‡
‡
(m, 2H; CH2), 0.90 (t, J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR (75.4 MHz,
3
(44.93) [M ], 119 (100) [p-CH3C6H4CO ]; elemental analysis calcd (%) for
C20H28O: C 84.45, H 9.92; found: C 84.49, H 9.91.
CDCl3): d ˆ 215.16, 200.48, 131.04, 128.96, 128.13, 127.21, 100.57, 98.52,
À1
ˆ ˆ
ˆ
41.27, 17.89, 13.66; IR (neat): nÄ ˆ 1937 (C C C), 1683 cm (C O); MS
1-(4'-Trifluoromethylphenyl)-1-butylnona-2,3-dien-1-one (1q): The reac-
tion of oct-1-en-3-yne (2.00 g, 18.5mmol) with nBuLi (1.6m in cyclohexane,
16 mmol) and 4-trifluoromethylbenzoic acid N,N-dimethylamide (4.00 g,
18.4 mmol) afforded 1q (4.04 g, 75%) as a liquid. 1H NMR (300 MHz,
CDCl3): d ˆ 7.69 (d, J ˆ 8.1 Hz, 2H; 2ArH), 7.54 (d, J ˆ 8.1 Hz, 2H; 2ArH),
‡
‡
(70 eV): m/z (%): 186 (9.78) [M ], 71 (100) [C3H7CO ]; HRMS: calcd for
C13H14O: 186.1045; found: 186.1052.
Typical procedure for the preparation of 1k p:3-Butyldeca-3,4-dien-2-
one (1k): Oct-1-en-3-yne[27] (1.25g, 11.5mmol) was added to a solution of
nBuLi (2m in cyclohexane, 10 mmol) in dry THF (60 mL) stirred under Ar
at À508C. The temperature was raised gradually to À258C and kept
between À25and À108C for 0.5h. After the starting enyne had completely
disappeared as determined by TLC, the reaction mixture was recooled to
3
5
ˆ ˆ
5.32 (tt, J(H,H) ˆ 9.9 Hz, J(H,H) ˆ 2.7 Hz, 1H; HC C C), 2.40 2.20 (m,
2H; CH2), 2.10 1.90 (m, 2H; CH2), 1.48 1.00 (m, 10H; 5CH2), 0.85(t,
3J(H,H) ˆ 7.2 Hz, 3 H ; CH3); 0.75(t, 3J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR
(CDCl3): d ˆ 214.01, 194.61, 142.03, 132.83 (q, 2J(C,F) ˆ 32.0 Hz), 128.89,
124.64 (q, 3J(C,F) ˆ 3.2 Hz), 123.72 (q, 1J(C,F) ˆ 272.3 Hz), 107.72, 95.71,
31.04, 30.10, 28.54, 28.34, 27.45, 22.31, 22.27, 13.86, 13.77; IR (neat): nÄ ˆ
À788C. This was followed by the addition of
a solution of N,N-
dimethylacetamide (1.30 g, 15mmol) in THF (10 mL). After being stirred
for 2 h at À788C, the reaction mixture was poured into ice-cooled HCl
(0.2n, 100 mL), extracted with ether (3 Â 50 mL), and dried over anhy-
drous MgSO4. After removal of the solvent under reduced pressure, the
residue was purified by column chromatography on silica gel (hexanes/
etherˆ 100:1) to afford 1k (1.07 g, 51%). 1H NMR (300 MHz, CDCl3): d ˆ
1600, 1580, 1492 cmÀ1; MS (70 eV): m/z (%): 338 (3.82) [M ], 173 (100) [p-
‡
‡
CF3C6H4CO ]; HRMS: calcd for C20H25F3O: 338.1857; found: 338.1850.
Typical procedure for the coupling cyclization reaction of 1,2-allenyl
ketone 1a with iodobenzene:Conditions A : A mixture of Pd(PPh3)4
(23 mg, 0.002 mmol), Ag2CO3 (11 mg, 0.04 mmol), Et3N (81 mg, 0.8 mmol),
iodobenzene (163 mg, 0.8 mmol), 1a (100 mg, 0.4 mmol), and toluene
(5mL) was stirred at 80 8C for 12 h under Ar. After the reaction was
complete as monitored by TLC, the solvent was removed, and the residue
was purified by column chromatography on silica gel (hexanes) to afford
3aa (98 mg, 75%).
ˆ ˆ
5.56 5.40 (m, 1H; CH C C), 2.17 (s, 3H; CH3), 2.12 1.90 (m, 4H;
2CH2), 1.45 1.08 (m, 10H; 5CH 2), 0.90 0.80 (m, 6H; 2CH3); 13C NMR
(75.4 MHz, CDCl3) d ˆ 212.32, 199.45, 109.69, 95.40, 31.33, 30.11, 28.69,
ˆ ˆ
28.23, 26.88, 26.18, 22.36, 22.29, 13.96, 13.88; IR (neat): nÄ ˆ 1944 (C C C),
‡
‡
1680 cmÀ1 (C O); MS (70 eV): m/z (%): 208 (2.77) [M ], 43 (100) [C3H7 ];
ˆ
HRMS: calcd for C14H24O: 208.1827; found: 208.1795.
2-Dodecyl-3-phenyl-5-methylfuran (3aa): 1H NMR (300 MHz, CDCl3):
d ˆ 7.45 7.15 (m, 5H; C 6H5), 6.03 (s, 1H; CH), 2.69 (t, 3J(H,H) ˆ 7.7 Hz,
2H; CH2), 2.26 (s, 3H; CH3), 1.72 1.58 (m, 2H; CH2), 1.45 1.08 (m, 18H;
9CH2), 0.85(t, 3J(H,H) ˆ 6.6 Hz, 3H; CH3); 13C NMR (CDCl3): d ˆ 150.29,
149.80, 134.80, 128.54, 127.66, 126.15, 121.37, 107.10, 32.01, 31.00, 29.73,
29.65, 29.45, 28.83, 27.03, 26.77, 22.78, 22.60, 14.21, 13.94, 13.55; IR (neat):
3-Pentylnona-3,4-dien-2-one (1l): The reaction of nona-1-en-3-yne[28]
(2.12 g, 16.5mmol) with nPrLi (1.6m in Et2O, 15mmol) and N,N-
dimethylacetamide (1.44 g, 16.5mmol) afforded 1l (2.04 g, 66%).
1H NMR (300 MHz, CDCl3): d ˆ 5.56 5.40 (m, 1H; HC C C), 2.20 (s,
ˆ ˆ
3H; CH3), 2.12 1.90 (m, 4H, 2CH2), 1.45 1.08 (m, 10H; 5CH 2), 0.90
À1
‡
nÄ ˆ 1600, 1580, 1492 cmÀ1; MS (70 eV): m/z (%): 326 (23.66) [M ], 171
ˆ ˆ
ˆ
0.75(m, 6H; 2CH 3); IR (neat): nÄ ˆ 1944 (C C C), 1679 cm (C O); MS
‡
‡
‡
(70 eV): m/z (%): 208 (3.85) [M ], 43 (100) [C3H7 ]; HRMS: calcd for
(100) [M À C11H23]; HRMS: calcd for C23H34O: 326.2610; found: 326.2596.
C14H24O: 208.1827; found: 208.1858.
2-Dodecyl-3-(4'-nitrophenyl)-5-methylfuran (3ab): The reaction of 1a
(75mg, 0.3 mmol) with p-nitrophenyl iodide (50 mg, 0.2 mmol) afforded
3-Pentyldeca-3,4-dien-2-one (1m): The reaction of nona-1-en-3-yne (1.34 g,
11 mmol) with nBuLi (2.0m in cyclohexane, 10 mmol) and N,N-dimethy-
lacetamide (1.04 g, 12 mmol) afforded 1m (1.27 g 57%) as a liquid.
1
3ab (67 mg, 90%) as a yellow solid. M.p. 43 458C (n-hexane); H NMR
(300 MHz, CDCl3): d ˆ 8.14 (d, 3J(H,H) ˆ 9.0 Hz, 2H; 2ArH), 7.42 (d,
3
1H NMR (300 MHz, CDCl3): d ˆ 5.56 5.40 (m, 1H; HC C C), 2.20 (s,
3J(H,H) ˆ 9.0 Hz, 2H; 2ArH), 6.04 (s, 1H, CH), 2.67 (t, J(H,H) ˆ 7.5Hz,
ˆ ˆ
3H; CH3), 2.12 1.90 (m, 4H; 2CH2), 1.45 1.08 (m, 12H; 6CH 2),
2H; CH2), 2.23 (s, 3H; CH3), 1.73 1.54 (m, 2H; CH2), 1.41 1.08 (m, 18H;
2452
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2447 2456

Substituted Furans
2447 2456
9CH2), 0.85(t, 3J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
d ˆ 152.11, 150.70, 145.72, 141.56, 127.57, 123.87, 119.77, 106.31, 31.87, 29.62,
29.59, 29.57, 29.49, 29.31, 29.28, 29.27, 29.42, 27.21, 22.64, 14.06, 13.33; IR
(neat): nÄ ˆ 1600, 1580, 1516, 1344 cmÀ1; MS (70 eV): m/z (%): 372 (6.60)
(C C), 1610, 1580, 1264, 1170 cmÀ1; MS (70 eV): m/z (%): 223 (15.35)
[M ‡H], 222 (80.64) [M ], 179 (100) [M À C3H7]; HRMS: calcd for
ˆ
‡
‡
‡
C13H18O3: 222.1256; found: 222.1249.
2-Butyl-3-(4'-methoxyphenyl)-5-methylfuran (3bf): The reaction of 1b
(104 mg, 0.75mmol) with p-methoxyphenyl iodide (117 mg, 0.5mmol)
afforded 3bf (78 mg, 64%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ
7.27 (d, 3J(H,H) ˆ 6.7 Hz, 2H; 2ArH), 6.92 (d, 3J(H,H) ˆ 6.7 Hz, 2H;
2ArH), 6.04 (s, 1H; CH), 3.83 (s, 3H; OCH3), 2.69 (t, 3J(H,H) ˆ 7.7 Hz,
2H; CH2), 2.29 (s, 3H; CH3), 1.70 1.60 (m, 2H; CH2), 1.42 1.28 (m., 2H;
CH2), 0.89 (t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); 13C NMR (125MHz, CDCl 3):
d ˆ 157.02, 148.50, 127.63, 126.20, 119.81, 113.50, 112.90, 106.10, 54.21, 29.93,
‡
‡
‡
[M ‡H], 371 (35.85) [M ], 216 (100) [M À C11H23]; elemental analysis
calcd (%) for C23H33NO3: C 74.36, H 8.95; found: C 74.11, H 9.11.
2-Dodecyl-3-(4'-methoxycarbonylphenyl)-5-methylfuran (3ac): The reac-
tion of 1a (150 mg, 0.6 mmol) with p-methoxycarbonylphenyl iodide
(79 mg, 0.3 mmol) afforded 3ac (108 mg, 94%) as a liquid. 1H NMR
(300 MHz, CDCl3): d ˆ 7.95(d, 3J(H,H) ˆ 8.4 Hz, 2H; 2ArH), 7.33 (d,
3J(H,H) ˆ 8.4 Hz, 2H; 2ArH), 6.03 (s, 1H; CH), 3.84 (s, 3H; OCH3), 2.66
(t, 3J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.22 (s, 3H; CH3), 1.68 1.52 (m, 2H; CH2),
1.33 1.06 (m, 18H, 9CH2), 0.80 (t, 3J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 167.01, 151.28, 150.18, 139.46, 129.83, 127.53, 127.16,
120.57, 106.61, 52.00, 31.91, 29.65, 29.63, 29.61, 29.53, 29.34, 29.32, 29.31,
25.61, 21.49, 12.84, 12.43; IR (neat): nÄ ˆ 1590, 1518, 1460, 1350, 1180 cmÀ1
;
‡
‡
MS (70 eV): m/z (%): 244 (44.53) [M ], 201 (100) [M À C3H7]; HRMS:
calcd for C16H20O2: 244.1463; found: 244.1468.
2-Heptyl-3-(4'-methoxylcarbonylphenyl)-5-methylfuran (3cc): The reac-
tion of 1c (108 mg, 0.6 mmol) with p-(methoxycarbonyl)phenyl iodide
(80 mg, 0.3 mmol) afforded 3cc (93 mg, 98%) as a liquid. 1H NMR
(300 MHz, CDCl3): d ˆ 8.03 (d, 3J(H,H) ˆ 9.0 Hz, 2H; 2ArH), 7.40 (d,
3J(H,H) ˆ 9.0 Hz, 2H; 2ArH), 6.11 (s, 1H; CH), 3.92 (s, 3H; OCH3), 2.74
(t, 3J(H,H) ˆ 8.1 Hz, 2H; CH2), 2.30 (s, 3H; CH3), 1.72 1.50 (m, 2H; CH2),
ˆ
28.56, 27.14, 22.68, 14.10, 13.40; IR (neat): nÄ ˆ 1726 (C O), 1610, 1580,
‡
‡
1276, 1110 cmÀ1; MS (70 eV): m/z (%): 384 (10.20) [M ], 43 (100) [C3H7 ];
HRMS: calcd for C25H36O3: 384.2664; found: 384.2657.
2-Butyl-3-phenyl-5-methylfuran (3ba): The reaction of 1b (69 mg,
0.5mmol) with iodobenzene (204 mg, 1 mmol) afforded 3ba (78 mg,
73%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.37 7.12 (m, 5H,
C6H5), 5.98 (s, 1H; CH), 2.63 (t, J ˆ 7.5Hz, 2H; CH 2), 2.20 (s, 3H; CH3),
3
1.36 1.16 (m, 8H; 4CH2), 0.87 (t, J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 166.99, 151.26, 150.17, 139.43, 129.81, 127.50, 127.13,
1.65 1.50 (m, 2H; CH ), 1.38 1.20 (m, 2H; CH2), 0.82 (t, 3J(H,H) ˆ
120.53, 106.58, 52.00, 31.72, 29.27, 28.96, 28.56, 27.12, 22.60, 14.06, 13.40; IR
2
(neat): nÄ ˆ 1722 (C O), 1609, 1578, 986, 777 cmÀ1; MS (70 eV): m/z (%):
7.5Hz, 3H; CH 3); 13C NMR (75.4 MHz, CDCl3): d ˆ 150.15, 149.70,
134.70, 128.44, 127.57, 126.05, 121.28, 107.02, 30.90, 26.68, 22.50, 13.85,
13.44; IR (neat): nÄ ˆ 1600, 1580, 1492 cmÀ1; MS (70 eV): m/z (%): 214
ˆ
‡
‡
314 (32.39) [M ], 229 (100) [M À C6H13]; HRMS: calcd for C20H26O3
314.1882; found: 314.1868.
‡
‡
(52.12) [M ], 171 (100) [M À C3H7]; HRMS: calcd for C15H18O: 214.1358;
The cross coupling reaction of deuterated 1,2-allenyl ketone [D]1c with p-
(methoxycarbonyl)phenyl iodide: The reaction of deuterated 1,2-allenyl
ketone [D]1c (181 mg, 1.0 mmol) with 2c (131 mg, 0.5mmol) afforded 3cc
(140 mg, 89%).
found: 214.1409.
2-Butyl-3-(4'-nitrophenyl)-5-methylfuran (3bb): The reaction of 1b
(207 mg, 1.5mmol) with p-nitrophenyl iodide (249 mg, 1.0 mmol) afforded
3bb (239 mg, 92%) as a yellow solid. M.p. 41 438C (n-hexane); 1H NMR
(300 MHz, CDCl3): d ˆ 8.18 (d, 3J(H,H) ˆ 8.9 Hz, 2H; 2ArH), 7.42 (d,
2-Heptyl-3-(4'-methoxyphenyl)-5-methylfuran (3cf): The reaction of 1c
(135mg, 0.75mmol) with p-methoxyphenyl iodide (117 mg, 0.5mmol)
afforded 3cf (90 mg, 63%) as a liquid. 1H NMR (400 MHz, CDCl3): d ˆ
7.27 (d, 3J(H,H) ˆ 6.7 Hz, 2H; 2ArH), 6.92 (d, 3J(H,H) ˆ 6.7 Hz, 2H;
2ArH), 6.04 (s, 1H; CH), 3.83 (s, 3H; OCH3), 2.69 (t, 3J(H,H) ˆ 7.8 Hz,
2H; CH2), 2.29 (s, 3H; CH3), 1.70 1.62 (m, 2H; CH2), 1.34 1.23 (m, 8H;
4CH2), 0.89 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3); IR (neat): nÄ ˆ 1590, 1518,
3
3J(H,H) ˆ 8.9 Hz, 2H; 2ArH), 6.07 (s, 1H; CH), 2.69 (t, J(H,H) ˆ 7.7 Hz,
2H; CH2), 2.26 (s, 3H; CH3), 1.73 1.58 (m, 2H; CH2), 1.46 1.30 (m, 2H;
CH2), 0.85(t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); IR (KBr): nÄ ˆ 1600, 1580, 1510,
‡
‡
1344 cmÀ1; MS (70 eV): m/z (%): 259 (28.75) [M ], 216 (100) [M À C3H7];
elemental analysis calcd (%) for C15H17NO3: C 69.48, H 6.61, N 5.40; found:
C 69 .53, H 6.77, N 5.14.
‡
1460, 1350, 1180 cmÀ1; MS (70 eV): m/z (%): 287 (10.51) [M ‡H], 286
‡
‡
(39.36) [M ], 201 (100) [M À C6H13]; HRMS: calcd for C19H26O2 286.1933;
2-Butyl-3-(4'-methoxycarbonylphenyl)-5-methylfuran (3bc): The reaction
of 1b (138 mg, 1.0 mmol) with p-methoxycarbonylphenyl iodide (131 mg,
0.5mmol) afforded 3bc (115mg, 85%) as a liquid. 1H NMR (300 MHz,
CDCl3): d ˆ 7.98 (d, 3J(H,H) ˆ 8.5Hz, 2H; 2ArH), 7.36 (d, 3J(H,H) ˆ
8.5Hz, 2H; 2ArH), 6.06 (s, 1H; CH), 3.87 (s, 3H; OCH 3), 2.69 (t,
3J(H,H) ˆ 7.7 Hz, 2 H ; CH2), 2.26 (s, 3H; CH3), 1.73 1.58 (m, 2H; CH2),
1.43 1.28 (m, 2H; CH2), 0.85(t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 167.04, 151.25, 150.21, 139.46, 129.83, 127.55, 127.17,
120.59, 106.62, 52.01, 30.70, 26.86, 22.44, 13.79, 13.40; IR (neat): nÄ ˆ 1726
found 286.1907.
2-Heptyl-3-phenyl-5-(cyclohexyl)furan (3da): The reaction of 1d (124 mg,
0.5mmol) with iodobenzene (204 mg, 1.0 mmol) afforded 3da (119 mg,
74%) as a liquid. 1H NMR (300 MHz, CDCl3) d ˆ 7.50 7.20 (m, 5H; C6H5),
3
6.08 (s, 1H; CH), 2.76 (t, J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.70 2.55 (m, 1H;
CH), 2.20 2.00 (m, 2H; CH2), 1.90 1.60 (m, 6H; 3CH2), 1.50 1.20 (m,
12H; 6CH2), 0.90 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (75.4 MHz,
CDCl3): d ˆ 158.67, 149.71, 134.87, 128.40, 127.55, 125.95, 120.78, 104.10,
37.17, 31.78, 31.53, 29.30, 29.01, 28.63, 26.96, 26.17, 25.95, 22.62, 14.07; IR
(C O), 1610, 1580, 1276, 1110 cmÀ1; MS (70 eV): m/z (%): 273 (12.76)
[M ‡H], 272 (41.96) [M ], 229 (100) [M À C3H7]; HRMS: calcd for
ˆ
‡
‡
‡
‡
(neat): nÄ ˆ 1600, 1500 cmÀ1; MS (70 eV): m/z (%): 324 (36.70) [M ], 239
‡
C17H20O3: 272.1413; found: 272.1411.
(100) [M À C6H13]; HRMS: calcd for C23H32O: 324.2453; found: 324.2458.
2-Butyl-3-(3',5'-pyrimidinyl)-5-methylfuran (3bd): The reaction of 1b
(104 mg, 0.75mmol) with 5-bromopyrimidine (80 mg, 0.5mmol) afforded
3bd (77 mg, 71%) as a solid. M.p. 45 48 8C (n-hexane); 1H NMR
(300 MHz, CDCl3): d ˆ 9.06 (s, 1H; ArH), 8.71 (s, 2H; 2ArH), 6.08 (s, 1H;
CH), 2.69 (t, 3J(H,H) ˆ 7.7 Hz, 2H; CH2), 2.26 (s, 3H; CH3), 1.73 1.58 (m,
2-Heptyl-3-(4'-methoxycarbonylphenyl)-5-(cyclohexyl)furan (3dc): The
reaction of 1d (186 mg, 0.75mmol) with p-(methoxycarbonyl)phenyl
iodide (131 mg, 0.5mmol) afforded 3dc (146 mg, 76%) as a liquid.
1H NMR (300 MHz, CDCl3): d ˆ 8.03 (d, 3J(H,H) ˆ 8.7 Hz, 2H; 2ArH),
7.42 (d, 3J(H,H) ˆ 8.9 Hz, 2H; 2ArH), 6.09 (s, 1H; CH), 3.91 (s, 3H;
OCH3), 2.75(t, 3J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.65 2.52 (m, 1H; CH), 2.15
1.95(m, 2H; CH 2), 1.90 1.60 (m, 6H; 3CH2), 1.50 1.10 (m, 12H; 6CH2),
0.87 (t, 3J(H,H) ˆ 6.6 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ
167.01, 159.11, 150.84, 139.63, 129.78, 127.42, 127.11, 120.09, 103.71, 51.95,
37.07, 31.73, 31.45, 29.24, 28.96, 28.45, 27.16, 26.10, 25.89, 22.58, 14.04; IR
3
2H; CH2), 1.43 1.34 (m, 2H; CH2), 0.89 (t, J(H,H) ˆ 7.3 Hz, 3H; CH3);
13C NMR (75.4 MHz, CDCl3): d ˆ 156.20, 154.88, 151.83, 151.15, 128.66,
114.53, 105.76, 30.72, 26.66, 22.36, 13.73, 13.35; IR (neat): nÄ ˆ 1592, 1560,
‡
‡
1546 cmÀ1; MS (70 eV): m/z (%): 217 (9.28) [M ‡H], 216 (28.31) [M ], 173
‡
(100) [M À C3H7]; HRMS: calcd for C13H16N2O: 216.1263; found:
(neat): nÄ ˆ 1724 (C O), 1610, 1278 cmÀ1; MS (70 eV): m/z (%): 382 (45.84)
ˆ
216.1255.
‡
‡
[M ], 297 (100) [M À C6H13]; HRMS: calcd for C25H34O3: 382.2508;
2-Butyl-3-(E-2'-methoxycarbonylethenyl)-5-methylfuran (3be): The reac-
tion of 1b (104 mg, 0.75mmol) with methyl ( Z)-3-iodopropenoate (106 mg,
found: 382.2458.
0.5mmol) afforded 3be (68 mg, 61%) as a liquid. 1H NMR (300 MHz,
2-Heptyl-3-phenyl-5-tert-butylfuran (3ea): The reaction of 1e (111 mg,
0.5mmol) with iodobenzene (408 mg, 2.0 mmol) afforded 3ea (110 mg,
74%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.42 7.32 (m, 4H,
4ArH), 7.28 7.18 (m, 1H, ArH), 6.06 (s, 1H; CH), 2.75(t, 3J(H,H) ˆ
7.2 Hz, 2H; CH2), 1.76 1.62 (m, 2H; CH2), 1.40 1.20 (m, 8H; 4CH2),
1.31 (s, 9H, 3CH3), 0.88 (t, 3J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 161.83, 149.82, 134.87, 128.39, 127.54, 125.93,
3
ˆ
CDCl3): d ˆ 7.47 (d, J(H,H) ˆ 15.6 Hz, 1H; COC CH), 6.01 (s, 1H, CH),
3
ˆ
5.93 (d, J(H,H) ˆ 15.6 Hz, 1H; COCH C), 3.71 (s, 3H; OCH3), 2.62 (t,
3J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.20 (s, 3H; CH3), 1.66 1.51 (m, 2H; CH2),
1.41 1.28 (m, 2H; CH2), 0.86 (t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 167.94, 157.44, 151.43, 135.64, 117.84, 114.78, 103.22,
ˆ
51.38, 30.75, 25.94, 22.24, 13.72, 13.32; IR (neat): nÄ ˆ 1720 (C O), 1640
Chem. Eur. J. 2003, 9, 2447 2456
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2453

S.-m. Ma et al.
FULL PAPER
120.62, 103.23, 32.47, 31.81, 29.27, 29.03, 29.02, 28.57, 26.95, 22.63, 14.09; IR
13.75, 11.77; IR (KBr): nÄ ˆ 1550, 1410, 1140 cmÀ1; MS (70 eV): m/z (%): 217
‡
‡
‡
(neat): nÄ ˆ 1600, 1566, 909, 763 cmÀ1; MS (70 eV): m/z (%): 298 (32.48)
(44.11) [M ‡H], 216 (63.07) [M ], 173 (100) [M À C3H7]; HRMS: calcd
‡
‡
[M ], 283 (100) [M À CH3]; HRMS: calcd for C21H30O: 298.2297; found:
for C13H16N2O: 216.1263; found: 216.1250.
298.2315.
2-Methyl-3-allyl-4-(4'-nitrophenyl)furan (3jb): The reaction of 1,2-dienyl
ketone 1j (183 mg, 1.5mmol) with p-nitrophenyl iodide (249 mg, 1.0 mmol)
afforded 3jb as a yellow solid (191 mg, 79%). 1H NMR (400 MHz, CDCl3):
d ˆ 8.05(d, 3J(H,H) ˆ 7.1 Hz, 2H; 2ArH), 7.15(d, 3J(H,H) ˆ 7.1 Hz, 3H;
2-Phenyl-3-(4'-nitrophenyl)-5-methylfuran (3 fb): The reaction of 1 f
(119 mg, 0.75mmol) with p-nitrophenyl iodide (125mg, 0.5mmol) afford-
ed 3 fb (71 mg, 51%) as a yellow oil. 1H NMR (300 MHz, CDCl3): d ˆ 8.18
(d, 3J(H,H) ˆ 8.1 Hz, 2H; 2ArH), 7.54 (d, 3J(H,H) ˆ 8.1 Hz, 2H; 2ArH),
7.50 7.40 (m, 2H; 2Ar'H), 7.38 7.20 (m, 3H; 3Ar'H), 6.22 (s, 1H; CH),
2.41 (s, 3H); 13C NMR (75.4 MHz, CDCl3): d ˆ 152.31, 148.52, 146.48,
141.65, 130.63, 128.89, 128.63, 128.06, 126.57, 123.94, 120.99, 109.11, 13.53;
IR (neat): nÄ ˆ 1600, 1512, 1342, 1180 cmÀ1; MS (70 eV): m/z (%): 280
2ArH and CH), 5.78 5.65 (m, 1H; CH C), 4.89 (dd, 3J(H,H) ˆ 10.1 Hz,
ˆ
2J(H,H) ˆ 1.7 Hz, 1 H; C CH), 4.78 (dd, 3J(H,H) ˆ 7.1 Hz, 2J(H,H) ˆ
ˆ
1.7 Hz, 1H; C CH), 3.05(d, 3J(H,H) ˆ 5.3 Hz, 2H; CH2), 2.10 (s, 3H;
ˆ
CH3); IR (KBr): nÄ ˆ 1640 (C C), 1600, 1510, 1340 cmÀ1; MS (70 eV): m/z
ˆ
‡
‡
(%): 244 (19.31) [M ‡H], 243 (100) [M ]; elemental analysis calcd (%) for
‡
‡
(28.65) [M ‡H], 279 (100) [M ]; HRMS: calcd for C17H13NO3: 279.08954;
C14H13NO3: C 69.12, H 5.39, N 5.76; found: C 69.51, H 5.52, N 5.73.
found: 279.08952.
The cross-coupling reaction of 1,2-allenyl ketone 1k with iodobenzene:
Conditions A: The reaction of 1,2-allenyl ketone 1k (104 mg, 0.5mmol)
with iodobenzene (204 mg, 1 mmol) afforded 3ka (81 mg, 57%) and 4k
(22 mg, 11%).
2-Phenyl-3-(4'-methoxycarbonylphenyl)-5-methylfuran (3 fc): The reaction
of 1 f (119 mg, 0.75mmol) with p-(methoxycarbonyl)phenyl iodide
(131 mg, 0.5mmol) afforded 3 fc (75mg, 51%) as an oil. 1H NMR
(300 MHz, CDCl3): d ˆ 7.99 (d, 3J(H,H) ˆ 8.7 Hz, 2H; 2ArH), 7.56 7.45
(m, 4H; 4Ar'H), 7.42 7.16 (m, 3H; 2ArH and Ar'H), 6.20 (s, 1H; CH),
3.92 (s, 3H; OCH3), 2.39 (s, 3H; CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ
166.95, 151.76, 147.64, 139.50, 131.04, 129.85, 128.44, 128.42, 128.33, 127.51,
2-Pentyl-3-phenyl-4-butyl-5-methylfuran (3ka): 1H NMR (300 MHz,
CDCl3): d ˆ 7.42 7.16 (m, 5H; C6H5), 2.54 (t, 3J(H,H) ˆ 8.0 Hz, 2H;
CH2), 2.29 (t, 3J(H,H) ˆ 7.3 Hz, 2H; CH2), 2.26 (s, 3H; CH3), 1.76 1.50 (m,
2H; CH2), 1.40 1.10 (m, 8H; 4CH2), 0.87 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3),
0.87 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ
149.95, 145.22, 134.97, 129.75, 128.42, 126.55, 122.46, 119.32, 32.70, 31.74,
28.88, 26.59, 23.50, 22.63, 22.60, 14.24, 14.03, 11.96; IR (neat): nÄ ˆ 1608,
ˆ
126.24, 122.10, 109.55, 52.07, 13.54; IR (neat): nÄ ˆ 1726 (C O), 1608, 1560,
‡
1276, 1178, 1110 cmÀ1; MS (70 eV): m/z (%): 293 (24.90) [M ‡H], 292
‡
(100) [M ]; HRMS: calcd for C19H16O3: 292.1100; found: 292.1114.
2-Phenyl-3-(4'-nitrophenyl)-5-propylfuran (3gb): The reaction of 1g
(140 mg, 0.75mmol) with p-nitrophenyl iodide (125mg, 0.5mmol) afford-
ed 3gb (118 mg, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3): d ˆ 8.09
(d, 3J(H,H) ˆ 8.9 Hz, 2H, 2ArH), 7.47 (d, 3J(H,H) ˆ 8.9 Hz, 2H, 2ArH),
7.42 7.37 (m, 2H, 2Ar'H), 7.26 7.16 (m, 3H; 3Ar'H), 6.15(s, 1H; CH),
2.61 (t, 3J(H,H) ˆ 7.5Hz, 2H; CH 2), 1.78 1.60 (m, 2H; CH2), 0.97 (t,
3J(H,H) ˆ 7.5Hz, 3H; CH 3); 13C NMR (75.4 MHz, CDCl3): d ˆ 156.53,
148.33, 146.40, 141.71, 130.69, 128.86, 128.57, 127.98, 126.54, 123.87, 120.75,
108.36, 29.93, 21.24, 13.78; IR (neat): nÄ ˆ 1600, 1514, 1344 cmÀ1; MS
‡
1585, 1495, 701 cmÀ1; MS (70 eV): m/z (%): 284 (29.72) [M ], 227 (100)
‡
[M À C4H9]; HRMS: calcd for C20H28O: 284.2140; found: 284.2157.
2-Methyl-3-butyl-5-pentylfuran (4k): 1H NMR (300 MHz, CDCl3): d ˆ 5.77
(s, 1H; CH), 2.52 (t, 3J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.26 (t, 3J(H,H) ˆ 7.2 Hz,
2H; CH2), 2.16 (s, 3H; CH3), 1.68 1.50 (m, 2H; CH2), 1.50 1.40 (m, 2H;
CH2), 1.40 1.30 (m, 6H; 3CH2), 0.91 (t, 3J(H,H) ˆ 7.5Hz, 3H; CH 3), 0.90
3
(t, J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ 153.53,
144.71, 119.41, 106.43, 32.62, 31.49, 28.05, 27.86, 24.56, 22.45, 22.36, 14.02,
13.94, 11.35; IR (neat): nÄ ˆ 2958, 2929, 1578, 1467 cmÀ1; MS (70 eV): m/z
‡
‡
(70 eV): m/z (%): 307 (54.11) [M ], 278 (100) [M À C2H5]; HRMS: calcd
‡
‡
(%): 208 (28.69) [M ], 151 (100) [M À C4H9]; HRMS: calcd for C14H24O:
for C19H17NO3: 307.1208; found: 307.1227.
208.18272; found: 208.17948.
2-Phenyl-3-(4'-methoxycarbonylphenyl)-5-propylfuran (3gc): The reaction
of 1g (140 mg, 0.75mmol) with p-(methoxycarbonyl)phenyl iodide
(131 mg, 0.5mmol) afforded 3gc (116 mg, 73%) as an oil. 1H NMR
(300 MHz, CDCl3): d ˆ 8.02 (d, 3J(H,H) ˆ 8.5Hz, 2H; 2ArH), 7.56 7.44
(m, 4H; 2ArH and 2Ar'H), 7.35 7.20 (m, 3H; 3Ar 'H), 6.22 (s, 1H; CH),
3.93 (s, 3H; OCH3), 2.69 (t, 3J(H,H) ˆ 7.5Hz, 2H; CH 2), 1.85 1.68 (m, 2H;
CH2), 1.05(t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
d ˆ 66.86, 155.95, 147.43, 139.54, 131.07, 129.78, 128.35, 128.28, 127.42,
Typical procedure for coupling cyclization reaction of 1,2-allenyl ketone 1k
with iodobenzene:Conditions B:
A mixture of Pd(PPh3)4 (29 mg,
0.05mmol), 1,2-dienyl ketone 1k (104 mg, 1.0 mmol), K2CO3 (138 mg,
1.0 mmol), TBAB (32 mg, 0.1 mmol), iodobenzene (204 mg, 2.0 mmol), and
DMA (2.5mL) was stirred under Ar at 100 8C for 10 h. H2O was added and
the mixture was extracted by ether, dried over MgSO4, and evaporated.
The residue was purified by column chromatography on silica gel (hexanes)
to afford 3ka (101 mg, 72%).
126.19, 121.82, 108.78, 108.77, 51.97, 29.93, 21.24, 13.77; IR (neat): nÄ ˆ 1724
‡
(C O), 1610, 1560, 1278 cmÀ1; MS (70 eV): m/z (%): 320 (65.59) [M ], 291
ˆ
2-Pentyl-3-(4'-methoxycarbonylphenyl)-4-butyl-5-methylfuran (3kc): The
reaction of 1k (208 mg, 1.0 mmol) with p-(methoxycarbonyl)phenyl iodide
(131 mg, 0.5mmol) afforded 3kc (161 mg, 94%). 1H NMR (300 MHz,
CDCl3): d ˆ 8.05(d, 3J(H,H) ˆ 8.1 Hz, 2H; 2ArH), 7.30 (d, 3J(H,H) ˆ
8.1 Hz, 2H; 2ArH), 3.92 (s, 3H; OCH3), 2.52 (t, 3J(H,H) ˆ 7.5Hz, 2H;
CH2), 2.30 (t, 3J(H,H) ˆ 6.6 Hz, 2H; CH2), 2.23 (s, 3H; CH3), 1.70 1.50 (m,
2H; CH2), 1.40 1.10 (m, 8H; 4CH2), 0.84 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3),
0.76 (t, 3J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ
167.11, 150.19, 145.45, 139.88, 129.52, 129.22, 127.95, 121.40, 118.68, 52.02,
32.36, 31.38, 28.47, 26.34, 23.18, 22.29, 22.27, 13.93, 13.72, 11.61; IR (neat):
‡
(100) [M À C2H5]; HRMS: calcd for C21H20O3: 320.1413; found: 320.1411.
2,3-Dimethyl-4-(4'-nitrophenyl)furan (3hb): The reaction of 3h (182 mg,
2.0 mmol) with p-nitrophenyl iodide (249 mg, 1.0 mmol) afforded 3hb
(171 mg, 79%). M.p. 91 928C (n-hexane); 1H NMR (300 MHz, CDCl3):
d ˆ 8.21 (d, 3J(H,H) ˆ 9.1 Hz, 2H; 2ArH), 7.50 (d, 3J(H,H) ˆ 9.1 Hz, 2H;
2ArH), 7.46 (s, 1H; CH), 2.22 (s, 3H; CH3), 2.04 (s, 3H; CH3); IR (KBr):
nÄ ˆ 1600, 1560, 1510, 1340, 1144 cmÀ1; MS (70 eV): m/z (%): 218 (22.21)
‡
‡
[M ‡H], 217 (100) [M ]; elemental analysis calcd (%) for C12H11NO3: C
66.35, H 5.10, N 6.45; found: C 66.34, H 5.04, N 6.33.
nÄ ˆ 1728 (C O), 1612, 1276, 774 cmÀ1; MS (70 eV): m/z (%): 342 (6.67)
ˆ
2,3-Dimethyl-4-(4'-methoxycarbonylphenyl)furan (3hc): The reaction of
1h (144 mg, 1.5mmol) with p-(methoxycarbonyl)phenyl iodide (262 mg,
1.0 mmol) afforded 3hc (156 mg, 68%). M.p. 69 718C (n-hexane);
1H NMR (300 MHz, CDCl3): d ˆ 8.01 (d, 3J(H,H) ˆ 6.8 Hz, 2H; 2ArH),
7.42 (d, 3J(H,H) ˆ 6.8 Hz, 2H; 2ArH), 7.41 (s, 1H; CH), 3.82 (s, 3H;
OCH3), 2.23 (s, 3H; CH3), 2.02 (s, 3H; CH3); MS (70 eV): m/z (%): 231
‡
‡
[M ], 43 (100) [C3H7 ]; HRMS: calcd for C22H30O3: 342.2195; found:
342.2188.
2-Pentyl-3-(E-2'-methoxycarbonylethenyl)-4-butyl-5-methylfuran (3ke):
The reaction of 1k (166 mg, 0.8 mmol) with methyl (E)-3-iodopropenoate
(106 mg, 0.5mmol) afforded 3ke (94 mg, 64%). 1H NMR (300 MHz,
‡
‡
ˆ
(17.06) [M ‡H], 230 (100) [M ]; IR (KBr): nÄ ˆ 1724 (C O), 1609, 1276,
1110 cmÀ1; elemental analysis calcd (%) for C14H14O3: C 73.03, H 6.12;
found: C 72.95, H 6.19.
3
3
ˆ
CDCl3): d ˆ 7.49 (d, J(H,H) ˆ 16.2 Hz, 1H; COC CH), 5.97 (d, J(H,H) ˆ
16.2 Hz, 1H; COCH C), 3.70 (s, 3H; OCH3), 2.60 (t, 3J(H,H) ˆ 7.5Hz,
ˆ
2H; CH2), 2.35(t, 3J(H,H) ˆ 6.9 Hz, 2H; CH2), 2.10 (s, 3H; CH3), 1.60
1.40 (m, 2H; CH2), 1.40 1.10 (m, 8H; 4CH2), 0.85(t, 3J(H,H) ˆ 7.2 Hz, 3H;
2-Methyl-3-butyl-4-(3',5'-pyrimidinyl)furan (3id): The reaction of 1i
(207 mg, 1.5 mmol) with 5-bromopyrimidine (159 mg, 1.0 mmol) afforded
3id (209 mg, 97%). M.p. 39 408C (n-hexane); 1H NMR (300 MHz,
CDCl3): d ˆ 9.10 (s, 1H; ArH), 8.70 (s, 2H; 2ArH), 7.38 (s, 1H; CH), 2.41
(t, 3J(H,H) ˆ 7.4 Hz, 2H; CH2), 2.24 (s, 3H; CH3), 1.47 1.04 (m, 4H;
2CH2), 0.80 (t, 3J(H,H) ˆ 7.1 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
d ˆ 157.03, 155.28, 149.78, 137.87, 127.89, 120.75, 117.91, 32.58, 23.13, 22.34,
CH3), 0.82 (t, J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
3
d ˆ 168.34, 157.36, 146.74, 136.66, 117.97, 116.25, 114.13, 51.41, 32.00, 31.73,
28.20, 26.67, 23.90, 22.39, 22.35, 13.94, 13.89, 11.20; IR (neat): nÄ ˆ 1722
(C O), 1640 (C C), 1626, 1169 cmÀ1; MS (70 eV): m/z (%): 292 (31.33)
ˆ
ˆ
‡
‡
[M ], 43 (100) [C3H7 ]; HRMS: calcd for C18H28O3: 292.2039; found:
292.2054.
2454
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2447 2456

Substituted Furans
2447 2456
‡
‡
2-Pentyl-3-(4'-methoxyphenyl)-4-butyl-5-methylfuran (3kf): The reaction
of 1k (208 mg, 1.0 mmol) with p-methoxyphenyl iodide (117 mg, 0.5mmol)
afforded 3kf (80 mg, 51%) and 3ka (39 mg, 27%). 3kf: 1H NMR
(300 MHz, CDCl3): d ˆ 7.15(d, 3J(H,H) ˆ 8.7 Hz, 2H; 2ArH), 6.92 (d,
3J(H,H) ˆ 8.7 Hz, 2H; 2ArH), 3.84 (s, 3H; OCH3), 2.50 (t, 3J(H,H) ˆ
(70 eV): m/z (%): 418 (64.57) [M ], 362 (100) [M À C4H8]; HRMS: calcd
for C28H34O3: 418.2508; found: 418.2539.
2-(4'-Trifluoromethylphenyl)-3-butyl-4-(4''-methoxycarbonylphenyl)-5-
pentylfuran (3qc): Treatment of 1q (338 mg, 1.0 mmol) with 2c (131 mg,
0.5mmol) afforded 3qc (50 mg, 21%) as a solid. M.p. 60 618C (Et2O/
hexanes); 1H NMR (300 MHz, CDCl3): d ˆ 8.03 (dt, 3J(H,H) ˆ 8.5Hz,
6J(H,H) ˆ 1.8 Hz, 2H; 2ArH), 7.68 (d, 3J(H,H) ˆ 8.2 Hz, 2H; 2Ar'H), 7.48
(d, 3J(H,H) ˆ 8.2 Hz, 2H; 2Ar'H), 7.37 (dt, 3J(H,H) ˆ 8.5Hz, 6J(H,H) ˆ
1.8 Hz, 2H; 2ArH), 3.93 (s, 3H; OCH3), 2.55 (t, 3J(H,H) ˆ 7.0 Hz, 2H;
CH2), 2.42 (td, 3J(H,H) ˆ 7.3 Hz, 6J(H,H) ˆ 1.8 Hz, 2H; CH2), 1.60 1.30
3
7.5Hz, 2H; CH 2), 2.28 (t, J(H,H) ˆ 7.5Hz, 2H; CH 2), 2.24 (s, 3H; CH3),
1.60 1.50 (m, 2H; CH2), 1.30 1.10 (m, 8H; 4CH2), 0.86 (t, 3J(H,H) ˆ
6.6 Hz, 3H; CH3), 0.79 (t, 3J(H,H) ˆ 7.8 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 158.12, 149.52, 144.76, 130.52, 126.93, 121.68,
119.20, 113.59, 55.16, 32.45, 31.49, 28.64, 26.33, 23.26, 22.37, 22.36, 13.99,
13.80, 11.70; IR (neat): nÄ ˆ 1590, 1512, 1246, 1174, 734 cmÀ1; MS (70 eV): m/
3
(m, 6H; 3CH2), 1.30 1.10 (m, 4H; 2CH2), 0.94 (t, J(H,H) ˆ 7.0 Hz, 3H;
‡
‡
CH3), 0.82 (t, J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
3
z (%): 292 (31.33) [M ], 43 (100) [C3H7 ]; HRMS: calcd for C21H30O2:
d ˆ 215.19, 193.77, 166.63, 141.73, 139.53, 133.15 (q, 2J(C,F) ˆ 32.9 Hz),
130.06, 129.25, 128.48, 127.35 (q, 1J(C,F) ˆ 296.3 Hz), 126.10, 124.84 (q,
314.2246; found: 314.2220.
2-Butyl-3-phenyl-4-pentyl-5-methylfuran (3la): The reaction of 1l (208 mg,
1.0 mmol) with iodobenzene (408 mg, 2.0 mmol) afforded 3la (196 mg,
69%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.42 7.16 (m, 5H;
3J(C,F) ˆ 3.8 Hz), 110.81, 110.06, 52.19, 31.45, 30.37, 30.18, 28.17, 27.48,
À1
ˆ
22.65, 22.35, 13.95, 13.86; IR (KBr): nÄ ˆ 1724 (C O), 1654, 1607, 1326 cm
;
‡
‡
3
3
MS (70 eV): m/z (%): 472 (9.72) [M ], 299 (100) [M À p-CF3C6H4CO];
elemental analysis calcd (%) for C28H31F3O3: C 71.17, H 6.61; found: C
70.89, H 6.52.
C6H5), 2.54 (t, J(H,H) ˆ 8.0 Hz, 2H; CH2), 2.29 (t, J(H,H) ˆ 7.3 Hz, 2H;
CH2), 2.25(s, 3H; CH 3), 1.70 1.50 (m, 2H; CH2), 1.40 1.10 (m, 8H;
4CH2), 0.87 (t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3), 0.87 (t, 3J(H,H) ˆ 6.7 Hz, 3H;
CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ 149.66, 144.95, 134.71, 129.51,
128.16, 126.30, 122.23, 119.13, 31.48, 31.09, 29.86, 26.09, 23.48, 22.38, 22.27,
13.93, 13.81, 11.69; IR (neat): nÄ ˆ 2929, 1608, 1585, 1496 cmÀ1; MS (70 eV):
Acknowledgement
‡
‡
m/z (%): 284 (53.14) [M ], 241 (100) [M À C3H7]; HRMS: calcd for
C20H28O: 284.2140; found: 284.2180.
Financial support from the Major State Basic Research Development
Program (Grant No. G2000077500), National Science Foundation of China,
and Shanghai Municipal Committee of Science and Technology are greatly
appreciated. S.M. is the recipient of 1999 Qiu Shi Award for Young
Scientific Workers issued by Hong Kong Qiu Shi Foundation of Science and
Technology (1999 2003).
2,4-Dipentyl-3-phenyl-5-methylfuran (3ma): The reaction of 1m (222 mg,
1.0 mmol) with iodobenzene (408 mg, 2.0 mmol) afforded 3ma (176 mg,
59%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.42 7.16 (m, 5H;
3
3
C6H5), 2.51 (t, J(H,H) ˆ 7.3 Hz, 2H; CH2), 2.28 (t, J(H,H) ˆ 7.3 Hz, 2H;
CH2), 2.25(s, 3H; CH 3), 1.70 1.50 (m, 2H; CH2), 1.40 1.10 (m, 10H;
5CH2), 0.84 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3), 0.78 (t, 3J(H,H) ˆ 7.3 Hz, 3H;
CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ 149.92, 145.18, 134.94, 129.73
(2C), 128.38 (2C), 126.53, 122.43, 119.36, 31.71 (2C), 30.08, 30.03, 26.56,
23.71, 22.60, 22.50, 14.20, 14.17, 11.94; IR (neat): nÄ ˆ 2929, 1608, 1585, 1495,
[1] a) M. V. Sargent, F. M. Dean, Comprehensive Heterocyclic Chemistry,
Vol. 4 (Eds.: A. R. Katrizky, C. W. Rees), Pergamon Press, New York,
1984, pp. 599 656; D. M. X. Donnelly, M. J. Meegan, Comprehensive
Heterocyclic Chemistry, Vol. 4 (Eds.: A. R. Katrizky, C. W. Rees),
Pergamon Press, New York, 1984, pp. 657 712; b) Natural Products
Chemistry (Ed.: K. Nakanishi), Kodansha, Toyko, 1974, pp. 392 403;
c) M. Shipman, Contemp. Org. Synth. 1995, 2, 1 17.
‡
‡
759, 701 cmÀ1; MS (70 eV): m/z (%): 298 (48.06) [M ], 241 (100) [M
À
C4H9]; HRMS: calcd for C21H30O: 298.2297; found: 298.2262.
2-Butyl-3-phenyl-4-pentyl-5-isopropylfuran (3na): The reaction of 1n
(236 mg, 1.0 mmol) with iodobenzene (408 mg, 2.0 mmol) afforded 3na
(187 mg, 60%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.42 7.16 (m,
5H; C6H5), 3.00 (7, 3J(H,H) ˆ 6.7 Hz, 1H; CH), 2.54 (t, 3J(H,H) ˆ 7.3 Hz,
2H; CH2), 2.30 (t, 3J(H,H) ˆ 7.3 Hz, 2H; CH2), 1.70 1.56 (m, 2H; CH2),
1.40 1.00 (m, 8H; 4CH2), 1.28 (d, 3J(H,H) ˆ 6.7 Hz, 6H; 2CH3), 0.86 (t,
3J(H,H) ˆ 7.3 Hz, 3 H ; CH3), 0.78 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3): d ˆ 153.29, 149.39, 134.93, 129.55, 128.11, 126.21,
121.89, 117.03, 31.58, 30.95, 30.39, 26.25, 26.12, 23.30, 22.36, 22.28, 21.91,
13.91, 13.81; IR (neat): nÄ ˆ 1608, 1583, 701 cmÀ1; MS (70 eV): m/z (%): 312
[2] G. Vernin, G. Vernin, Chemistry of Heterocyclic Compounds in
Flavoours and Aromas (Ed.: G. Vernin.), Ellis Horwood, Chichester,
¬
¬
1982, pp. 74 85; G. Vernin, C. Parkanyi, Chemistry of Heterocyclic
Compounds in Flavoours and Aromas (Ed.: G. Vernin.), Ellis
Horwood, Chichester, 1982, pp. 161 165.
[3] B. H. Lipshutz, Chem. Rev. 1986, 86, 795 819.
[4] For recent reviews, see: a) X. Hou, H. Y. Cheung, T. Y. Hon, P. L.
Kwan, T. H. Lo, S. Y. Tong, H. N. C. Wong Tetrahedron 1998, 54,
1955 2020; b) B. A. Keay, Chem. Soc. Rev. 1999, 28, 209 215.
[5] For the synthesis of 2,3,4-trisubstituted furans, see: a) K. Takai, M.
Tezuka, Y. Kataoka, K. Utimoto, J. Org. Chem. 1990, 55, 5310 5312;
b) Y. Kataoka, M. Tezuka, K. Takai, K. Utimoto, Tetrahedron 1992, 48,
3495 3502; c) N. Greeves, J. S. Torode, Synthesis 1993, 1109 1112;
d) M. C. Pirrung, Y. R. Lee, Tetrahedron Lett. 1994, 35, 6231 6234.
[6] For the synthesis of 2,3,5-trisubstituted furans, see: a) H. Sheng, S. Lin,
Y. Huang, Synthesis 1987, 1022 1023; b) H. M. L. Davies, K. R.
Romines, Tetrahedron 1988, 44, 3343 3348; c) Y. Fukuda, H.
Shiragami, K. Utimoto, H. Nozaki, J. Org. Chem. 1991, 56, 5816
5819; d) A. Arcadi, S. Cacchi, R. C. Larock, F. Marinelli, Tetrahedron
Lett. 1993, 34, 2813 2816; e) M. Tiecco, L.Testaferri, M. Tingoli, F.
Marini, Synlett 1994, 373 374; f) J. A. Marshall, C. A. Sehon, J. Org.
Chem. 1995, 60, 5966 5968; g) B. Seiller, C. Bruneau, P. H. Dixneuf,
Tetrahedron 1995, 51, 13089 13102; h) D. M. Sammond, T. Samma-
kia, Tetrahedron Lett. 1996, 37, 6065 6068; i) A. Arcadi, E. Rossi,
Tetrahedron Lett. 1996, 37, 6811 6814; j) S. P. Bew, D. W. Knight,
Chem. Commun. 1996, 1007 1008; k) J. A. Marshall, C. A. Sehon, J.
Org. Chem. 1997, 62, 4313 4320; l) A. Arcadi, E. Rossi, Tetrahedron
1998, 54, 15253 15272; m) C. M. Marson, S. Harper, J. Org. Chem.
1998, 63, 9223 9231; n) C. D. Brown, J. M. Chong, L. Shen, Tetrahe-
dron 1999, 55, 14233 14242; o) F. T. Luo, A. C. Bajji, A. Jeevanan-
dam, J. Org. Chem. 1999, 64, 1738 1740; p) J. A. Marshall, D. Zou,
Tetrahedron Lett. 2000, 41, 1347 1350; q) F. Qing, W. Gao, J. Ying, J.
Org. Chem. 2000, 65, 2003 2006; r) A. Arcadi, G. Cerichelli, M.
‡
‡
(41.07) [M ], 269 (100) [M À C3H7]; HRMS: calcd for C22H32O: 312.2453;
found: 312.2458.
2-(2'-Methylbutyl)-3-phenyl-4-pentyl-5-methylfuran (3oa): The reaction of
1o (222 mg, 1.0 mmol) with iodobenzene (408 mg, 2.0 mmol) afforded 3oa
(201 mg, 67%) as a liquid. 1H NMR (300 MHz, CDCl3): d ˆ 7.42 7.16 (m,
5H; C6H5), 2.53 (dd, 2J(H,H) ˆ 14.7, 3J(H,H) ˆ 6.1 Hz, 1H; CH), 2.32 (t,
3
3
2J(H,H) ˆ 14.7, J(H,H) ˆ 7.9 Hz, 1H; CH), 2.28 (t, J(H,H) ˆ 6.7 Hz, 2H;
CH2), 2.25(s, 3H; CH 3), 1.76 1.62 (m, 1H; CH), 1.40 1.00 (m, 8H; 4CH2),
0.90 0.70 (m, 9H; 3CH3); 13C NMR (75.4 MHz, CDCl3): d ˆ 148.86,
144.96, 134.81, 129.65, 128.15, 126.27, 123.24, 119.12, 34.52, 33.32, 31.48,
29.83, 29.20, 23.44, 22.27, 19.15, 13.93, 11.72, 11.38; IR (neat): nÄ ˆ 1608,
1495, 759, 701 cmÀ1; MS (70 eV): m/z (%): 298 (32.58) [M ], 241 (100)
[M À C4H9]; HRMS: calcd for C21H30O: 298.2297; found: 298.2254.
‡
‡
2-(4'-Methylphenyl)-3-butyl-4-(4''-methoxycarbonylphenyl)-5-pentylfuran
(3pc): Treatment of 1p (400 mg, 1.41 mmol) with 2c (200 mg, 0.76 mmol)
afforded 3pc (285mg, 90%). 1H NMR (300 MHz, CDCl3): d ˆ 8.03 (d,
3
3J(H,H) ˆ 8.3 Hz, 2H, 2ArH), 7.47 (d, J(H,H) ˆ 8.3 Hz, 2H; 2ArH), 7.01
(d, 3J(H,H) ˆ 8.3 Hz, 2H; 2ArH), 7.60 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 2ArH),
3.88 (s, 3H; OCH3), 2.60 2.45(m, 4H; 2CH 2), 2.32 (s, 3H; CH3), 1.66 1.54
(m, 2H; CH2), 1.38 1.08 (m, 8H; 4CH2), 0.79 (t, 3J(H,H) ˆ 6.9 Hz, 3H;
3
CH3), 0.69 (t, J(H,H) ˆ 7.2 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3):
d ˆ 167.06, 151.43, 146.99, 139.33, 136.34, 129.64, 129.56, 129.17, 129.07,
128.32, 125.34, 123.32, 120.68, 52.07, 31.96, 31.35, 28.31, 26.38, 23.79, 22.53,
22.29, 21.19, 13.94, 13.64; IR (neat): nÄ ˆ 1726 (C O), 1610, 1510 cmÀ1; MS
ˆ
Chem. Eur. J. 2003, 9, 2447 2456
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2455

S.-m. Ma et al.
FULL PAPER
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¬
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be performed under Ar.
[22] Certain tetrasubstituted furans show high estrogen-receptor (ER)
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¬
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Received: December 12, 2002 [F4664]
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