Synthesis of heterocyclic systems by transition-metal-catalyzed cyclization-migration reactions - A diversity-oriented strategy for the construction of spirocyclic 3(2H)-furanones and 3-pyrrolones

Article abstract of DOI:10.1002/ejoc.200601060

Two platinum(II)-catalyzed heterocyclization-migration reactions that provide five-membered heterocycle products are described. With 5 mol-% of PtCl₂ as a catalyst, 2-alkynyl-2-hydroxy carbonyl compounds 1 are converted into 3(2H)-furanones 2 a

Full text of DOI:10.1002/ejoc.200601060

FULL PAPER
DOI: 10.1002/ejoc.200601060
Synthesis of Heterocyclic Systems by Transition-Metal-Catalyzed Cyclization-
Migration Reactions – A Diversity-Oriented Strategy for the Construction of
Spirocyclic 3(2H)-Furanones and 3-Pyrrolones
Jörg T. Binder,[a] Benedikt Crone,[a] Stefan F. Kirsch,*[a] Clémence Liébert,[a] and
Helge Menz[a]
Keywords: Platinum / Gold / Domino reactions / Cyclizations / Heterocycles
Two platinum(II)-catalyzed heterocyclization-migration reac- treated with primary amines in the presence of 5 mol-% of
tions that provide five-membered heterocycle products are
described. With 5 mol-% of PtCl2 as a catalyst, 2-alkynyl-2-
hydroxy carbonyl compounds 1 are converted into 3(2H)-fu-
ranones 2 at 80 °C in moderate to excellent yields under very
mild reaction conditions. The reaction is proposed to proceed
through an oxonium ion intermediate B, which triggers a ste-
reospecific 1,2-shift analogous to an α-ketol rearrangement.
When exploited in a different manner, the 2-alkynyl-2-hy-
droxy carbonyl compounds 1 afford 3-pyrrolones 3 in 33–
81% yield. For this purpose, the starting compounds 1 are
PtCl2 at 100 °C in a convenient one-pot process. These cycli-
zation-migration reactions give novel access to 3(2H)-fu-
ranones and 3-pyrrolones in which the 2-position bears aryl
or alkyl substituents. Synthetically challenging spirocyclic
compounds can be prepared in this fashion by ring contrac-
tion. Studies that define the scope and limitations of the cycli-
zation-migration synthesis of heterocyclic systems are also
described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Nitrogen[6] and oxygen[7] heterocycles play important
roles as structural elements of many naturally occurring and
Introduction
Cascade reactions that combine two distinct reactions biologically active substances. Although a tremendous
into a single transformation are a powerful method for con- number of synthetic methods to approach heterocyclic com-
structing architecturally complex molecules from relatively pounds is known, the development of newer and more ef-
simple starting materials.[1,2] For some time, our group has ficient protocols remains an area of ongoing interest in or-
been involved in the development of cascade reactions that ganic synthesis.[8,9] Only recently, has the transition-metal-
are initiated by transition-metal-catalyzed π-activation for catalyzed skeletal reorganization of unsaturated frame-
the synthesis of heterocyclic products.[3] Coupled with a di- works been appreciated to access heterocyclic com-
versity-oriented approach to heterocyclic compounds, these pounds.[10] Owing to their exceptional ability to activate π-
cascade reactions are particularly attractive because systems,[11] and especially alkynes,[12,13] toward intermo-
branching reaction pathways increase the structural diver- lecular and intramolecular nucleophilic attack, strategies in-
sity of products by altering the skeletal array.[4] This strat- volving π-activation by soft noble-metal cations have be-
egy is expected to rapidly evolve both molecular complexity come increasingly popular, mostly with AuI, AuIII, AgI, and
and structural diversity, as a single compound is subjected PtII compounds as transition-metal precatalysts.[14] While
to varying reaction conditions that enable tandem pro- being operationally simple and convenient to perform (nei-
cesses, leading to structurally distinct products. For exam- ther air nor humidity need to be excluded), such skeletal
ple, one variant of this chemistry, the rearrangement-cycli- rearrangements provide an attractive and atom-economical
zation reaction, provides at least three structurally unique route to functionalized heterocycles.[15]
products (furans,[3c] pyrroles,[3b] and 2H-pyrans[3a]) from
Recently, Larock[16] and others[17] reported a transition-
readily synthesized propargyl vinyl ethers. However, se- metal-catalyzed synthesis of substituted furans from 2-(1-
quences involving rearrangement processes are relatively alkynyl)-2-alken-1-ones, which produces highly substituted
underdeveloped in the production of diversity.[5]
furans [Equation (1)].[18] This reaction is believed to pro-
ceed by the formation of an oxonium ion intermediate. As
part of our program directed toward the development of a
diversity-oriented use of tandem reactions for the synthesis
of heterocyclic compounds,[19] we envisioned a general ap-
proach to the synthesis of 3(2H)-furanones 2 from 2-alk-
ynyl-2-hydroxy carbonyl compounds 1, which proceeds
[a] Department Chemie, Technische Universität München,
Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49-89-2891-3315
E-mail: stefan.kirsch@ch.tum.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1636
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
FULL PAPER
through the cationic cyclization sequence shown in
Scheme 1. Coordination of the triple bond of propargylic
alcohol 1 to a suitable transition-metal catalyst was ex-
pected to enhance the electrophilicity for an intramolecular
nucleophilic attack. The intermediate oxonium ion B
should then trigger an irreversible 1,2-shift analogous to a
formal α-ketol rearrangement,[20] and subsequent proton-
ation of the carbon–transition-metal bond should afford
the 3(2H)-furanones 2 and regenerate the catalyst. To ex-
pand the diversity of structures available from propargylic
alcohol 1, we planned to utilize primary amines for an in
situ condensation step, and the sequence concludes then
with a 1,2-migration to the adjacent iminium ion to give
3-pyrrolones 3. To the best of our knowledge, onium ion
rearrangements have not been used to terminate cationic
cyclizations, while the use of related pinacol rearrangements
has been demonstrated to be a powerful strategy for
designing cascade reactions by Overman[1a] and others.[21]
Results and Discussion
Preparation of Propargylic Alcohols
Numerous practical methods for the synthesis of 2-alk-
ynyl-2-hydroxy carbonyl systems are now available. In gene-
ral, these methods involve the addition of alkynes to 1,2-
diketones to provide tertiary alkynyl alcohols.[9i,23] In the
present study, we have developed a quite convenient synthe-
sis for the required 2-alkynyl-2-hydroxy carbonyl com-
pounds 1 from 2-alkynyl alcohol compounds 4 derived from
simple oxiranes.[24] The key development in implementing
this alternative sequence was our finding that o-iodoxyben-
zoic acid (IBX)[25] is an excellent reagent for the mild and
regioselective α-hydroxylation of 2-alkynyl carbonyl com-
pounds in DMSO at 23 °C without giving dehydrogenation
products.[26–28] Both cyclic and acyclic propargylic alcohols
1a–o are procurable on a large scale, although with variable
(33–91%) yields, by the direct oxidation of 2-alkynyl
alcohols 4 with 3.0 equiv. of IBX [Equations (2) and (3)].
(1)
(2)
(3)
Whereas cyclopentanone 4p was obtained in 55% yield,
the IBX-mediated hydroxylation of the seven- and eight-
membered ring systems gave the desired tertiary alcohols in
poor yields accompanied by a significant amount of decom-
position [Equation (4)].[29]
Scheme 1. Proposed pathway for the synthesis of 3(2H)-furanones
and 3-pyrrolones.
(4)
We herein report a detailed study of transition-metal-cat-
alyzed cyclization-migration reactions. As exemplified in
A representative series of 2-alkynyl-2-hydroxycyclohexa-
Scheme 1, these unique reactions are particularly attractive, nones bearing an additional methyl substituent was pre-
because a convenient one-pot process affords both 3(2H)- pared from 3-methylcyclohexene (5) by the sequence illus-
furanones 2 and 3-pyrrolones 3 from propargylic alcohols trated in Scheme 2. Epoxidation of 5 provided epoxide 6 as
1.[22]
a mixture of diastereomers (dr 50:50).[30] Alkynylation of
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1637

J. T. Binder, B. Crone, S. F. Kirsch, C. Liébert, H. Menz
FULL PAPER
this inseparable mixture with lithium phenylacetylide[24] in The utilization of 2-alkynyl-2-hydroxy carbonyl compounds
the presence of BF3·OEt2 at –78 °C in THF gave rise to the for transition-metal-catalyzed cyclization-migration reac-
secondary alcohols 7 and 8, which were separated by col- tions should significantly expand the range of suitable start-
umn chromatography. Both 7 and 8 were transformed in ing materials for the synthesis of functionally substituted
the presence of IBX in DMSO to the corresponding 2-alk- 3(2H)-furanones. Moreover, the projected synthetic route
ynyl-2-hydroxycyclohexanones without showing diastereo- represents a significant departure from the conventional
selectivity; 9a and 9b were separated by column chromatog- strategy for constructing 3(2H)-furanones, as the sequence
raphy on silica gel (9a: dr Ͼ 95:5; 9b: dr Ͼ 95:5); 10a and affords the desired heterocycles through simultaneous C5–
10b were separated by semipreparative HPLC (10a: dr O1 bond formation and introduction of the substituents at
80:20; 10b: dr 75:25).[31] Stereochemical assignments for C2.
these compounds were made on the basis of NOESY ex-
periments.
Our preliminary studies have been carried out on the
transition-metal-catalyzed conversion of alkynyl carbonyl
compound 1a into the spirocyclic 3(2H)-furanone 2a
(Table 1). These results were promising, as product forma-
tion was observed in the presence of gold(III), copper(I),
silver(I), and platinum(II) salts. Among these salts, AuCl3
is the most efficient catalyst based on reaction time and
yield. For example, AuCl3 (5 mol-%) provided the desired
compound 2a in CH2Cl2 at room temperature after 90 min
in 83% yield (Table 1, Entry 1). Increasing the reaction tem-
perature to 38 °C led to a slightly higher yield (95%). The
use of cationic silver(I) and gold(I) complexes provided a
low yield, mainly accompanied by a significant amount of
decomposition (Table 1, Entries 2 and 3). Pd(OAc)2,
(Ph3P)AuCl and CuI are not efficient catalysts for this con-
version. Alkynyl carbonyl compound 1a was efficiently
transformed into 3(2H)-furanone 2a when heated in toluene
at 80 °C in the presence of PtCl2 (5 mol-%) (Table 1, En-
try 7). However, PtCl2-catalyzed isomerization was ob-
served at an impractical rate at 23 °C in CH2Cl2, in part due
to the poor solubility of PtCl2 in CH2Cl2. In the absence of
a transition-metal salt or in the presence of a catalytic
amount of HBF4, 3(2H)-furanone 2a was not obtained at
Scheme 2. Synthesis of 9a, 9b, 10a, and 10b.
Synthesis of 3(2H)-Furanones by a Transition-Metal-
Catalyzed Heterocyclization/1,2-Migration Reaction
Substituted 3(2H)-furanones play an important role as all.
structural elements of many natural products (e.g., ereman-
tholide A,[32] jatrophone,[33] and geiparvarin[34]). Moreover,
Table 1. Transition metal-catalyzed conversion of 1a into 2a.
pharmaceutical activity, such as inhibitory activity on
COX-2,[35] cytotoxic activity against tumor cells,[36] and in-
hibitory activity on MAO,[37] has been reported for several
substances containing the 3(2H)-furanone moiety.[38] The
construction of 3(2H)-furanones typically relies on classical
condensation methods such as the acid-catalyzed cyclocon-
densation of substituted αЈ-hydroxy 1,3-diketones, whereas
the bond formation between C5 and O1 is used in a cycliza-
tion step with the substitution pattern and the hydroxy
group at C2 being installed at an earlier stage.[39,40] An al-
ternative strategy involves unsaturated frameworks as start-
ing materials for transition-metal-catalyzed 5-endo hetero-
cyclizations.[41] A wide variety of other methods have been
developed for the synthesis of these heterocycles, including
the reaction of 3-silyloxyfurans with aldehydes,[42] transfor-
mation of 3-alkoxyfurans into 2-alkoxyfuranones,[43] intra-
molecular Wadsworth–Emmons condensation of γ-acyloxy-
β-oxo phosphonates,[44] and cyclization of dianion equiva-
lents with α-chloroacetic chlorides.[45] No attention has
been paid to 2-alkynyl-2-hydroxy carbonyl compounds as
Entry
Catalyst
Time [min] Yield[a] 2a [%] Yield[a,b] 1a [%]
1[c]
2[c]
3[c]
4[c]
5[d]
6[c]
7[e]
8[c]
9[c]
AuCl3
AgSbF6
(Ph3P)AuBF4
(Ph3P)AuCl
CuI
Pd(OAc)2
PtCl2
90
90
90
90
120
90
90
90
90
83
50
0
0
22
0
93
0
0
0
12
10
96
67
98
0
RuCl3
HBF4
86
23
[a] Isolated yield after column chromatography. [b] Recovered start-
ing material 1a. [c] Conditions: 1a (0.03 ), 5 mol-% catalyst, 23 °C,
CH2Cl2. [d] Conditions: 1a (0.08 ), 10 mol-% catalyst, 80 °C,
DMF. [e] Conditions: 1a (0.03 ), 5 mol-% catalyst, 80 °C, toluene.
To probe the scope and limitations of the transition-
possible 3(2H)-furanone precursors, although they are metal-catalyzed cyclization-migration reactions, propargylic
readily accessible and easily manipulated (as shown above). alcohols 1b–r were allowed to react. As illustrated in
1638
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
FULL PAPER
Table 2, the AuCl3-catalyzed reaction is general for a range ing six- and seven-membered ring systems. Substrate 1p de-
of substrates bearing different aryl substituents (R3 = aryl) rived from cyclopentanone did not react in the presence of
at the alkyne terminus. Unfortunately, substrates containing PtCl2.
alkyl substituents (R3 = alkyl) reacted considerably less
cleanly than did their aryl analogues. Thus, treatment of
Table 3. PtCl2-catalyzed conversion of 1 into 2.[a]
propargylic alcohols 1h, 1i, and 1j with AuCl3 at 23 °C in
CH2Cl2 afforded complex reaction mixtures, which con-
tained only small amounts of the desired furanones. As an
exception, substrate 1f (R3 = nPent) reacted smoothly to
give furanone 2f in 66% yield (Table 2, Entry 5). Notably,
solvent had a marked influence on catalytic efficiency. Reac-
tions of 2-alkynyl-2-hydroxy carbonyl compound 1a in the
presence of 5 mol-% AuCl3 at room temperature followed
the order: CH2Cl2 (3 h, 93% yield) Ͼ C6H6 (3 h, 42% yield)
Ͼ THF (3 h, 23% yield) ≈ CH3CN (3 h, 20% yield). Vary-
ing the concentration of 1a in CH2Cl2 revealed that the op-
timal concentration was 0.03 . With substrate concentra-
tions Ͻ0.01 , the reaction was slowed markedly. On the
other hand, increasing the concentration (Ͼ0.1 ) led to
low yields due to concomitant decomposition of the start-
ing material.
Table 2. AuCl3-catalyzed conversion of 1 into 2.[a]
[a] Conditions: 1 (0.03 ), 5 mol-% PtCl2, 80 °C, toluene. [b] Iso-
lated yield after column chromatography. [c] Volatility of 2l is likely
responsible for the moderate yield. [d] Determined by 1H NMR
spectroscopy.
Entry Substrate
R3
Product
Yield[b] 2 [%]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1h
1i
4-F-C6H4
2-MeO-C6H4
4-tBu-C6H4
3-thienyl
nPent
c-C6H11
2b
2c
2d
2e
2f
2h
2i
70 (4 h)
81 (5 h)
75 (4 h)
76 (5 h)
66 (2 h)
25 (7 h)
11 (6 h)
33 (18 h)
Whereas the present study focused mainly on the synthe-
sis of spirocyclic 3(2H)-furanones, this new cyclization-mi-
gration reaction is also applicable to acyclic systems, al-
though the yields were modest. For example, substrates 1o
(R1 = R2 = nPr) and 1s (R1 = R2 = Ph)[47] reacted by mi-
gration of alkyl and aryl groups [Equations (5) and (6)].
(CH2)3OTHP
CH2OTHP
1j
2j
[a] Conditions: 1 (0.03 ), 5 mol-% AuCl3, 23 °C, CH2Cl2. [b] Iso-
lated yield after column chromatography.
To further expand the scope of this method, we then ex-
amined the use of PtCl2 to catalyze the formation of 3(2H)-
furanones. Our expectation was that the platinum(II) salts
may have an advantage over AuCl3, offering greater sub-
strate scope (e.g., R3 = alkyl) while maintaining competitive
yields for R3 = aryl. Moreover, the use of non-hygroscopic
PtCl2 is more convenient due to the fact that, with AuCl3,
moisture should be excluded because of its strong hygro-
scopicity. As summarized in Table 3, a number of alkynes 1
were effectively converted into 3(2H)-furanones with par-
ticularly practical reaction conditions: 5 mol-% PtCl2,
80 °C, and toluene (0.03 ). As with AuCl3, the reaction
tolerated substitution of the substrate with R3 being both
(5)
(6)
Unfortunately, substrates that contained a methyl group
aromatic and heteroaromatic groups.[46] Gratifyingly, sub- for R2 provided poor yields of the desired products. The
strates containing alkyl, alkenyl, and silyl substituents at the markedly reduced reactivity of these substrates is probably
alkyne terminus provided good yields of the desired prod- due to the decrease in the migratory aptitude for the methyl
ucts under the reaction conditions. In a similar fashion, group, which facilitates competing reaction pathways such
substrates 1q and 1r were transformed into 2q and 2r, as the elimination of water. In the case of 1n, the attempted
respectively (Table 3, Entries 13 and 14). Again in these formation of the naturally occurring compound bullatenone
cases, ring contraction was observed to give the correspond- (2n)[48] gave (E)-endione 12 exclusively (79% yield) utilizing
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1639

J. T. Binder, B. Crone, S. F. Kirsch, C. Liébert, H. Menz
FULL PAPER
PtCl2 (5 mol-%) in toluene at 80 °C for 12 h. The use of
We have also briefly examined the proposed proto-deme-
AuCl3 at room temperature resulted primarily in the forma- tallation step to set free the platinum catalyst. When tri-
tion of the two enone products 11 (32% yield) and 12 (28% methylsilyl ether 14a was subjected to the standard PtCl2-
yield) after 4 h [Equation (7)].
catalyzed conditions with an excess of D2O as an additive,
deuterium incorporation into the 3(2H)-furanone at C-4
was observed [Equation (8)].
(7)
In both cases, the occurrence of 12 can be rationalized by
a sequence consisting of elimination and subsequent triple-
bond hydration. Although a Meyer–Schuster mechanism[49]
cannot be ruled out for the direct formation of 12 from 1n,
the fact that enedione 12 can be prepared without concomi-
tant formation of 11 with longer reaction times and higher
temperatures is consistent with the generation of 12 by
double-bond isomerization of 11.
Of primary importance, the cyclization-migration se-
quence for the conversion of 2-alkynyl-2-hydroxy carbonyl
compounds 1 to 3(2H)-furanones was found to proceed ste-
reospecifically. As depicted in Scheme 3, the methyl-substi-
tuted compounds 9a and 10a led to 3(2H)-furanone 13a
exclusively, whereas 9b and 10b delivered 13b.[50] The dia-
stereomer observed in the 3(2H)-furanone synthesis re-
ported here follows in each case from a rearrangement that
is likely to proceed through the cyclic oxonium ion interme-
diate B (Scheme 4). The fact that both cyclohexanones 9a
and 10a rearrange to give the same furanone product, as
do 9b and 10b, is rationalized also by this model. Neverthe-
less, there exists no direct experimental proof for cationic
intermediate B.
(8)
This result is consistent with the cyclization-migration
mechanism as proposed in Schemes 1 and 4, in which the
proto-demetallation at C4 is believed to be the final step in
the domino process. In general, trialkylsilyl ethers 14 (V =
SiMe3) and 15 (V = SiEt3) underwent PtCl2-initiated ring-
contracting cyclization to give the corresponding 3(2H)-fu-
ranones in good yields [Equation (9)].
(9)
These reactions were performed under otherwise iden-
tical conditions in undistilled toluene. Cleavage of the tetra-
hydropyranyl group of 14j under the reaction conditions is
likely responsible for the moderate yield in forming spirocy-
cle 2j. In the case of the catalyzed transformation 14a Ǟ
2a, tertiary alcohol 1a was detected as an intermediate.
Thus, we assume that the silyl ether is cleaved in the pres-
ence of PtCl2 and “wet” toluene at 80 °C prior to the cycli-
zation-migration process. The reactions of trimethylsilyl
ethers 14 catalyzed by AuCl3 in undistilled CH2Cl2 at room
temperature were remarkably clean, taking place without
the formation of significant amounts of byproducts [Equa-
tion (10)].
Scheme 3. Stereospecific course of the cyclization-migration reac-
tions.
(10)
Under these conditions, yields starting from trimethyl-
silyl ethers 14 are slightly superior to those realized with
tertiary alcohols 1 in dry CH2Cl2. Notably, the reaction of
aromatic substrates was as clean as the reaction of sub-
strates 14f and 14j having alkyl substituents.
Scheme 4. Plausible mechanism (illustrated for the formation of
13a and 13b from 9a: W = H, X = Me, Y = H, and Z = H; from
9b: W = Me, X = H, Y = H, and Z = H; from 10a: W = H, X =
H, Y = H, and Z = Me; from 10b: W = H, X = H, Y = Me, and
Z = H).
1640
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
FULL PAPER
Synthesis of 3-Pyrrolones by a PtCl2-Catalyzed
Heterocyclization/1,2-Migration Reaction
condensation conditions to improve the yields of the one-
pot sequence without isolation of the imine intermediates
were unsuccessful.
Table 4. PtCl2-catalyzed conversion of 1 into 3.[a]
To further broaden the diversity of structures available
from 2-alkynyl-2-hydroxy carbonyl compounds, we then ex-
amined a conceptually novel approach to 3-pyrrolones. Our
expectation was that, upon treatment with primary amines,
the standard reaction conditions utilized for the synthesis of
3(2H)-furanones would deliver directly pyrrolone products.
During the envisioned one-pot assembly, an additional
Entry Substrate
R3
R4
Product Yield[b] 2 [%]
amine condensation step was expected to occur before
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1d
1e
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
3-NO2-C6H4
CH2Ph
iBu
3aa
3ab
3ac
3ad
3ae
3da
3ef
3eg
3fh
3ja
75
35
37
33
81
52
73
78
73
44
PtCl2-catalyzed heterocyclization.[3b,51]
Despite the abundant literature available for both the sig-
nificance and the preparation of 3(2H)-furanones, synthetic
routes to their aza analogues, 3-pyrrolones, are rare. The
vast majority of the previous routes to 3-pyrrolones have
involved intramolecular condensation methods through
bond formation between N1 and C5.[52] For example, this
strategy has been effectively utilized to synthesize 3-pyrro-
lones as building blocks for the construction of non-peptide
peptidomimetic scaffolds.[53] An alternative approach to the
synthesis of substituted 3-pyrrolones is through HgII-medi-
ated 5-endo cyclization of amino ynones.[54] Owing to their
restricted availability, the pharmaceutical features of 3-pyr-
rolones lack detailed investigations. Therefore, we feel that a
general strategy to access 3-pyrrolones starting from readily
obtained 2-alkynyl-2-hydroxy carbonyl compounds may be
useful.
iPr
Ph
4-tBu-C6H4
3-thienyl
3-thienyl
nPent
3-Cl-C6H4
4-iPr-C6H4
4-MeO-C6H4
Ph
10
1j
CH2OTHP
[a] Conditions: 1 (0.03 ), R3-NH2 (1.3 equiv.), 5 mol-% PtCl2,
100 °C, toluene. [b] Isolated yield after column chromatography.
In the presence of catalytic amounts of AuCl3, the de-
sired 3-pyrrolones were obtained in poor yields as exem-
plified for the one-pot synthesis of pyrrolone 3eg [Equa-
tion (11)].
To realize the single-step process, this new cyclization-
migration sequence was initially examined with propargyl
alcohol 1a and aniline. As there was no precedent for the
projected conversion, we set out to explore the feasibility of
this transformation with the conditions previously em-
ployed for the synthesis of 3(2H)-furanones. Unfortunately,
reaction of 1a and aniline in the presence of catalytic
amounts of PtCl2 (5 mol-%) at 80 °C in toluene led to a
complex reaction mixture, which only contained small
amounts of the desired 3-pyrrolone 3aa. Nevertheless, the
product was characterized by diagnostic 13C NMR signals
at δ = 175.1 and 80.9 ppm. Further optimization revealed
(11)
Conclusions
Two new variants of domino reactions initiated by transi-
that a brief exposure of ketone 1a and aniline to PtCl2 tion-metal-catalyzed alkyne activation were described. In
(5 mol-%) in toluene at room temperature followed by reac- one, 2-alkynyl-2-hydroxy carbonyl compounds and 2-alk-
tion at 100 °C for 24 h furnished pyrrolone 3aa in 75% ynyl-2-silyloxy carbonyl compounds are transformed into
yield. As summarized in Table 4, subjection of other 2-alk- a variety of 3(2H)-furanones. This sequence is effectively
ynyl-2-hydroxy carbonyl compounds 1 and amines (R4- catalyzed by PtCl2 and AuCl3. In the second more limited
NH2) to the general protocol [(1) substrate 1, R4-NH2 variant, identical starting compounds are utilized to give
(1.3 equiv.), PtCl2 (5 mol-%), 23 °C, 30 min, toluene; (2) spirocyclic 3-pyrrolones in the presence of primary amines
100 °C, 24 h] afforded a number of related 3-pyrrolones 3. and catalytic amounts of PtCl2. Both sequences are pro-
Although product formation was observed in all cases, posed to proceed through a heterocyclization followed by a
yields varied widely (33–81%). This reaction is not as gene- 1,2-alkyl migration. The ability to transform simple 2-alk-
ral as the synthesis of 3(2H)-furanones discussed previously. ynyl-2-hydroxy carbonyl compounds into either 3(2H)-fu-
For example, isobutylamine and 1a provided 33% yield of ranones or 3-pyrrolones illustrates the type of reaction
the desired product, whereas isopropylamine was trans- pathways that are essential to rapidly evolve both diversity
formed in 81% yield to 3-pyrrolone 3ae. Analysis of crude and complexity. From a synthetic point of view, the results
1
reaction mixtures by H NMR spectroscopy indicated that described herein provide convenient access to two classes of
the incomplete formation of the intermediate imine is most heterocycles, which could find wide application in the de-
likely responsible for the low yields. Attempts to modify the sign of pharmaceutically active compounds.
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1641

J. T. Binder, B. Crone, S. F. Kirsch, C. Liébert, H. Menz
FULL PAPER
6.2, 13.7 Hz, 1 H), 4.32 (s, 1 H), 7.33–7.38 (m, 3 H), 7.46 (dd, J =
7.3, 1.4 Hz, 2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 22.9,
27.7, 37.3, 42.5, 74.1, 87.5, 87.8, 122.0, 128.3, 128.8, 131.8,
207.5 ppm. LRMS (EI): m/z (%) = 214 (80) [M]+, 185 (62), 157
(58), 129 (100). HRMS: calcd. for C14H14O2 214.0994, found
214.0993.
Experimental Section
General: All reactions involving water-sensitive chemicals were car-
ried out in flame-dried glassware with magnetic stirring under Ar.
Common solvents [pentane (P), ethyl acetate (EtOAc), tetra-
hydrofuran (THF), diethyl ether (Et2O), and CH2Cl2] were distilled
prior to use. All other reagents and solvents were used as received.
1H NMR spectra were obtained with 500 MHz and 360 MHz FT-
NMR spectrometers. 13C NMR spectra were recorded at
90.6 MHz. Chemical shifts are reported in ppm relative to the sol-
vent signal. Multiplicity is indicated as follows: s (singlet), d (doub-
let), t (triplet), m (multiplet), dd (doublet of doublets), and app
(apparent). Flash chromatography was performed with E. Merck
silica gel (43–60 µm). The eluent used is reported in parentheses.
Thin-layer chromatography (TLC) was performed on precoated
glass-backed plates (Merck Kieselgel 60 F254), and components
were visualized by observation under UV light or by treating the
plates with KMnO4/H2SO4 followed by heating.
Synthesis of 2-Alkynyl-2-hydroxy Carbonyl Compounds 9 and 10:
According to the preparation of 4a, a solution of 2-methyl-7-oxa-
bicyclo[4.1.0]heptane (6,[30] 850 mg, 7.59 mmol) in THF (32 mL)
was treated with (2-phenylethynyl)lithium [from nBuLi (8.36 mmol)
and phenylacetylene (0.83 mL, 7.59 mmol)] and BF3·Et2O
(0.95 mL, 7.59 mmol) at –78 °C for 3 h. The regioisomers 7 and 8
were separated by flash chromatography (10% EtOAc/P), and the
less polar fraction provided 7 (844 mg, 3.95 mmol, 52% yield) as a
colorless oil, which was a mixture of diastereomers. The more polar
fraction provided 8 (584 mg, 2.73 mmol, 36% yield) as a yellow oil,
which was a mixture of diastereomers. According to the prepara-
tion of 1a, a solution of 7 (211 mg, 0.99 mmol) in DMSO (2 mL)
was oxidized with IBX (840 mg, 3 mmol) at room temperature for
16 h. Purification by flash chromatography (5% EtOAc/P) provided
9a (86 mg, 0.38 mmol, 38% yield) and 9b (92 mg, 0.41 mmol, 41%
Representative Procedure for the Alkynylation of Oxiranes.[24] Syn-
thesis of trans-2-(2-Phenylethynyl)cyclohexanol (4a): A solution of
nBuLi in hexanes (2.5 , 4.8 mL, 12.1 mmol) was added dropwise
1
at –78 °C to
a solution of the phenylacetylene (1.21 mL,
yield), which were Ͼ95% pure by H NMR analysis. According to
11.0 mmol) in dry THF (40 mL). The resulting solution was stirred
for 30 min at –78 °C, and then BF3·Et2O (1.39 mL, 11.0 mmol) was
added, followed by a solution of cyclohexene oxide (1.08 g,
11.0 mmol) in THF (4 mL). The mixture was stirred at –78 °C for
4 h (until TLC analysis indicated complete consumption of the
starting material). The reaction was quenched by the addition of
saturated aqueous NH4Cl (25 mL), and the layers were separated.
The aqueous layer was extracted with diethyl ether (2ϫ50 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (10%
EtOAc/P) to afford 4a (1.61 g, 8.1 mmol, 81% yield). 1H NMR
(360 MHz, CDCl3): δ = 1.24–1.34 (m, 3 H), 1.49 (dq, J = 12.7,
2.9 Hz, 1 H), 1.68–1.73 (m, 1 H), 1.77–1.81 (m, 1 H), 2.04–2.10 (m,
2 H), 2.34 (br. s, 1 H), 2.44 (ddd, J = 11.6, 9.3, 3.8 Hz, 1 H), 3.55
(dt, J = 9.7, 4.1 Hz, 1 H), 7.28–7.30 (m, 3 H), 7.40–7.43 (m, 2 H)
ppm. 13C NMR (90.6 MHz, CDCl3): δ = 24.4, 25.0, 31.2, 33.3,
39.8, 73.7, 82.9, 91.0, 123.5, 128.1, 128.4, 131.9 ppm. The NMR
spectroscopic data are identical to those reported.[24]
the preparation of 1a, a solution of 8 (262 mg, 1.22 mmol) in
DMSO (2.5 mL) was oxidized with IBX (1.04 g, 3.70 mmol) at
room temperature for 24 h. 10a and 10b were separated by semipre-
parative HPLC [YMC ODS-A, 250 mmϫ20 mm, 50:50 H2O/
CH3CN, 15 mL/min, 254 nm; 10a, tR = 21.1 min; 10b, tR
=
22.7 min]. 10a was obtained as a colorless oil (61 mg, 0.27 mmol,
22% yield), which was contaminated to the extent of 20% with 10b.
10b was obtained as a colorless oil (83 mg, 0.37 mmol, 30%), which
was contaminated to the extent of 25% with 10a. 9a: 1H NMR
(360 MHz, CDCl3): δ = 1.14 (d, J = 6.6 Hz, 3 H), 1.54–1.69 (m, 2
H), 1.74–1.87 (m, 1 H), 2.11–2.19 (m, 2 H), 2.52–2.60 (m, 1 H),
3.14–3.24 (m, 1 H), 4.38 (s, 1 H), 7.30–7.34 (m, 3 H), 7.42–7.47 (m,
2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 14.5, 22.5, 36.9,
41.1, 43.3, 74.4, 87.3, 88.4, 122.2, 128.5, 128.9, 131.9, 209.6 ppm.
HRMS: calcd. for C15H16O2 228.1150, found 228.1150. 9b: 1H
NMR (500 MHz, CDCl3): δ = 1.39 (d, J = 7.4 Hz, 3 H), 1.73–1.76
(m, 1 H), 1.83–1.98 (m, 3 H), 2.05–2.10 (m, 1 H), 2.37–2.40 (m, 1
H), 2.94–2.99 (m, 1 H), 3.94 (s, 1 H), 7.28–7.32 (m, 3 H), 7.38–7.44
(m, 2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 18.6, 19.3, 34.1,
41.7, 43.0, 76.1, 87.6, 88.8, 122.6, 128.9, 129.4, 132.1, 210.1 ppm.
HRMS: calcd. for C15H16O2 228.1150, found 228.1142. 10a: 1H
NMR (500 MHz, CDCl3): δ = 0.91 (d, J = 7.2 Hz, 3 H), 1.82–1.99
(m, 3 H), 2.44–2.56 (m, 2 H), 2.71–2.76 (m, 1 H), 3.00–3.08 (m, 1
H), 4.18 (s, 1 H), 7.30–7.34 (m, 3 H), 7.44–7.46 (m, 2 H) ppm. 13C
NMR (90.6 MHz, CDCl3): δ = 12.3, 22.2, 29.1, 37.1, 44.0, 76.6,
86.9, 89.0, 122.2, 128.4, 128.9, 131.9, 208.3 ppm. HRMS: calcd.
for C15H16O2 228.1150, found 228.1139. 10b: 1H NMR (250 MHz,
CDCl3): δ = 1.28 (d, J = 6.0 Hz, 3 H), 1.63–2.10 (m, 5 H), 2.48–
2.56 (m, 1 H), 2.97–3.07 (m, 1 H), 4.30 (s, 1 H), 7.31–7.34 (m, 3
H), 7.44–7.47 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
16.0, 26.2, 31.0, 36.8, 46.9, 78.2, 85.7, 88.5, 122.2, 128.5, 128.9,
131.9, 207.8 ppm. LRMS (EI): m/z (%) = 228 (82) [M]+, 199 (69),
157 (50), 129 (100). HRMS: calcd. for C15H16O2 228.1150, found
228.1148.
Representative Procedure for the IBX-Mediated α-Hydroxylation.[26]
Synthesis of 2-Hydroxy-2-(2-phenylethynyl)cyclohexanone (1a): IBX
(0.42 mmol, 118 mg) was added to a solution of alcohol 4a (84 mg,
0.42 mmol) in DMSO (0.9 mL), and the reaction vial was sealed,
protected from light, and the mixture was stirred at room tempera-
ture. After 4 h, additional IBX (0.84 mmol, 235 mg) was added.
The reaction mixture was then stirred at room temperature for 11 h
(until TLC analysis indicated complete consumption of starting
material), diluted with CH2Cl2 (10 mL), and stirring was continued
for 30 min to precipitate the insoluble byproduct, which was re-
moved by filtration. The precipitate was washed with CH2Cl2
(2ϫ5 mL), and the combined filtrates were subsequently treated
with saturated aqueous NaHCO3 (20 mL). The phases were sepa-
rated, and the aqueous phase was extracted with CH2Cl2
(2ϫ5 mL). The combined organic phases were washed with water
(30 mL) and brine (30 mL), dried (Na2SO4), and concentrated un-
der reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (10% EtOAc/P) to afford 1a as a pale yellow oil
Representative Procedure for 3(2H)-Furanone Formation Catalyzed
by AuCl3 (Method A). 2-Phenyl-1-oxaspiro[4.4]non-2-en-4-one (2a):
A solution of AuCl3 (5 mol-%, 7.0 mg) in MeCN (0.5 mL) was
(72 mg, 0.34 mmol, 80% yield): Rf = 0.39 (20% EtOAc/P). 1H added to a solution of 1a (100 mg, 0.46 mmol) in CH2Cl2 (16 mL),
NMR (500 MHz, CDCl3): δ = 1.69 (dt, J = 13.6, 3.9 Hz, 1 H), 1.76 and the reaction vial was sealed. The resulting solution was stirred
(dt, J = 3.5, 13.1 Hz, 1 H), 1.91–1.93 (m, 1 H), 2.12 (tt, J = 13.6,
3.6 Hz, 1 H), 2.11–2.20 (m, 1 H), 2.57–2.61 (m, 2 H), 3.04 (dt, J =
at room temperature for 90 min (until TLC analysis indicated com-
plete consumption of the starting material). The solvent was re-
1642
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
FULL PAPER
moved under reduced pressure. Purification of the residue by flash
chromatography on silica gel (P/EtOAc, 85:15) gave furanone 2a as
a colorless solid (82 mg, 0.38 mmol, 83% yield); Rf = 0.42 (P/
CDCl3): δ = 0.90 (t, J = 6.8 Hz, 3 H), 1.28–1.41 (m, 4 H), 1.57–
1.70 (m, 2 H), 1.76–2.03 (m, 8 H), 2.46 (t, J = 7.6 Hz, 2 H), 5.39
(s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 14.0, 22.4, 25.7,
25.9, 31.0, 31.4, 37.0, 98.6, 102.4, 192.5, 206.8 ppm. LRMS (EI):
m/z (%) = 208 (19) [M]+, 167 (100), 124 (9), 96 (15). HRMS: calcd.
for C13H20O2 208.1463, found 208.1465.
1
EtOAc, 80:20). H NMR (360 MHz, CDCl3): δ = 1.95–2.10 (m, 8
H), 6.01 (s, 1 H) 7.50 (tt, J = 7.0, 1.5 Hz, 2 H), 7.57 (tt, J = 7.0,
1.5 Hz, 1 H), 7.84 (dt, J = 7.0, 1.5 Hz, 2 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 25.7 (t), 37.2 (t), 98.9 (s), 99.9 (d), 127.1
(d), 128.8 (d), 129.4 (s), 132.5 (d), 183.7 (s), 206.1 (s) ppm. LRMS
(EI): m/z (%) = 214 (42) [M]+, 173 (90), 102 (100), 77 (12). HRMS:
calcd. for C14H14O2 214.0994, found 214.0991.
2-(Cyclohexylmethyl)-1-oxaspiro[4.4]non-2-en-4-one (2g): Method
B: 75% yield. 1H NMR (360 MHz, CDCl3): δ = 0.95–1.05 (m, 2
H), 1.07–1.34 (m, 3 H), 1.67–2.04 (m, 14 H), 2.37 (d, J = 6.8 Hz,
2 H), 5.39 (s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 25.8,
26.2, 26.3, 33.2, 36.1, 37.1, 38.8, 98.6, 103.4, 191.3, 206.7 ppm.
LRMS (EI): m/z (%) = 234 (17) [M]+, 193 (100), 179 (9), 124 (14).
HRMS: calcd. for C15H22O2 234.1620, found 234.1620.
Representative Procedure for 3(2H)-Furanone Formation Catalyzed
by PtCl2 (Method B). 2-Phenyl-1-oxaspiro[4.4]non-2-en-4-one (2a):
PtCl2 (5 mol-%, 6.3 mg) was added to a solution of 1a (100 mg,
0.46 mmol) in toluene (16 mL), and the reaction vial was sealed.
The resulting pale yellow solution was stirred at 80 °C for 90 min
(until TLC analysis indicated complete conversion). The mixture
was concentrated under reduced pressure. Purification of the resi-
due by flash chromatography on silica gel (P/EtOAc, 85:15) gave
furanone 2a as a colorless solid (93 mg, 0.43 mmol, 93% yield).
2-Cyclohexyl-1-oxaspiro[4.4]non-2-en-4-one (2h): Method A: 25%
yield, Method B: 78% yield. 1H NMR (360 MHz, CDCl3): δ =
1.18–1.46 (m, 2 H), 1.67–2.07 (m, 14 H), 2.35–2.47 (m, 1 H), 5.36
(s, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 25.7, 25.8, 25.9,
30.0, 37.1, 39.8, 98.2, 100.6, 196.0, 206.9 ppm. LRMS (EI): m/z (%)
= 220 (15) [M]+, 179 (100). HRMS: calcd. for C14H20O2 220.1463,
found 220.1466.
Representative Procedure for 3(2H)-Furanone Formation Catalyzed
by AuCl3 with “wet” CH2Cl2 and Trimethylsilyl Ethers 14 (Method
C). 2-Phenyl-1-oxaspiro[4.4]non-2-en-4-one (2a): A solution of
AuCl3 (5 mol-%, 13.0 mg) in MeCN (0.5 mL) was added to a solu-
tion of trimethylsilyl ether 14a (150 mg, 0.52 mmol) in undistilled
CH2Cl2 (30 mL), and the flask was protected from light. The re-
sulting solution was stirred in an open flask at room temperature
for 120 min. The solvent was removed under reduced pressure. Pu-
rification of the residue by flash chromatography on silica gel (P/
EtOAc, 85:15) gave furanone 2a as a colorless solid (103 mg,
0.48 mmol, 93% yield).
2-[3-(Tetrahydropyran-2-yloxy)propyl]-1-oxaspiro[4.4]non-2-en-4-
one (2i): Method A: 11% yield, Method B: 82% yield. 1H NMR
(250 MHz, CDCl3): δ = 1.51–1.59 (m, 4 H), 1.64–1.71 (m, 1 H),
1.74–2.01 (m, 11 H), 2.59 (t, J = 7.6 Hz, 2 H), 3.38–3.54 (m, 2 H),
3.75–3.88 (m, 2 H), 4.57 (t, J = 3.4 Hz, 1 H), 5.42 (s, 1 H) ppm.
13C NMR (90.6 MHz, CDCl3): δ = 19.9, 25.7, 25.9, 26.6, 28.2, 31.0,
37.2, 62.7, 66.5, 98.9, 99.3, 102.8, 192.0, 206.9 ppm. LRMS (EI):
m/z (%) = 280 (1) [M]+, 152 (90), 137 (38), 85 (100). HRMS: calcd.
for C16H24O4 280.1675, found 280.1676.
2-(4-Fluorophenyl)-1-oxaspiro[4.4]non-2-en-4-one (2b): Method A:
70% yield, Method B: 90% yield. H NMR (360 MHz, CDCl3): δ
2-[3-(Tetrahydropyran-2-yloxy)methyl]-1-oxaspiro[4.4]non-2-en-4-
1
one (2j): Method A: 33% yield, Method B: 70% yield, Method C:
= 1.86–2.02 (m, 6 H), 2.05–2.16 (m, 2 H), 5.95 (s, 1 H), 7.16 (t, J
= 8.5 Hz, 2 H), 7.76–7.87 (m, 2 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 25.8, 37.3, 99.2, 99.8, 116.2 (d, J = 22 Hz), 125.8 (d,
J = 22 Hz), 129.5 (d, J = 9 Hz), 165.4 (d, J = 255 Hz), 182.6,
205.9 ppm. LRMS (EI): m/z (%) = 232 (48) [M]+, 191 (100), 120
(95). HRMS: calcd. for C14H13FO2 232.0900, found 232.0898.
1
82% yield. H NMR (360 MHz, CDCl3): δ = 1.57–1.76 (m, 4 H),
1.77–1.93 (m, 8 H), 1.94–2.08 (m, 2 H), 3.51–3.59 (m, 1 H), 3.80–
3.89 (m, 1 H), 4.32 (d, J = 16.1 Hz, 1 H), 4.50 (d, J = 16.1 Hz, 1
H), 4.72 (t, J = 3.2 Hz, 1 H), 5.65 (s, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 19.0, 25.4, 25.7, 30.3, 37.1, 62.2, 63.3, 98.6,
99.2, 102.5, 188.4, 206.1 ppm. LRMS (EI): m/z (%) = 252 (2)
[M]+, 211 (23), 152 (78), 85 (100). HRMS: calcd. for C14H20O4
252.1362, found 252.1352.
2-(2-Methoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one (2c): Method
A: 81% yield, Method B: 91% yield. 1H NMR (250 MHz, CDCl3):
δ = 1.86–2.11 (m, 8 H), 3.93 (s, 3 H), 6.35 (s, 1 H), 6.97–7.09 (m,
2 H), 7.45–7.55 (m, 1 H), 7.92 (dd, J = 7.8 Hz, J = 1.7 Hz, 1 H)
ppm. 13C NMR (90.6 MHz, CDCl3): δ = 25.9, 37.3, 55.7, 96.4,
105.1, 111.5, 118.3, 120.7, 128.4, 133.8, 159.3, 179.8, 207.8 ppm.
LRMS (EI): m/z (%) = 244 (40) [M]+, 203 (100), 132 (59). HRMS:
calcd. for C15H16O3 244.1099, found 244.1101.
2-(Cyclohex-1-enyl)-1-oxaspiro[4.4]non-2-en-4-one (2k): Method B:
1
68% yield. H NMR (360 MHz, CDCl3): δ = 1.62–1.69 (m, 2 H),
1.70–1.78 (m, 2 H), 1.80–1.93 (m, 6 H), 1.95–2.05 (m, 2 H), 2.21–
2.30 (m, 4 H), 5.49 (s, 1 H), 6.82–6.83 (m, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 21.7, 22.1, 24.7, 25.8, 26.0, 37.2, 98.0, 99.3,
128.5, 135.6, 184.3, 206.6 ppm. LRMS (EI): m/z (%) = 218 (33)
[M]+, 177 (100), 106 (38), 91 (23). HRMS: calcd. for C14H18O2
218.1307, found 218.1306.
2-(4-tert-Butylphenyl)-1-oxaspiro[4.4]non-2-en-4-one (2d): Method
A: 75% yield, Method B: 87% yield. 1H NMR (250 MHz, CDCl3):
δ = 1.33 (s, 9 H), 1.92–2.09 (m, 8 H), 5.96 (s, 1 H), 7.61 (dd, J =
6.4 Hz, J = 8.6 Hz, 4 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ =
25.8, 31.2, 35.2, 37.3, 98.9, 99.4, 125.9, 126.6, 127.1, 156.5, 183.9,
206.1 ppm. LRMS (EI): m/z (%) = 270.1 (28) [M]+, 229.1 (100),
143.2 (35). HRMS: calcd. for C18H22O2 270.1620, found 270.1618.
2-(Prop-2-enyl)-1-oxaspiro[4.4]non-2-en-4-one (2l): Method B: 40%
1
yield. H NMR (250 MHz, CDCl3): δ = 1.80–1.98 (m, 8 H), 2.00
(s, 3 H), 5.40 (s, 1 H), 5.58 (s, 1 H), 5.93 (s, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 19.0, 25.8, 37.2, 98.6, 101.5, 121.3, 134.0,
183.8, 207.0 ppm. LRMS (EI): m/z (%) = 178 (50) [M]+, 137 (100),
66 (90). HRMS: calcd. for C11H14O2 178.0994, found 178.0993.
2-(Thiophen-3-yl)-1-oxaspiro[4.4]non-2-en-4-one (2e): Method A:
1
76% yield, Method B: 65% yield. H NMR (250 MHz, CDCl3): δ
= 1.86–2.09 (m, 8 H), 5.81 (s, 1 H), 7.37–7.44 (m, 2 H), 7.96 (dd,
J = 2.5 Hz, J = 1.7 Hz, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3):
δ = 25.8, 37.3, 98.8, 99.8, 126.2, 127.2, 128.6, 132.1, 179.1,
206.0 ppm. LRMS (EI): m/z (%) = 220 (55) [M]+, 179 (99), 108
(100). HRMS: calcd. for C12H12O2S 220.0558, found 220.0560.
2-(Trimethylsilanyl)-1-oxaspiro[4.4]non-2-en-4-one (2m): Method B:
57% yield. H NMR (360 MHz, CDCl3): δ = 0.26 (s, 9 H), 1.72–
1
1.80 (m, 2 H), 1.83–2.00 (m, 6 H), 5.76 (s, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = –2.8, 26.1, 37.7, 97.2, 114.2, 201.1,
209.0 ppm. LRMS (EI): m/z (%) = 210 (25) [M]+, 169 (100), 98
(23), 83 (34), 73 (42). HRMS: calcd. for C11H18O2Si 210.1076,
found 210.1074.
2-Pentyl-1-oxaspiro[4.4]non-2-en-4-one (2f): Method A: 66% yield,
Method B: 65% yield, Method C: 76% yield. 1H NMR (250 MHz,
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1643

J. T. Binder, B. Crone, S. F. Kirsch, C. Liébert, H. Menz
FULL PAPER
5-Phenyl-2,2-dipropylfuran-3-one (2o): Method B: 51% yield. 1H
NMR (250 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 6 H), 1.28–1.41
(m, 4 H), 1.82 (dd, J = 9.0 Hz, J = 7.6 Hz, 4 H), 6.00 (s, 1 H),
7.45–7.59 (m, 3 H), 7.84 (dd, J = 8.1 Hz, J = 1.4 Hz, 2 H) ppm.
13C NMR (90.6 MHz, CDCl3): δ = 14.3, 16.3, 38.7, 94.6, 101.4,
127.3, 129.0, 129.2, 132.7, 184.8, 206.9 ppm. LRMS (EI): m/z (%)
= 244 (2) [M]+, 202 (100), 173 (82), 102 (64). HRMS: calcd. for
C16H20O2 244.1463, found 244.1462.
7.58 (m, 3 H), 7.82 (td, J = 7.1 Hz, J = 1.5 Hz, 2 H) ppm. 13C
NMR (90.6 MHz, CDCl3): δ = 14.6, 23.2, 33.7, 35.8, 44.3, 99.8,
100.7, 127.4, 129.2, 129.6, 132.7, 184.4, 206.4 ppm. LRMS (EI):
m/z (%) = 228 (18) [M]+, 187 (44), 173 (60), 102 (100). HRMS:
calcd. for C15H16O2 228.1150, found 228.1153. According to
Method B, a solution of 10a (dr 80:20, 54 mg, 0.24 mmol) in tolu-
ene (8 mL) was treated with PtCl2 (5 mol-%, 3.2 mg) at 80 °C for
5 h. 1H NMR analysis of the crude reaction mixture indicated a
13a/13b ratio of 80:20. Purification of the crude product by flash
chromatography on silica gel (P/EtOAc, 85:15) provided 13a in
88% yield (48 mg, 0.21 mmol). According to Method B, a solution
of 9b (dr Ͼ 95:5, 89 mg, 0.39 mmol) in toluene (13 mL) was treated
with PtCl2 (5 mol-%, 5.0 mg) at 80 °C for 4 h. 1H NMR analysis
of the crude reaction mixture indicated a 13b/13a ratio of Ͼ95:5.
Purification of the crude product by flash chromatography on silica
gel (P/EtOAc, 85:15) provided 13b in 76% yield (68 mg,
0.30 mmol). 1H NMR (360 MHz, CDCl3): δ = 0.87 (d, J = 6.8 Hz,
3 H), 1.60–1.71 (m, 1 H), 1.80–2.09 (m, 4 H), 2.17–2.26 (m, 1 H),
2.29–2.40 (m, 1 H), 6.04 (s, 1 H), 7.46–7.57 (m, 3 H), 7.83 (dt, J =
1.6, 7.0 Hz, 2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 11.9,
23.2, 33.6, 36.5, 4.7, 100.5, 101.3, 127.2, 129.0, 129.3, 132.6, 184.3,
205.8 ppm. LRMS (EI): m/z (%) = 228 (20) [M]+, 187 (38), 173
(65), 102 (100). HRMS: calcd. for C15H16O2 228.1150, found
228.1144. According to Method B, a solution of 10b (dr 75:25,
41 mg, 0.18 mmol) in toluene (6 mL) was treated with PtCl2 (5 mol-
%, 2.4 mg) at 80 °C for 6 h. 1H NMR analysis of the crude reaction
mixture indicated a 13b/13a ratio of 75:25. Purification of the crude
product by flash chromatography on silica gel (P/EtOAc, 85:15)
provided 13b in 85% yield (35 mg, 0.15 mmol).
2-Phenyl-1-oxaspiro[4.5]dec-2-en-4-one (2q): Method B: 85% yield.
1H NMR (360 MHz, CDCl3): δ = 1.67–1.86 (m, 10 H), 5.98 (s, 1
H), 7.46–7.58 (m, 3 H), 7.84–7.88 (m, 2 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 22.1, 24.7, 32.1, 90.9, 99.4, 127.3, 129.0,
129.6, 132.6, 183.6, 207.0 ppm. LRMS (EI): m/z (%) = 228 (39)
[M]+, 173 (100), 102 (71). HRMS: calcd. for C15H16O2 228.1150,
found 228.1151.
2-Phenyl-1-oxaspiro[4.6]undec-2-en-4-one (2r): Method B: 50%
1
yield. H NMR (360 MHz, CDCl3): δ = 1.68–2.00 (m, 12 H), 5.91
(s, 1 H), 7.45–7.57 (m, 3 H), 7.81–7.86 (m, 2 H) ppm. 13C NMR
(90.6 MHz, CDCl3): δ = 22.8, 29.3, 35.6, 93.7, 98.7, 127.2, 128.9,
129.6, 132.6, 183.4, 208.2 ppm. LRMS (EI): m/z (%) = 242 (49)
[M]+, 173 (100), 102 (71). HRMS: calcd. for C16H18O2 242.1307,
found 242.1306.
2,2,5-Triphenylfuran-3-one (2s): Method B: 56% yield. 1H NMR
(360 MHz, CDCl3): δ = 6.12 (s, 1 H), 7.31–7.40 (m, 6 H), 7.51–
7.60 (m, 7 H), 7.98 (d, J = 7.0 Hz, 2 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 93.1, 99.9, 126.8, 127.4, 128.6, 128.6, 128.9, 129.1,
133.1, 138.5, 184.3, 202.2 ppm. LRMS (EI): m/z (%) = 312 (65)
[M]+, 165 (64), 105 (100), 77 (29). HRMS: calcd. for C22H16O2
312.1150, found 312.1148.
Representative Procedure for 3-Pyrrolone Formation Catalyzed by
PtCl2 (Method D). 1,2-Diphenyl-1-azaspiro[4.4]non-2-en-4-one
(3aa): PtCl2 (5 mol-%, 3.2 mg) was added to a solution of 1a
(50 mg, 0.23 mmol) and aniline (27.8 mg, 0.30 mmol) in toluene
(8 mL), and the reaction vial was sealed, protected from light, and
stirred at room temperature for 30 min. The reaction mixture was
then heated to 100 °C and stirred at 100 °C for 24 h. The mixture
was concentrated under reduced pressure. Purification of the resi-
due by flash chromatography on silica gel (P/EtOAc, 70:30) gave
3-pyrrolone 3aa as a colorless solid (49.9 mg, 0.17 mmol, 75%
Attempted Synthesis of Bullatenone (2n): According to Method A,
a solution of 3-hydroxy-3-methyl-5-phenylpent-4-yn-2-one (1n,
100 mg, 0.53 mmol) in CH2Cl2 (17 mL) was treated with AuCl3
(5 mol-%, 7.2 mg) at 23 °C for 4 h. Purification of the crude prod-
uct by repeated flash chromatography on silica gel (P/EtOAc,
80:20) provided bullatenone (2n), 3-methylene-1-phenylpentane-
1,4-dione (11), and (E)-3-methyl-1-phenylpent-2-ene-1,4-dione
1
(12). Bullatenone (2n):[48] 7% yield. H NMR (250 MHz, CDCl3):
δ = 1.49 (s, 6 H), 5.96 (s, 1 H), 7.43–7.55 (m, 3 H), 7.80–7.84 (m,
2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ =23.1, 88.8, 98.4,
127.1, 128.8, 129.0, 132.6, 183.5, 207.1 ppm. 3-Methylene-1-phenyl-
1
yield). Rf = 0.65 (P/EtOAc, 70:30). H NMR (250 MHz, CDCl3):
δ = 1.50–1.61 (m, 2 H), 1.81–1.92 (m, 2 H), 2.00–2.23 (m, 4 H),
5.57 (s, 1 H), 7.03–7.07 (m, 2 H), 7.24–7.33 (m, 3 H) ppm. 13C
NMR (62.9 MHz, CDCl3): δ = 26.5, 36.5, 80.9, 101.0, 127.2, 128.4,
128.9, 129.2, 129.3, 130.3, 131.7, 140.3, 175.1, 205.8 ppm. LRMS
(EI): m/z (%) = 289 (30) [M]+, 248 (100), 130 (29), 77 (21). HRMS:
calcd. for C20H19NO 289.1467, found 289.1466.
1
pentane-1,4-dione (11): 32% yield. H NMR (360 MHz, CDCl3): δ
= 2.42 (s, 3 H), 3.96 (s, 3 H), 5.94 (s, 1 H), 6.24 (s, 1 H), 7.46 (t, J
= 7.9 Hz, 2 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 2 H)
ppm. 13C NMR (90.6 MHz, CDCl3): δ =25.7 (CH3), 41.1 (CH2),
128.5 (CH2), 128.7 (CH), 129.0 (CH), 133.6 (CH), 137.0 (C), 143.8
(C), 197.5 (C), 199.1 (C) ppm. (E)-3-Methyl-1-phenylpent-2-ene-1,4-
1-(3-Nitrophenyl)-2-phenyl-1-azaspiro[4.4]non-2-en-4-one
(3ab):
1
Method D: 35% yield. 1H NMR (250 MHz, CDCl3): δ = 1.53–1.59
(m, 2 H), 1.86–2.03 (m, 4 H), 2.11–2.23 (m, 2 H), 5.64 (s, 1 H),
7.22–7.40 (m, 7 H), 7.89–7.91 (m, 1 H), 8.02–8.06 (m, 1 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 26.5, 36.6, 80.9, 103.3, 121.6,
123.1, 128.7, 128.9, 130.0, 130.9, 130.9, 134.7, 142.0, 148.6, 174.6,
205.5 ppm. LRMS (EI): /z (%) = 334 (25) [M]+, 293 (100), 175 (22),
84 (72). HRMS: calcd. for C20H18N2O3 334.1317, found 334.1317.
dione (12): 28% yield. H NMR (250 MHz, CDCl3): δ = 2.09 (s, 3
H), 2.48 (s, 3 H), 7.44 (s, 1 H), 7.48–7.62 (m, 3 H), 7.93–7.56 (m,
2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 14.3 (CH2), 26.6
(CH2), 129.0 (CH), 129.3 (CH), 131.9 (CH), 134.1 (CH), 137.7 (C),
147.4 (C), 193.5 (C), 200.3 (C) ppm. HRMS: calcd. for C12H12O2
188.0837, found 188.0839. The double-bond geometry was deter-
mined by NOESY experiments.
Synthesis of 6-Methyl-2-phenyl-1-oxaspiro[4.4]non-2-en-4-one (13): 1-Benzyl-2-phenyl-1-azaspiro[4.4]non-2-en-4-one (3ac): Method D:
1
According to Method B, a solution of 9a (dr Ͼ 95:5, 60 mg,
0.26 mmol) in toluene (9 mL) was treated with PtCl2 (5 mol-%,
3.8 mg) at 80 °C for 4 h. 1H NMR analysis of the crude reaction
mixture indicated a 13a/13b ratio of Ͼ95:5. Purification of the
crude product by flash chromatography on silica gel (P/EtOAc,
85:15) provided 13a in 74% yield (44 mg, 0.19 mmol). 1H NMR
(360 MHz, CDCl3): δ = 1.00 (d, J = 7.11 Hz, 3 H), 1.61–1.75 (m,
37% yield. H NMR (360 MHz, CDCl3): δ = 1.59–1.68 (m, 2 H),
1.83–1.92 (m, 4 H), 2.04–2.09 (m, 2 H), 4.62 (s, 2 H), 5.23 (s, 1 H),
7.13–7.17 (m, 2 H), 7.20–7.28 (m, 3 H), 7.32–7.41 (m, 5 H) ppm.
13C NMR (90.6 MHz, CDCl3): δ = 26.4, 35.8, 47.3, 79.1, 98.7,
126.5, 127.5, 127.7, 128.7, 128.8, 130.3, 131.8, 138.7, 176.8,
205.1 ppm. LRMS (EI): m/z (%) = 303 (39) [M]+, 262 (34), 212
(100), 91 (45). HRMS: calcd. for C21H21NO 303.1623, found
1 H), 1.85–2.24 (m, 5 H), 2.37–2.52 (m, 1 H), 5.93 (s, 1 H), 7.44– 303.1624.
1644
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
1-Isobutyl-2-phenyl-1-azaspiro[4.4]non-2-en-4-one (3ad): Method D:
FULL PAPER
129.8, 137.9, 174.8, 205.1 ppm. LRMS (EI): m/z (%) = 327 (18)
[M]+, 242 (54), 227 (58), 198 (100). HRMS: calcd. for C20H25NO3
327.1834, found 327.1832.
1
33% yield. H NMR (360 MHz, CDCl3): δ = 0.73 (d, J = 6.6 Hz,
6 H), 1.58–1.70 (m, 1 H), 1.78–1.86 (m, 2 H), 1.88–1.95 (m, 2 H),
1.97–2.13 (m, 4 H), 3.15 (d, J = 8.0 Hz, 2 H), 5.06 (s, 1 H), 7.34–
7.37 (m, 2 H), 7.43–7.45 (m, 3 H) ppm. 13C NMR (90.6 MHz,
CDCl3): δ = 20.3, 26.7, 28.0, 35.5, 51.3, 78.9, 98.4, 127.6, 128.7,
129.9, 132.8, 176.5, 205.1 ppm. LRMS (EI): m/z (%) = 269 (25)
[M]+, 226 (100). HRMS: calcd. for C18H23NO 269.1780, found
269.17780.
Supporting Information (see also the footnote on the first page of
1
this article): H NMR spectra of 2a–s, 13a–b, and 13aa–13ja, and
copies of 13C NMR spectra of 2a–s, 13a–b, and 3aa–3ja.
1-Isopropyl-2-phenyl-1-azaspiro[4.4]non-2-en-4-one (3ae): Method
D: 81% yield. 1H NMR (250 MHz, CDCl3): δ = 1.13 (d, J =
7.0 Hz, 6 H), 1.81–2.11 (m, 8 H), 3.66–3.77(m, 1 H), 4.94 (s, 1 H),
7.33–7.45 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 24.2,
26.8, 35.2, 48.1, 79.5, 99.4, 128.0, 128.2, 129.5, 134.0, 176.5,
204.7 ppm. LRMS (EI): m/z (%) = 255 (60) [M]+, 212 (100), 110
(33), 67 (34). HRMS: calcd. for C17H21NO 255.1623, found
255.1623.
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie
(FCI) and the Deutsche Forschungsgemeinschaft (DFG). We are
grateful to Andrea Rothballer and Markus Scheerer for excellent
technical assistance. We also thank Olaf Ackermann for HPLC as-
sistance. S. F. K. thanks Prof. Dr. Thorsten Bach (TU München)
and Dr. Klaas Lohmann (BASF AG) for helpful discussions and
great ideas.
2-(4-tert-Butylphenyl)-1-phenyl-1-azaspiro[4.4]non-2-en-4-one (3da):
1
Method D: 52% yield. H NMR (250 MHz, CDCl3): δ = 1.25 (s,
9 H), 1.45–1.51 (m, 2 H), 1.79–1.86 (m, 2 H), 2.00–2.13 (m, 4 H),
5.52 (s, 1 H), 7.01–7.05 (m, 2 H), 7.22–7.29 (m, 7 H) ppm. 13C
NMR (62.9 MHz, CDCl3): δ = 26.5, 31.2, 34.9, 36.5, 81.0, 100.6,
125.4, 127.2, 128.6, 128.7, 129.2, 129.3, 140.5, 153.9, 175.0,
205.7 ppm. LRMS (EI): m/z (%) = 345 (5) [M]+, 304 (18), 145 (21),
121 (100). HRMS: calcd. for C24H27NO 345.2093, found 345.2095.
[1] a) L. E. Overman, L. D. Pennington, J. Org. Chem. 2003, 68,
7143–7157; b) L. E. Overman, Acc. Chem. Res. 1992, 25, 352–
359.
[2] For selected reviews, see: a) K. C. Nicolaou, D. J. Edmonds,
P. G. Bulger, Angew. Chem. 2006, 118, 7292–7344; Angew.
Chem. Int. Ed. 2006, 45, 7134–7186; b) L. F. Tietze, Chem. Rev.
1996, 96, 115–136; c) S. E. Denmark, A. Thorarensen, Chem.
Rev. 1996, 96, 137–166; d) G. A. Molander, C. R. Harris,
Chem. Rev. 1996, 96, 307–338; e) L. F. Tietze, U. Beifuss, An-
gew. Chem. 1993, 105, 137–170; Angew. Chem. Int. Ed. Engl.
1993, 32, 131–163.
[3] a) H. Menz, S. F. Kirsch, Org. Lett. 2006, 8, 4795–4797; b) J. T.
Binder, S. F. Kirsch, Org. Lett. 2006, 8, 2151–2153; c) M. H.
Suhre, M. Reif, S. F. Kirsch, Org. Lett. 2005, 7, 3925–3927.
[4] For leading references, see: a) D. S. Tan, Nat. Chem. Biol. 2005,
1, 74–84; b) A. B. Beeler, S. E. Schaus, J. A. Porco Jr, Curr.
Opin. Chem. Biol. 2005, 9, 277–284; c) M. D. Burke, E. M. Ber-
ger, S. L. Schreiber, J. Am. Chem. Soc. 2004, 126, 14095–14104;
d) K. Young-kwon, A. A. Midori, A. Takayoshi, J. O. La-
menzo, E. F. Dean, N. Patterson, P. A. Clemons, S. L. Schrei-
ber, J. Am. Chem. Soc. 2004, 126, 14740–14745; e) M. D. Burke,
S. L. Schreiber, Angew. Chem. 2003, 116, 48–60; Angew. Chem.
Int. Ed. 2003, 43, 46–58; f) M. D. Burke, E. M. Berger, S. L.
Schreiber, Science 2003, 302, 613–618; g) E. A. Couladouros,
A. T. Strongilos, Angew. Chem. 2002, 114, 3829–3832; Angew.
Chem. Int. Ed. 2002, 41, 3677–3680; h) S. L. Schreiber, Science
2000, 287, 1964–1969.
[5] For recent examples, see inter alia: a) A. R. Yeager, G. K. Min,
J. A. Porco Jr, S. E. Schaus, Org. Lett. 2006, 8, 5065–5068; b)
N. Kumar, M. Kiuchi, J. A. Tallarico, S. L. Schreiber, Org. Lett.
2005, 7, 2535–2538.
[6] a) A. Fürstner, Angew. Chem. 2003, 115, 3706–3728; Angew.
Chem. Int. Ed. 2003, 42, 3582–3603; b) J. R. Liddell, Nat. Prod.
Rep. 2002, 19, 773–781; c) D. O. Hagan, Nat. Prod. Rep. 2000,
17, 435–446; d) D. L. Boger, C. W. Boyce, M. A. Labroli, C. A.
Sehon, Q. Jin, J. Am. Chem. Soc. 1999, 121, 54–62; e) R. J.
Sundberg, in: Comprehensive Heterocyclic Chemistry II, vol. 2
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Elsevier,
Oxford, 1996, p. 119.
1-(3-Chlorophenyl)-2-(thiophen-3-yl)-1-azaspiro[4.4]non-2-en-4-one
(3ef): Method D: 73% yield. 1H NMR (360 MHz, CDCl3): δ =
1.40–1.45 (m, 2 H), 1.74–1.92 (m, 4 H), 2.01–2.09 (m, 2 H), 5.50
(s, 1 H), 6.84 (dd, J = 1.8, 4.5 Hz, 1 H), 6.90 (td, J = 1.6, 7.5 Hz,
1 H), 7.06 (t, J = 1.9 Hz, 1 H), 7.13–7.17 (m, 2 H), 7.19–7.24 (m,
2 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 26.4, 36.4, 80.7,
100.2, 126.3, 127.6, 127.7, 128.0, 128.8, 129.4, 130.3, 132.1, 135.0,
141.7, 168.4, 205.2 ppm. LRMS (EI): m/z (%) = 329 (32) [M]+, 290
(37), 288 (100), 164 (24). HRMS: calcd. for C18H16ClNO 329.0641,
found 329.0581.
1-(4-Isopropylphenyl)-2-(thiophen-3-yl)-1-azaspiro[4.4]non-2-en-4-
1
one (3eg): Method D: 78% yield. H NMR (250 MHz, CDCl3): δ
= 1.25 (d, J = 6.9 Hz, 3 H), 1.40–1.33 (m, 2 H), 1.77–1.83 (m, 2
H), 1.94–2.17 (m, 4 H), 2.86–2.98 (m, 1 H), 5.52 (s, 1 H), 6.91 (dd,
J = 1.4, 5.0 Hz, 1 H), 7.00–7.04 (m, 2 H), 7.11–7.20 (m, 4 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 24.0, 26.3, 33.8, 36.3, 80.7, 98.6,
125.7, 127.4, 128.0, 128.7, 129.5, 132.4, 137.6, 148.9, 168.5,
205.3 ppm. LRMS (EI): m/z (%) = 337 (30) [M]+, 296 (100), 186
(18). HRMS: calcd. for C21H23NOS 337.1500, found 337.1507.
1-(4-Methoxyphenyl)-2-pentyl-1-azaspiro[4.4]non-2-en-4-one (3fh):
1
Method D: 73% yield. H NMR (250 MHz, CDCl3): δ = 0.82 (t,
J = 6.5 Hz, 6 H), 1.18–1.33 (m, 6 H), 1.43–1.55 (m, 2 H), 1.71–
1.92 (m, 4 H), 1.98–2.06 (m, 4 H), 2.14 (t, J = 7.7 Hz, 2 H), 3.84
(s, 3 H), 5.11 (s, 1 H), 6.90–6.94 (m, 2 H), 7.05–7.08 (m, 2 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 14.0, 22.4, 26.0, 26.9, 29.1, 31.5,
35.9, 55.6, 79.9, 96.1, 114.7, 130.6, 131.3, 159.5, 179.0, 204.7 ppm.
LRMS (EI): m/z (%) = 313 (34) [M]+, 272 (100), 257 (29), 229 (22).
HRMS: calcd. for C20H27NO2 313.2042, found 313.2039.
1-Phenyl-2-[(tetrahydropyran-2-yloxy)methyl]-1-azaspiro[4.4]non-2-
en-4-one (3ja): Method D: 44 % yield. 1H NMR (360 MHz,
CDCl3): δ = 1.28–1.33 (m, 2 H), 1.45–1.68 (m, 4 H), 1.76 (br. s, 4
H), 1.88–1.96 (m, 2 H), 2.03–2.07 (m, 2 H), 3.42–3.48 (m, 1 H),
3.62–3.67 (m, 1 H), 4.02 (d, J = 15.2 Hz, 1 H), 4.31 (d, J = 15.2 Hz,
1 H), 4.55 (t, J = 3.1 Hz, 1 H), 5.40 (s, 1 H), 7.17–7.19 (m, 2 H),
7.39–7.44 (m, 3 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 18.7,
25.4, 26.0, 30.2, 35.9, 61.8, 62.5, 80.4, 96.8, 98.3, 128.8, 129.7,
[7] a) X. L. Hou, Z. Yang, H. N. C. Wong, in: Progress in Hetero-
cyclic Chemistry, vol. 15 (Eds.: G. W. Gribble, T. L. Gilchrist),
Pergamon, Oxford, 2003, p. 167–205; b) D. M. X. Donnelly,
M. J. Meegan, in: Comprehensive Heterocyclic Chemistry, vol.
4 (Eds.: A. R. Katritzky, C. W. Rees), Pergamon, Oxford, 1984,
p. 657–712; c) B. H. Lipshutz, Chem. Rev. 1986, 86, 795–819;
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1645

J. T. Binder, B. Crone, S. F. Kirsch, C. Liébert, H. Menz
FULL PAPER
d) F. A. Dean, Naturally Occurring Oxygen Ring Compounds,
Butterworth, London, 1963; e) F. Q. Alali, X.-X. Liu, J. L.
McLaughlin, J. Nat. Prod. 1999, 62, 504–540.
For recent reviews, see: a) S. F. Kirsch, Org. Biomol. Chem.
2006, 4, 2076–2080; b) R. C. D. Brown, Angew. Chem. 2005,
117, 872–874; Angew. Chem. Int. Ed. 2005, 44, 850–852; c) G.
Balme, Angew. Chem. 2004, 116, 6396–6399; Angew. Chem. Int.
Ed. 2004, 43, 6238–6241; d) B. Gabriele, G. Salerno, M. Costa,
Synlett 2004, 2468–2483.
For selected examples, see: a) O. V. Larionov, A. de Meijere,
Angew. Chem. 2005, 117, 5809–5813; Angew. Chem. Int. Ed.
2005, 44, 5664–5667; b) Y. Yamamoto, H. Hayashi, T. Saigoku,
H. Nishiyama, J. Am. Chem. Soc. 2005, 127, 10804–10805; c)
D. Suzuki, Y. Nobe, Y. Watai, R. Tanaka, Y. Takayama, F.
Sato, H. Urabe, J. Am. Chem. Soc. 2005, 127, 7474–7479; d) S.
Kamijo, C. Kanazawa, Y. Yamamoto, J. Am. Chem. Soc. 2005,
127, 9260–9266; e) D. Tejedor, D. González-Cruz, A. Santos-
Expósito, J. J. Marrero-Tellado, P. de Armas, F. García-Tel-
lado, Chem. Eur. J. 2005, 11, 3502–3510; f) R. Dhawan, B. A.
Arndtsen, J. Am. Chem. Soc. 2004, 126, 468–469; g) C.-K.
Jung, J.-C. Wang, M. J. Krische, J. Am. Chem. Soc. 2004, 126,
4118–4119; h) X. Han, R. A. Widenhoefer, J. Org. Chem. 2004,
69, 1738–1740; i) A. W. Sromek, A. V. KelЈin, V. Gevorgyan,
Angew. Chem. 2004, 116, 2330–2332; Angew. Chem. Int. Ed.
2004, 43, 2280–2282; j) D. Tejedor, F. García-Tellado, J. J. Mar-
rero-Tellado, P. de Armas, Chem. Eur. J. 2003, 9, 3122–3131;
k) S. Ma, J. Zhang, L. Lu, Chem. Eur. J. 2003, 9, 2447–2456.
For reviews, see: a) C. Bruneau, Angew. Chem. 2005, 117, 2380–
2386; Angew. Chem. Int. Ed. 2005, 44, 2328–2334; b) A. M.
Echavarren, C. Nevado, Chem. Soc. Rev. 2004, 33, 431–436; c)
M. Méndez, V. Mamane, A. Fürstner, Chemtracts 2003, 16,
397; d) M. Méndez, A. M. Echavarren, Eur. J. Org. Chem.
2002, 15–28.
For leading references on alkene activation, see: a) C. Brouwer,
C. He, Angew. Chem. 2006, 118, 1776–1779; Angew. Chem. Int.
Ed. 2006, 45, 1744–1747; b) C.-G. Yang, C. He, J. Am. Chem.
Soc. 2005, 127, 6966–6967; c) C. F. Bender, R. A. Widenhoefer,
J. Am. Chem. Soc. 2005, 127, 1070–1071.
For selected references on gold-catalyzed alkyne activation, see:
a) J. Sun, M. P. Conley, L. Zhang, S. A. Kozmin, J. Am. Chem.
Soc. 2006, 128, 9705–9710; b) C. Ferrer, A. M. Echavarren, An-
gew. Chem. 2006, 118, 1123–1127; Angew. Chem. Int. Ed. 2006,
45, 1105–1109; c) J. Barluenga, A. Diéguez, A. Fernández, F.
Rodríguez, F. J. Fañanás, Angew. Chem. 2006, 118, 2145–2147;
Angew. Chem. Int. Ed. 2006, 45, 2091–2093; d) N. Marion, S.
Díez-González, P. de Frémont, A. R. Noble, S. P. Nolan, An-
gew. Chem. 2006, 118, 3729–3732; Angew. Chem. Int. Ed. 2006,
45, 3647–3650; e) P. Dube, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 12062–12063; f) E. Genin, P. Y. Toullec, S. Antoniotti, C.
Brancour, J.-P. Genet, V. Michelet, J. Am. Chem. Soc. 2006,
128, 3112–3113; g) D. Hildebrandt, G. Dyker, J. Org. Chem.
2006, 71, 6728–6733; h) T. J. Harrison, J. A. Kozak, M. Cor-
bella-Pane, G. R. Dake, J. Org. Chem. 2006, 71, 4525–4529; i)
A. Buzas, F. Gagosz, Org. Lett. 2006, 8, 515–518; j) A.
Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006–3019; k) C.
Nieto-Oberhuber, S. López, M. P. Muñoz, E. Jiménez-Núñez,
E. Buñuel, D. J. Cárdenas, A. M. Echavarren, Chem. Eur. J.
2006, 12, 1694–1702; l) A. S. K. Hashmi, R. Salathé, W. Frey,
Chem. Eur. J. 2006, 12, 6991–6996; m) A. S. K. Hashmi, J. P.
Weyrauch, E. Kurpejovic, T. M. Frost, B. Miehlich, W. Frey,
J. W. Bats, Chem. Eur. J. 2006, 12, 5806–5814; n) A. S. K.
Hashmi, M. Rudolph, J. P. Weyrauch, M. Wölfle, W. Frey, J. W.
Bats, Angew. Chem. 2005, 117, 2858–2861; Angew. Chem. Int.
Ed. 2005, 44, 2798–2801; o) M. J. Johansson, D. J. Gorin, S. T.
Staben, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 18002–18003;
p) L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2005, 127, 6962–
6963; q) X. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc.
2005, 127, 5802–5803; r) C. Nevado, A. M. Echavarren, Chem.
Eur. J. 2005, 11, 3155–3164; s) C. Nieto-Oberhuber, M.
Paz Muñoz, E. Buñuel, C. Nevado, D. J. Cárdenas, A. M.
Echavarren, Angew. Chem. 2004, 116, 2456–2460; Angew.
Chem. Int. Ed. 2004, 43, 2402–2406; t) L. Zhang, S. A. Kozmin,
J. Am. Chem. Soc. 2004, 126, 11806–11807; u) A. S. K.
Hashmi, T. M. Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122,
11553–11554.
[8]
[13]
For leading references on platinum-catalyzed alkyne activation,
see: a) B. G. Pujanauski, B. A. Bhanu Prasad, R. Sarpong, J.
Am. Chem. Soc. 2006, 128, 6786–6787; b) A. Fürstner, C.
Aissa, J. Am. Chem. Soc. 2006, 128, 6306–6307; c) A. Fürstner,
P. W. Davies, J. Am. Chem. Soc. 2005, 127, 15024–15025; d) A.
Fürstner, P. W. Davies, T. Gress, J. Am. Chem. Soc. 2005, 127,
8244–8245; e) B. A. Bhanu Prasad, F. K. Yoshimoto, R. Sar-
pong, J. Am. Chem. Soc. 2005, 127, 12468–12469; f) A. S. K.
Hashmi, J. P. Weyrauch, M. Rudolph, E. Kurpejovi, Angew.
Chem. 2004, 116, 6707–6709; Angew. Chem. Int. Ed. 2004, 43,
6545–6547; g) V. Mamane, T. Gress, H. Krause, A. Fürstner, J.
Am. Chem. Soc. 2004, 126, 8654–8655; h) T. J. Harrison, G. R.
Dake, Org. Lett. 2004, 6, 5023–5026; i) F. Marion, J. Coulomb,
C. Courillon, L. Fensterbank, M. Malacria, Org. Lett. 2004, 6,
1509–1511; j) B. Martin-Matute, C. Nevado, D. J. Cardenas,
A. M. Echavarren, J. Am. Chem. Soc. 2003, 125, 5757–5766; k)
M. Mendez, M. P. Munoz, C. Nevado, D. J. Cardenas, A. M.
Echavarren, J. Am. Chem. Soc. 2001, 123, 10511–10520.
For reviews on gold-catalyzed reactions, see: a) S. Ma, S. Yu,
Z. Gu, Angew. Chem. 2005, 118, 206–209; Angew. Chem. Int.
Ed. 2005, 45, 200–203; b) A. S. K. Hashmi, Angew. Chem.
2005, 117, 7150–7154; Angew. Chem. Int. Ed. 2005, 44, 6990–
6993; c) A. Hoffmann-Röder, N. Krause, Org. Biomol. Chem.
2005, 3, 387–391; d) A. Arcadi, S. D. Giuseppe, Curr. Org.
Chem. 2004, 8, 795–812; e) A. S. K. Hashmi, Gold Bull. 2004,
37, 51–65; f) A. S. K. Hashmi, Gold Bull. 2003, 36, 3–9; g) G.
Dyker, Angew. Chem. 2000, 112, 4407–4409; Angew. Chem. Int.
Ed. 2000, 39, 4237–4239.
For the construction of heterocycles by noble-metal-catalyzed
skeletal reorganization, see inter alia: a) V. Belting, N. Krause,
Org. Lett. 2006, 8, 4489–4492; b) X. Han, R. A. Widenhoefer,
Angew. Chem. 2006, 118, 1779–1781; Angew. Chem. Int. Ed.
2006, 45, 1747–1749; c) N. Morita, N. Krause, Angew. Chem.
2006, 118, 1930–1933; Angew. Chem. Int. Ed. 2006, 45, 1897–
1899; d) Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian,
R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066–9073;
e) X. Yao, C.-J. Li, Org. Lett. 2006, 8, 1953–1955; f) B. Gockel,
N. Krause, Org. Lett. 2006, 8, 4485–4488; g) Y. Liu, M. Liu, S.
Guo, H. Tu, Y. Zhou, H. Gao, Org. Lett. 2006, 8, 3445–3448;
h) A. W. Sromek, M. Rubina, V. Gevorgyan, J. Am. Chem. Soc.
2005, 127, 10500–10501; i) D. J. Gorin, N. R. Davis, F. D. To-
ste, J. Am. Chem. Soc. 2005, 127, 11260–11261; j) M. Alfonsi,
A. Arcadi, M. Aschi, G. Bianchi, F. Marinelli, J. Org. Chem.
2005, 70, 2265–2273; k) Y. Liu, F. Song, Z. Song, M. Liu, B.
Yan, Org. Lett. 2005, 7, 5409–5412; l) N. Morita, N. Krause,
Org. Lett. 2004, 6, 4121–4123; m) A. S. K. Hashmi, J. P. Wey-
rauch, W. Frey, J. W. Bats, Org. Lett. 2004, 6, 4391–4394; n) N.
Krause, A. Hoffmann-Röder, J. Canisius, Synthesis 2002, 1759–
1774; o) A. Hoffmann-Röder, N. Krause, Org. Lett. 2001, 3,
2537–2538.
[9]
[14]
[10]
[15]
[11]
[12]
[16]
[17]
[18]
a) T. Yao, X. Zhang, R. C. Larock, J. Org. Chem. 2005, 70,
7679–7685; b) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem.
Soc. 2004, 126, 11164–11165.
a) X. Liu, Z. Pan, X. Shu, X. Duan, Y. Liang, Synlett 2006,
1962–1964; b) N. T. Patil, H. Wu, Y. Yamamoto, J. Org. Chem.
2005, 70, 4531–4534.
For related cyclizations, see: a) A. S. K. Hashmi, L. Schwarz,
J.-H. Choi, T. M. Frost, Angew. Chem. 2000, 112, 2382–2385;
Angew. Chem. Int. Ed. 2000, 39, 2285–2288; b) A. S. K.
Hashmi, T. L. Ruppert, T. Knofel, J. W. Bats, J. Org. Chem.
1997, 62, 7295–7304; c) A. S. K. Hashmi, Angew. Chem. 1995,
107, 1749–1751; Angew. Chem. Int. Ed. Engl. 1995, 34, 1581–
1583; d) J. A. Marshall, C. A. Sehon, J. Org. Chem. 1995, 60,
5966–5968; e) J. A. Marshall, E. M. Wallace, P. S. Coan, J. Org.
Chem. 1995, 60, 796–797; f) J. A. Marshall, X. J. Wang, J. Org.
1646
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1636–1647

Diversity-Oriented Construction of 3(2H)-Furanones and 3-Pyrrolones
FULL PAPER
Chem. 1992, 57, 3387–3396; g) J. A. Marshall, X. J. Wang, J.
Org. Chem. 1991, 56, 960–969; h) ref.[15g]
[35]
S. S. Shin, Y. Byun, K. M. Lim, J. K. Choi, K.-W. Lee, J. H.
Moh, J. K. Kim, Y. S. Jeong, J. Y. Kim, Y. H. Choi, H.-J. Koh,
Y.-H. Park, Y. I. Oh, M.-S. Noh, S. Chung, J. Med. Chem.
2004, 47, 792–804.
Y. Ishida, H. Tsuruta, S. T. Tsuneta, T. Uno, K. Watanabe, Y.
Aizono, Biosci. Biotechnol. Biochem. 1998, 62, 2146–2150.
A. Carotti, A. Carrieri, S. Chimichi, M. Boccalini, B. Cosi-
melli, C. Gnerre, A. Carotti, P.-A. Carrupt, B. Testa, Bioorg.
Med. Chem. Lett. 2002, 12, 3551–3555.
S. W. Felman, I. Jirkovsky, K. A. Memoli, L. Borella, C. Wells,
J. Russell, J. Ward, J. Med. Chem. 1992, 35, 1183–1190.
a) X. Shao, C. Tamm, Tetrahedron Lett. 1991, 32, 2891–2892;
b) A. B. Smith III, P. A. Levenberg, P. J. Jerris, R. M. Scarbor-
ough Jr, P. M. Wovkulich, J. Am. Chem. Soc. 1981, 103, 1501–
1513.
For synthetic equivalents of αЈ-hydroxy 1,3-diketones, see inter
alia: a) S. Chimichi, M. Boccalini, B. Cosimelli, F. Dall’Acqua,
G. Viola, Tetrahedron 2003, 59, 5215–5223; b) S. Chimichi, M.
Boccalini, B. Cosimelli, G. Viola, D. Vedaldi, F. Dall’Acqua,
Tetrahedron Lett. 2002, 43, 7473–7476; c) Y. Inoue, K. Ohuchi,
S. Imaizumi, Tetrahedron Lett. 1988, 29, 5941–5942; d) D. P.
Curran, D. H. Singleton, Tetrahedron Lett. 1983, 29, 2079–
2082.
a) J. Liu, M. Liu, S. Guo, H. Tu, Y. Zhou, H. Gao, Org. Lett.
2006, 8, 3445–3448; b) M. Reiter, H. Turner, R. Mills-Webb, V.
Gouverneur, J. Org. Chem. 2005, 70, 8478–8485; c) J. E. Bal-
dwin, R. C. Thomas, L. I. Kruse, L. Silberman, J. Org. Chem.
1977, 42, 3846–3852.
[19] For recent examples of gold-catalyzed domino processes, see:
a) A. Buzas, F. Gagosz, J. Am. Chem. Soc. 2006, 128, 12614–
12615; b) J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc.
2006, 128, 7436–7437; c) E. Jiménez-Núñez, C. K. Claverie, C.
Nieto-Oberhuber, A. M. Echavarren, Angew. Chem. 2006, 118,
5578–5581; Angew. Chem. Int. Ed. 2006, 45, 5452–5455; d) I. V.
Seregin, V. Gevorgyan, J. Am. Chem. Soc. 2006, 128, 12050–
12051; e) C. Nieto-Oberhuber, S. López, E. Jiménez-Núñez,
A. M. Echavarren, Chem. Eur. J. 2006, 12, 5916–5923; f) J.
Zhang, H.-G. Schmalz, Angew. Chem. 2006, 118, 6856–6859;
Angew. Chem. Int. Ed. 2006, 45, 6704–6707; g) A. L. Zhang, J.
Am. Chem. Soc. 2005, 127, 16804–16805; h) A. S. K. Hashmi,
L. Grundl, Tetrahedron 2005, 61, 6231–6236.
[20] a) Y. Nagao, S. Tanaka, A. Ueki, M. Kumazawa, S. Goto, T.
Ooi, S. Sano, M. Shiro, Org. Lett. 2004, 6, 2133–2136; b) R. E.
Hartung, D. G. Hilmey, L. A. Paquette, Adv. Synth. Catal.
2004, 346, 713–716; c) L. A. Paquette, J. E. Hofferberth, Org.
React. 2003, 62, 477; d) H. Brunner, H. B. Kagan, G. Kreutze,
Tetrahedron: Asymmetry 2003, 14, 2177–2187; e) H. Brunner,
F. Stöhr, Eur. J. Org. Chem. 2000, 2777–2786.
[21] a) J. P. Markham, S. T. Staben, F. D. Toste, J. Am. Chem. Soc.
2005, 127, 9708–9709; b) B. M. Trost, D. C. Lee, J. Am. Chem.
Soc. 1988, 110, 6556–6558; c) M. Sworin, W. L. Neumann, J.
Org. Chem. 1988, 53, 4894–4896; d) T. Sano, J. Toda, Y. Tsuda,
Heterocycles 1984, 22, 53–58.
[22] Parts of this study have been published in preliminary form,
see: S. F. Kirsch, J. T. Binder, C. Liébert, H. Menz, Angew.
Chem. 2006, 118, 6010–6013; Angew. Chem. Int. Ed. 2006, 118,
5878–5880.
[36]
[37]
[38]
[39]
[40]
[41]
[42]
J. D. Winkler, K. Oh, S. M. Asselin, Org. Lett. 2005, 7, 387–
389.
S. Sayama, Heterocycles 2005, 65, 1347–1358.
a) P. Sampson, V. Roussis, G. J. Drtina, F. L. Koerwitz, D. F.
Wiemer, J. Org. Chem. 1986, 51, 2525–2529; for similar cyclis-
ation strategy, see: b) K. Kato, H. Nouchi, K. Ishikura, S.
Takaishi, S. Motodate, H. Tanaka, K. Okudaira, T. Mochida,
R. Nishigaki, K. Shigenobu, H. Akita, Tetrahedron Lett. 2006,
62, 2545–2554.
[23] a) P. K. Dhondi, J. D. Chisholm, Org. Lett. 2006, 8, 67–69; b)
B. Jiang, Z. Chen, X. Tang, Org. Lett. 2002, 4, 3451–3453.
[24] M. Yamaguchi, I. Hirao, Tetrahedron Lett. 1983, 24, 391–394.
[25] For the synthesis of IBX, see: a) C. Hartmann, V. Meyer, Ber.
Dtsch. Chem. Ges. 1893, 26, 1727–1732; b) M. Frigerio, M.
Santagostino, S. Sputore, J. Org. Chem. 1999, 64, 4537–4538.
[26] S. F. Kirsch, J. Org. Chem. 2005, 70, 10210–10212.
[27] B. Crone, S. F. Kirsch, Chem. Commun. 2006, 764–766.
[28] a) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc.
2000, 122, 7596–7597; b) K. C. Nicolaou, T. Montagnon, P. S.
[43]
[44]
[45] P. Langer, T. Krummel, Chem. Eur. J. 2001, 7, 1720–1727.
[46] In these cases, AuCl3 is superior in terms of rate.
Baran, Y.-L. Zhong, J. Am. Chem. Soc. 2002, 124, 2245–2258; [47] 1s was prepared according to published procedures.[15h]
c) K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem.
2002, 114, 1038–1042; Angew. Chem. Int. Ed. 2002, 41, 993–
996; d) K. C. Nicolaou, D. L. F. Gray, T. Montagnon, S. T.
Harrison, Angew. Chem. 2002, 114, 1444–1447; Angew. Chem.
Int. Ed. 2002, 41, 996–1000.
[48] a) H. Saimoto, T. Hiyama, H. Nozaki, J. Am. Chem. Soc. 1981,
103, 4975–4977; b) W. Parker, R. A. Raphael, D. I. Wilkinson,
J. Chem. Soc. 1958, 3871–3875.
[49] S. Swaminathan, K. V. Narayanan, Chem. Rev. 1971, 71, 429–
438.
[50] When the alkynyl carbonyl compound was employed as a mix-
ture of diastereomers, the diastereomeric products 13a and 13b
were obtained in ratios identical to those of the starting mate-
rial.
[29] In the case of 4q, 2-(2-phenylethynyl)cycloheptanone was iso-
lated in 77% yield (3.0 equiv. IBX, 24 h, 23 °C, DMSO).
[30] K. Kaneda, K. Jitsukawa, T. Itoh, S. Teranishi, J. Org. Chem.
1980, 45, 3004–3009.
[31] YMC ODS-A, 250 mmϫ20 mm, 50:50 H2O/CH3CN, 15 mL/
min, 254 nm.
[32] P. W. Le Quesne, S. B. Levery, M. D. Menachery, T. F. Bren-
nan, R. F. Raffauf, J. Chem. Soc., Perkin Trans. 1 1978, 1572–
1580.
[33] a) A. B. Smith III, M. A. Guaciaro, S. R. Schow, P. M. Wovku-
lich, B. H. Toder, T. W. Hall, J. Am. Chem. Soc. 1981, 103, 219–
222; b) S. M. Kupchan, C. W. Sigel, M. J. Matz, C. J. Gilmore,
R. F. Bryan, J. Am. Chem. Soc. 1976, 98, 2295–2300.
[34] a) P. J. Jerris, A. B. Smith III, J. Org. Chem. 1981, 46, 577–585;
b) D. L. Dreyer, A. Lee, Phytochemistry 1972, 11, 763–767.
[51] A. Arcadi, S. Di Giuseppe, F. Marinelli, E. Rossi, Adv. Synth.
Catal. 2001, 343, 443–446.
[52] a) H. McNab, L. C. Monahan, J. Chem. Soc., Perkin Trans. 1
1988, 869–873; b) R. Ghaffari-Tabrizi, P. Margaretha, H. W.
Schmalle, Helv. Chim. Acta 1984, 67, 1957–1962; c) E. Im-
mendörfer, Ber. Dtsch. Chem. Ges. 1915, 48, 605–616.
[53] A. B. Smith III, S. D. Knight, P. A. Sprengeler, R. Hirschmann,
Bioorg. Med. Chem. 1996, 4, 1021–1034.
[54] M. Overhand, S. M. Hecht, J. Org. Chem. 1994, 59, 4721–4722.
Received: December 6, 2006
Published Online: February 9, 2007
Eur. J. Org. Chem. 2007, 1636–1647
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1647