Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects

Article abstract of DOI:10.1016/j.tet.2012.09.070

Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.

Full text of DOI:10.1016/j.tet.2012.09.070

Tetrahedron 68 (2012) 9982e9998
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Tetrahedron
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[4þ3] Cycloaddition of C-3 substituted furans. Stereoselectivity induced by
coordination effects
a,
b
a,
y
a
c
ꢀ
*
~
ꢁ
Angel M. Montana , Pedro M. Grima , María Castellví , Consuelo Batalla , Merce Font-Bardia
a
ꢀ
ꢀ
ꢁ
Unidad de Química Organica Industrial y Aplicada, Departamento de Química Organica, Facultad de Química, Universidad de Barcelona, c/Martí i Franques 1-11,
08028 Barcelona, Spain
b Medicinal Chemistry Department, Laboratorios Ferrer Internacional, c/Juan de Sada, 28-32, 08028 Barcelona, Spain
c
ꢁ
Department of Crystallography, Mineralogy and Mineral Deposits, University of Barcelona, c/Martí Franques s/n, 08028-Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2012
Received in revised form 7 September 2012
Accepted 12 September 2012
Available online 19 September 2012
Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone
in the presence of a reducing metal, resulting in the formation of [4þ3]-cycloadducts with complete
cisetrans and endoeexo diastereoselectivity and in excellent yield. A certain variability of the conversion
and reaction yield could be observed, when changing the reaction conditions, but in all cases the ster-
eoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also,
a general method of assignment of stereochemistry of cycloadducts has been established by NMR,
considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on
the stereochemistry of diastereomeric cycloadducts.
Keywords:
[4þ3] Cycloadditions
Furan
Ó 2012 Elsevier Ltd. All rights reserved.
C-3 substituted furans
Coordination effects
Stereoselectivity
Oxyallyl cation
1. Introduction
and an oxyallyl cation as dienophile. With this information we
pretend in the future to modulate the reactivity and stereo-
The [4þ3] cycloaddition reaction is a very useful synthetic
methodology to prepare, in one step and good yield, poly-
functionalized cycloheptane building blocks with several stereo-
centres, which can be modified and easily transformed to obtain
cyclic and linear precursors for the synthesis of many natural and
non-natural products with high added value.1
selectivity of conveniently functionalized C-2 and/or C-3
substituted furans in this type of reactions.
It is well established that the reaction of 3-substituted furans
and a symmetric
situ from the corresponding
a,a
0-disubstituted oxyallyl cation, generated in
a,a
0-dihaloketone with a reducing
metal, affords four types of possible stereoisomers, existing as en-
antiomeric pairs (see Fig. 1). In the case of non-symmetric oxyallyl
cations eight possible isomers, existing as enantiomeric pairs, could
be formed due to the regiochemistry involved. In this last case the
relative proportion of regioisomers is controlled by frontier mo-
lecular orbitals (FMO) of the cycloaddends (via primary MO in-
teractions). Thus, the major product results from the relative
orientation that favors the maximum HOMOeLUMO overlap of
those orbitals with higher coefficients.4 However, the substituents
on the furan system also modulate the regioselectivity of cycload-
dition reactions.5
In the present work we have worked with the symmetric 1,3-
dimethyl-2-oxyallyl cation to simplify the reaction outcome and to
obviate the regiochemistry problem. However we will mention, for
comparative purposes, some examples found in the literature about
the cisetrans and endoeexo diastereoselectivity in the formation of
some regioisomeric cycloadducts from C-3 substituted furans.
We evaluated in the past the [4þ3]-cycloaddition of C-2 func-
tionalized furans in order to prepare cycloadducts having an oxa-
bicyclic structure with an acetalic bridge head, prone to be
transformed into a variety of added value molecules,2 in a diaster-
eoselective and/or enantioselective manner.3 In those studies we
were able to withdraw conclusions on the influence of the stereo-
electronic nature of the C-2 substituents on the yield and stereo-
selectivity of the resulting [4þ3]-cycloadducts.
Here, we present the results of our study of the influence of the
coordinating nature of C-3 substituted furans on the stereochemi-
cal outcome of the [4þ3]-cycloaddition reaction of these dienes
* Corresponding author. Tel.: þ34 93 402 16 81; fax: þ34 93 339 78 78; e-mail
ꢀ
~
address: angel.montana@ub.edu (A.M. Montana).
y
Present address: Faculty of Science and Technology, University of Twente,
P.O. Box 217, 7500 AE Enschede, The Netherlands.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.070

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9983
O
O
O
O
O
O
O
O
O
O
H3C
+
CH3
+
+
+
[4+3]-cycloaddition
X
X
X
X
X
rac- trans (I)
rac-trans (II)
rac-(Me, Me) cis-exo
rac-(Me, Me) cis-endo
O
O
O
O
O
X
X
X
cis-diaxial
O
Fig. 1. Stereochemical outcome from the [4þ3]-cycloaddition of C3-substituted furans and 1,3-dimethyl-2-oxyallyl cation.
The cis stereoselectivity is conditioned and determined by the
predominance of the W configuration adopted by the oxyallyl
cation in its coupling with the furan diene by a concerted process.
The (Z,Z) or W configuration of the oxyallyl cation is the major one
since it is the configuration of lower energy, having the methyl
groups far apart from each other. It has been estimated that the
population of dienophile molecules having this (Z,Z) configuration
represents the 98% in equilibrium.6
dimethylfuran is not highly electron rich it has two methyl groups
that hinder a compact approach of the W-configuration of the
oxyallyl cation. As a consequence the trans isomers are formed in an
extent of 21.3%, together with a considerable amount of cis-diaxial
(exo) cycloadduct (33.7%). The formation of the trans isomers, via
the stepwise process, seems to be favored (respect to furan as
substrate) not only by electronic but also by steric factors due to the
relative destabilization of the endo approach by the compact TS.
In the aforementioned work Hoffmann et al. studied the in-
fluence on the reaction outcome (diastereomeric proportions) of
several reaction conditions, modifying the reducing metal (and
thus the electrophilic nature of the oxyallyl cation, changing the
nature of the metallic contra-ion), modifying the solvent and its
solvating properties and even the presence of weak Lewis acids.
Also, we found some precedents in the literature that show how
not only the steric interactions are important to determine the ratio of
endo/exo isomers, but the chelation or coordination phenomena that
could take place between the substituents at C-3 or C-4 and the
contra-ion of the oxyallyl cation (dienophile). In these precedents the
authors did not take into account this coordination effect because
they were discussing other type of factors controlling the regio-,
chemo- or p-facial diastereoselectivity of the reaction. However, we
consider important to discuss and to unveil these phenomena as
responsible for the cis/trans and endo/exo selectivity in the [4þ3]-
cycloaddition reaction. The clarification of this aspect will be impor-
tant in order to develop more stereoselective processes in the future.
On the other hand, Barbosa et al.4e,9 and Mann et al.4c in their
studies on the [4þ3]-cycloaddition reaction of mono- di- and tri-
substituted furans with symmetric and non-symmetric oxyallyl
cations, apart from the regioselectivity observed, which is mainly
controlled by primary FMO interactions (dieneedienophile), they
isolated in all cases the endo isomer as the unique or major product,
no matter of the substitution pattern on the furan, especially for
those substituents with heteroatoms having coordination capabil-
ity. Also, Noyori et al.,4a,10 working with 3-substituted furans with
groups of different size and electronic nature (Me, Br, COOEt), ob-
tained isomeric mixtures of [4þ3]-cycloadducts. In these mixtures
the ratio endo/exo increased when increasing the coordination ca-
pability of the furan substituent with the contra-ion of the oxyallyl
cation4a (see Fig. 4), as we interpret now. Also, in this original work
the authors centered their discussion in the regioselectivity medi-
ated by the FMO interactions but they do not comment or ratio-
nalized this endo/exo variation.
The cis-diequatorial (endo) isomer is formed by a concerted
[4C(4
p)þ3C(2p)] cycloaddition, following a compact late transition
state that affords a cycloadduct with both Me groups in equatorial
disposition and the 4-piranone ring in a chair-like conformation.
The cis-diaxial (exo) stereoisomer is formed from an extended TS
that affords a cycloadduct having the 4-piranone ring in a boat-like
conformation. The trans isomers come from a stepwise process
initiated by an electrophilic attack of the oxyallyl cation to the furan
diene, followed by a ring closing. Before closing, the intermediate
may modify the conformation of the side chain, re-orientating the
methyl groups to decrease the steric interactions, affording the two
possible trans isomers (see Fig. 2).1
The endo/exo ratio is conditioned by the easiness of the dien-
eedienophile
p-stacking and the minimization of the steric in-
teractions in the approach of diene and dienophile.7
The formation of trans cycloadducts is conditioned by the fa-
cilitation of the stepwise mechanism due to a modification of the
electron density of the diene and the electrophilic nature of the
oxyallyl cation (rich dienes and highly electrophilic cations facili-
tate stepwise processes).7 The inductive and mesomeric effects, if
they are activating (þI, þM) or deactivating (ꢀI, ꢀM), will favor the
preferential attack on C-2 or C-5 of the furan diene (in the elec-
trophilic addition through the stepwise process) and the resulting
intermediates I1 or I2 (Fig. 2) will result stabilized or destabilized.
On the other hand, apart from these orientating effects, the pres-
ence of (þI) groups will favor the stepwise mechanism and (ꢀI)
groups will act in the opposite direction, due to the modification of
the electron density of the furan ring.7,8
Having in mind this background information, we observed in
our cycloaddition studies with C-3 substituted furans and also in
the results obtained by other authors some trends that we wanted
to confirm by the present work.
What one expects, when using C-3 monosubstituted and/or C-3
and C-4 disubstituted furans as dienes in [4þ3]-cycloaddition re-
actions, is an increase of the exo or even the trans isomers pro-
portion with respect to the furan itself as a diene in the same type of
reaction. This was observed by Hoffmann et al.6 in the reaction of
furan and 3,4-dimethylfuran with 1,3-dimethyl-2-oxyallyl cation
(see Fig. 3). This is due to the fact that, even though 3,4-
In a more recent study, Hoffmann et al.11 working on the chemo-
regio- and stereoselectivity of the [4þ3]-cycloaddition reaction of
C-3 substituted furans with oxyallyl cations derived from chiral silyl
enol ethers, obtained results that deserve some comments in this

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
Concerted process
M
O
O
Cis-exo product
Extended TS
(disf avoured)
X
O
Cis-endo product
(f avoured)
Compact TS
O
M
steric repulsion
X
co-ordination
Stepwise process
M
O
O
O
O
Trans (I) product
M
M
O
O
X
X
X
I1
Intermediate f ormed by electrophilic attack
M
O
O
O
O
Trans (II) product
M
O
O
M
X
X
X
I2
Fig. 2. Formation of cis isomers through compact and extended TS in a concerted process. Mechanism of formation of the trans isomers by a stepwise reaction.
context. In this work the authors used furans functionalized at C-3
with Br, SnBu3, SiEt3 and S(CO)Ph groups. In this study the chemo-,
vicinal oxygen atom of the chiral auxiliary or even the p-staking
effect with the aryl group of such chiral auxiliary. However, the au-
thors do not rationalized the important change in stereoselectivity
when using 3,4-dibromofurane versus 3-bromofurane (apart from
the simplification of the reaction crude, because the regiochemistry
problem disappears). In this particular substitution change none of
the aforementioned phenomena could be called to justify this im-
the regio- and especially the
p-facial stereoselectivity were ana-
lyzed. This last particular aspect added a great value to this study. In
the evaluation of the influence on the selectivity of different sub-
stitution patterns of both the oxyallyl cation and the furan diene, the
authors worked, among others, with 3-bromofuran and 3,4-
dibromofuran as substrates. They experimentally observed an in-
portant improvement of
p-facial selectivity. We think that impor-
crease of
3,4-dibromofuran as substrate instead of 3-bromofuran. In that
particular -facial stereoselectivity the decrease of freedom degrees
of both diene and dienophile are important to assure a certain level
of selectivity. This was rationalized by the authors when introduced
an additional methyl group on the oxyallyl cation, observing an
p
-facial diastereoselectivity from 7:1 to 17:1 when using
tant chelating effects from the bromine atoms on the silicon atom or
even possible halogen bridges12 could take place.
p
On the other hand, when working with a C-3 thiobenzoate furan
derivative a chelating effect, exerted by the sulfur and/or oxygen
atoms of the thiobenzoate substituent of furan, could also be
envisioned. This chelating effect may also contribute to interpret
the selectivity observed in other study cases carried out by Hoff-
mann et al. (Fig. 5).11
important increase of
p-facial diastereoselectivity. They proposed
a TS model in which they accounted for the W-configuration of the
oxyallyl cation by the introduction of a methyl group on it, as well as
the co-ordination of the silicon atom (from the SiEt3 group) to the
The stereoselection model proposed here involves not only the
minimization of interaction between close steric demanding

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9985
O
O
O
O
O
O
O
O
O
O
+
+
+
Zn/Cu
DME
R
R
R
R
R
R
R
R
R
R
exo (33.7
)
)
endo (45
)
R = Me
cis (78.7
trans (racemic) (21.3
trans (racemic) (17.4
)
exo (8.7
)
endo (73.9
)
R = H
cis (82.6%)
)
Fig. 3. Variation of the endo/exo/trans ratio with the substitution at C-3 and C-4 of furan in a [4þ3]-cycloaddition reaction.6
O
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
Ph
+
+
+
CH3
CH3
CH3
CH3
CH3
56:44
Fe2(CO)9, C6H6, 30ºC
Zn/Cu, DME, -10ºC
55:45
exo (19
)
endo (29
)
1.5 : 1
2 : 1
64:36
65:35
exo (18
)
endo (36
)
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
Ph
O
O
O
+
+
+
COOMe
COOMe
COOMe
55:45
COOMe
COOMe
Fe2(CO)9, C6H6, 30ºC
exo (0
)
endo (52
)
100 : 0
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
Ph
O
O
O
+
+
+
COOEt
Zn/Cu, DME, -10ºC
COOEt
COOEt
67:33
COOEt
COOEt
exo (0
)
endo (41
)
100 : 0
Fig. 4. [4þ3]-Cycloaddition of 3-substituted furans with 1-phenyl-2-oxyallyl cation.4a,10
groups in the TS, as proposed historically by Hoffmann, but addi-
tional coordination effects as described before. New models, in-
teractions and effects have been invoked to explain stereo-
selectivity in the [4þ3] cycloaddition reactions, and in some cases
these interactions are more important than the steric hindrance,
affording unexpected approaches of reacting subunits in the TS.
Some examples could be cited to illustrate these facts: the in-
teraction and approaching model of Harmata and Houk13 (Fig. 6),

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
O
O
R
O
R
Ph
R
R
O
Ph
O
O
Br
X
X
Br
I
O
II
(I, II) and (III, IV) are regioisomers when X = H, identical when X=Br
+
Ph
O
O
O
(I, IV) and (II, III) are diastereoisomers resulting from p-facial selectivity
OSiEt3
X = H
X = Br
R
S
Ph
O
R
Ph
S
O
Br
X
(all of them have the endo configuration for the side chain)
O
O
π
-facial selectivity = I+II / III+IV
X
Br
Br
X
IV
X = H
7:1
III
X = Br
17:1
O
O
Br
Br
coordination
coordination
Br
H
H
Si
Si
O
H
O
H
p- stacking
O
p- stacking
coordination
CH3
O
coordination
CH3
H
H
CH3
CH3
Steric demanding situation
Steric demanding situation
Compact TS to explain the selective formation of (I)
Fig. 5. Possible chelating effects of bromine atoms in the TS model proposed by Hoffmann to explain the
p-facial stereoselectivity (from the study case of Ref. 11).
SiMe3
O
SiMe3
Ph
O
O
O
Me
H
O
H
O
Ph
H
O
H
Me
O
M inimized steric repulsion
Me
O
Major product
Attractive CH···
π
interaction
Fig. 6. Example of a new dieneedienophile interaction model proposed by Harmata and Houk to explain stereoselection in [4þ3] cycloaddition reactions.
the model of Hsung14 or the model of Lautens15 among others. In
the stereoselection model proposed by Harmata and Houk, sup-
2. Results and discussion
ported by computational calculations, a new attractive CH/
teraction was envisioned, between one CH group at C2 of furan
substrate and the -system of the benzene ring of the side chain of
dienophile. This interaction conditioned the coupling of diene and
dienophile in an unexpected way, because this approach affords the
formation of the major product in a contra-steric and stepwise
manner, against the classical approach of Hoffmann (Fig. 5).
These facts should make the researches in this field to re-
consider the classical approaching models and to rationalize other
type of interactions, different from the simple unstabilizing steric
p
in-
These interesting results and phenomena described in the lit-
erature moved us to study the possible influence of the chelating
effects on the endo/exo stereoselectivity exerted by the groups at-
tached to C-3 of furan dienes in [4þ3]-cycloaddition reactions.
Thus, we prepared C3 substituted furans with groups of different
coordination capability, in order to study the cis/trans and endo/exo
stereoselectivity. We obviated the regioselectivity problems work-
ing with the symmetric oxyallyl cation derived from 2,4-dibromo-
3-pentanone (1) and/or 2,4-diiodo-3-pentanone (2).
The cycloaddition of simple furan, 3, under the same reaction
conditions, was used as a reference or standard as well as the
previously mentioned results found in the literature from the
[4þ3]-cycloaddition of differently substituted furans, like, for
p
interactions, like, for example, the CH/p interactions proposed by
Harmata and Houk or the coordinative effects of a Lewis acid used
as a catalyst.

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9987
example, 3,4-dimethylfuran, 2, among other study cases. We pre-
pared two furan derivatives having non-coordinating substituents
on C-3 and/or C-4: 3-methylfuran, 6 and 3,4-dimethylfuran, 9. On
the other hand, several furan derivatives with a coordinating group
attached to C-3 were synthesized (furans 10e14). These furans have
one or two coordinating heteroatoms (N, O) separated by a two-
bonds linker to the furan ring, in order to facilitate the approach
of heteroatoms (having electron lone pairs) to the ‘metallic’ contra-
ion of the oxyallyl dienophile. The hydroxymethyl derivative 12,
with the capability to act as hydrogen bond donor, was prepared in
order to evaluate if this phenomenon could condition the freedom
degrees of the oxyallyl dienophile and, as a consequence, the
stereoselectivity endo/exo. The use of ester/amide substrates (11,13)
versus the respective alcohol/amine derived functions (12, 14) was
considered to evaluate the influence of the different inductive ef-
fect of these two kinds of groups on the furan ring and the possible
hydrogen bond effects on both the yield and the stereoselectivity.
The use of a tertiary amine like 14 was used to evaluate what was
the predominant effect: the steric hindrance exerted by the two
ethyl groups of the NEt2 substituent versus the coordinating effect
of nitrogen atom through its electron lone pair.
signals by 1D and 2D NMR experiments (COSY, HETCOR, HMBC,
HSQC, etc.), including NOE experiments.
The reaction conditions were modified in order to evaluate the
influence on the reaction outcome of parameters, such as: nature of
the reducing metal and dihaloketone, reaction temperature, nature
of solvent, concentration, presence of NaI, etc. From this compar-
ative study it is possible to appreciate how the use of the system
ZneCu/dibromoketoneeNaI instead of Zn/diiodoketone afforded
worse conversion and yield (compare entries 6 vs 8 and 12 vs 13).
Other significant result is that the yield may be conditioned by the
nature of the metal, maintaining the other reaction parameters
constant. Thus, when using Cu (powder, bronze or submicron) in
place of Zn the yield decreases a 20e25%. This may be due to the
lower electrophilicity of the corresponding oxyallyl cation in the
case of using copper (compare entry 8 vs 10 and also 12 vs 14).7 In
all cases de reaction conditions were mild but designed to get short
reaction times in order to avoid equilibrations in alpha to the ke-
tone group in cycloadducts or their decomposition, as well as
possible side reactions.
The complete cis/trans stereoselectivity observed could be
interpreted by considering that the reaction takes place via a con-
certed mechanism and due to the reduction of the haloketone af-
fords an oxyallyl cation with a major (Z,Z) or W configuration.
The observed endo/exo diastereoselectivity for the C-3
substituted furans resulted, a priori, unexpected according to the
results observed in entries 1 to 5. The substitution at C-3 and/or at
C-5 of furan may determine a certain degree of steric interaction in
the approach of oxyallyl dienophile to the furan diene for a compact
TS, as illustrated in Fig. 8. This phenomenon may be the responsible
for the stereochemical outcome of the reaction of 3,4-
dimethylfurane observed by Hoffmann et al.6 and also by us in
the present work.
In our experiments with furans having coordinating groups on
C-3 we expected the appearance of a certain percentage of cis-
diaxial and trans cycloadducts as we observed for furan itself (en-
tries 1 and 2) and also for substrates 6 and 9 (entries 3e5), but we
did not observed at all the diastereomers trans or exo, after a careful
analysis of the reaction crude by high field 1H NMR, GC, and GCeMS
techniques. In all cases the only product detected and then isolated
was the cis-diequatorial or endo product. Studying by molecular
modeling the endo product and performing a conformational
analysis we inferred certain proximity in space of the methyl group
on C-2 and the group on C-7 of cycloadduct (coming from the
substituent of furan precursor). Taking into account this proximity
and the Van der Waals radii it is possible to understand that in the
late compact TS there would be an unstabilizing interaction be-
tween both groups. Why this interaction does not manifest in the
evolution to an extended TS or even to a stepwise mechanism? The
explanation may be found in a possible chelating or coordinating
effect taking place between heteroatoms (N or O, having lone pairs)
of the furan substituent and the metallic contra-ion of the oxyallyl
dienophile (Fig. 8) (Cu or Zn acting as Lewis acids), which com-
pensates the possible steric interaction, mentioned before, making
the compact TS the predominant or unique one.
The synthetic pathway to prepare the aforementioned furan
derivatives is summarized in Fig. 7 and described in detail in the
experimental part.
The results from the [4þ3]-cycloaddition reaction of substituted
furans and 1,3-dimethyl-2-oxyallyl cation (generated in situ from
dihaloketones), under different conditions, are summarized in
Table 1. The conversion of furan dienes, the yield of cycloadducts
and the cis/trans and endo/exo stereoselectivities are quoted.
Looking at the data it is possible to observe how the conversion
was complete or very high in most of the evaluated reaction con-
ditions and the yield of cycloadducts was also high. The diaster-
eoselectivity cis/trans and ciseendo/ciseexo was 100:0 for all cases
in which furans, having coordinating groups on C-3, were used as
substrates (entries 6e11). However, in the standard reaction
with furan (entries 1 and 2) and also in the reactions with
3-methylfuran, 6, (entry 3) and 3,4-dimethylfuran, 9, (entries 4 and
5), the cis/trans and endo/exo selectivity was different from 100:0.
The high yield observed could be explained considering that the
substitution on the furan ring is at one bond distance of the C-2
reactive center or at two bonds distance of the C-5 reactive center.
Thus, the steric hindrance of the C-3 group should not be very
important or determinant to condition the approach dien-
eedienophile. Other different situation is when a 3,4-disustituted
furan is considered. On the other hand, the obtention of similar
results no mater of the electronic nature of the groups: electron
withdrawing (entries 6e10 and 12e14) or electron donating (entry
15) may be interpreted as the variation of the electron density of
furan diene, induced by the evaluated substituents, is not impor-
tant for the reaction outcome. However, it is well known that in-
creasing the electron density increases the possibility of the
stepwise mechanism and consequently the formation of trans
cycloadducts. Moreover, the evaluation of the possibility of hy-
drogen bond formation of the hydroxymethyl derivative (entry 11)
did not show any relevant result at least for this particular reaction
model.
The assignment of the stereochemistry by NMR in cycloadducts
substituted at C-6 turns out to be simpler than that of the func-
tionalized systems on C-1.16
The composition of the reaction crude was studied very care-
fully by high field 1H NMR, GC, and GCeMS techniques, de-
termining the conversion of furans and the yield of cycloadducts
referred to the converted dienes. All reaction crudes were sub-
mitted to column chromatography to isolate the furan starting
material and to purify and characterize, physically and spectro-
scopically, the cycloadducts. The stereochemistry was established
after a careful analysis, comparison and correlation of the 1H and
13C signals (chemical shifts, multiplicity, and coupling constants) of
cycloadducts, after an unequivocal assignment of all spectral
As in that case, the substituent at C-6 arranges in space moving
away from the quasi-rigid bicyclic structure,16a so that it provokes
small effects on the chemical shifts of the NMR signals corre-
sponding to the oxabicyclic framework (which is much more af-
fected by the disposition of the other substituents of the rigid
structure). Thus, independently of the nature of the substituent at
C-6, it is possible to establish a method of general applicability for
the assignment of the relative stereochemistry of cycloadducts
from a detailed analysis and correlation of 1H NMR spectra.

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
O
O
O
OH
Cu/Quinoline
1)NaOH/MeOH
D, 165-180ºC
2) aq.HCl
O
O
O
68%
95%
4
6
5
O
O
1) NaBH4 / THF
2) aq. HCl
DIBALH, Et2O, -20ºC
30%
O
O
O
50%
9
8
7
O
1)SOCl2, 75ºC
2)EtOH, reflux
O
O
O
LiAlH4, Et2O, rt
95%
65%
OEt
OH
OH
10
11
12
O
O
1) SOCl2, 75ºC
2) HNEt2, THF, rt
O
O
LiAlH4, Et2O, rt
50%
72%
NEt2
13
14
NEt2
O
Fig. 7. Synthetic pathways for the C-3 substituted furans used as substrates.
The general trends in the correlation of 1H and 13C NMR spectra
5. d(H-5)(a)>d(H-5)(b) by 1,2 shielding effects with Me-(C-4).
6. The main differences in
3, C-9, and C-10.
d(
13C) are observed for carbons: C-1, C-
of diastereomeric (a/b) pairs of cycloadducts (a¼cis endo; b¼cis
exo) are summarized as follows:
7.
d(C-9) (a)<
d(C-9) (b) and
d(C-10) (a)<d(C-10) (b), due to the
g-gauche interactions in the (a) diastereoisomer.
1. The most significant differences in chemical shifts (d), multi-
8.
d(C-3) (a)<d(C-3) (b), caused by electron compression between
plicity and coupling constants between both diastereoisomers
are at the level of H-2, H-4, H-9, and H-10.
a sp3 orbital of the bridging oxygen and a pz orbital of the C-3
atom.
2. d(H-9) and d(H-10) of major diastereoisomer (a) are smaller
than the homologous signals in the minor stereoisomer (b),
which is caused by the different interaction of methyl groups
with the bridging oxygen.
3. J2,9 (a)<J2,9 (b)J4,10 (a)<J4,10 (b)J4,5 (a)s0, normally 4<J4,5<5 Hz;
J4,5 (b)z0
4. d(H-2) and d(H-4) of (a) are higher than d(H-2) and d(H-4) of
(b), because of the different interaction of those hydrogen
atoms with the bridging oxygen.
All the shielding and deshielding effects on the bicycle structure
exerted by the different substituents are very useful to establish
NMR patterns for the four possible diastereoisomers. Moreover,
these systems have the advantage of having hydrogen atoms at-
tached to the bridgeheads (H-1 and H-5), so that, the assignment of
stereochemistry turns out to be unequivocal, simply looking at
their coupling patterns (see Fig. 9), which are consistent with the

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9989
Table 1
Results obtained in the [4C(4
p
)þ3C(2
p)] cycloaddition reaction of C-3 substituted furans
O
O
O
O
O
O
O
O
O
O
+
+
+
R1
R2
R2
R1
R2
R2
R1
R1
R1
R2
c
b
d
a
rac-trans (I)
trans
rac- trans (II)
exo
endo
cis
Entry Substitution
pattern
Furan Cycloadduct Cycloaddition
method
Molar ratio: Solventa Reaction
Time (h)b Conversion Yield (%)c Ratio
Ratio
furan:DHK:
metal:NaI
temperature
(ꢁC)
of furan (%)c
cis/trans (%)d ciseendo:
aþb/cþd
ciseexo (%)d
a:b
1
2
3
R1¼R2¼H
3
3
6
15aed
15aed
16aed
Zn/DIK
Zn/DIK
Zn/DBK/NaI
1:3:3:0
240:1:1:0
1:3:3:3
ACN
Furan
ACN
0 to rt
0 to rt
a) 0
b) rt
2
2
1
2
100
100
100
80
99
60
99:1
99:1
96:4
91:8
91:8
69: 31
R1¼R2¼H
R1¼H R2¼CH3
4
5
R1¼R2¼CH3
R1¼R2¼CH3
9
9
17aed
17aed
ZneCu/DBK
1:0.6:1.2:0 DME
a) ꢀ15
1.5
0.25
1
2
1
4
4
4
4
1
1
1
4
100
100
61
58
79:21
93:7
57:43
54:46
b) rt
a) 0
b) rt
0
Zn/DBK/NaI
1:3:3:3
ACN
6
7
8
9
10
11
12
13
14
15
R1¼H; R2¼CO2Et
R1¼H; R2¼CO2Et
R1¼H; R2¼CO2Et
R1¼H; R2¼CO2Et
R1¼H; R2¼CO2Et
11
11
11
11
11
18a
18a
18a
18a
18a
19a
20a
20a
20a
21a
ZneCu/DBK/NaI 1:3:3:3
ZneCu/DBK/NaI 1:3:3:3
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
13
70
90
93
85
100
100
53
80
100
100e
80e
100e
95e
75
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
0
0
25
0
0
0
0
0
0
Zn/DIK
Zn/DIK
Cu/DIK
Zn/DIK
Zn/DIK
ZneCu/DBK/NaI 1:3:3:3
Cu/DIK
Zn/DIK
1:3:3:0
1:3:3:0
1:3:3:0
1:3:3:0
1:3:3:0
R1¼H; R2¼CH2OH 12
R1¼H; R2¼CONEt2 13
R1¼H; R2¼CONEt2 13
R1¼H; R2¼CONEt2 13
R1¼H; R2¼CH2NEt2 14
70
98
100e
77
1:3:3:0
1:3:3:0
1
81
a
Solvent dilution: 1 mL/mmol of furan in all cases, except for entries 4 and 5 in which 0.2 mL/mmol of furan was used and also in entry 2 in which furan was used as
a solvent.
b
c
Time until constant conversion of furan by GC (In all cases an internal standard and a calibration method have been used).
Yield on isolated product. The non-converted furan derivative was recovered by distillation, when volatile, or by CC when non-volatile.
Determined by 500 MHz 1H NMR, GC and/or GCeMS on the reaction crude.
d
e
These figures refer to the chemical selectivity. The substrate under the conditions of entries 6, 7, 8 and 13 was converted in a percentage lower than 100% but was
transformed exclusively into the desired final product. No by-products were detected and the unchanged starting material was efficiently recovered by CC and reused.
shifts and coupling constants of the rest of diagnostic hydrogen
atoms.
The assignment of the relative configuration established on the
basis of 1H NMR correlation has been confirmed by X-ray diffraction
analysis on single crystals of cycloadduct 20a (see Fig. 10 and
Table 2).
preparing furan substrates for [4þ3]-cycloaddition reactions in
order to obtain building blocks and intermediates or precursors of
added value molecules with a certain stereochemistry, which could
be easily derived from that of cycloadducts.
A general method of assignment of stereochemistry has been
established by NMR, considering diagnostic patterns of signals with
different multiplicity and chemical shifts depending on the ste-
reochemistry of diastereomeric cycloadducts.
3. Conclusions
Analyzing the results obtained in experiments of cycloaddition
using functionalized furans in the C-3 position, it is possible to
withdraw the following conclusions: (a) Neither the steric volume
nor the inductive electronic character of substituents on C-3 in the
furan substrate have a determinant effect on the reaction yield. (b)
A high cis/trans and endo/exo diastereoselectivity has been ob-
served for all C-3 substituted furan substrates, compared with the
non-substituted furans. In the case of substrates with C-3 sub-
stituents having coordinating atoms, able to act as electron donor
entities, a ciseendo stereospecificity was observed and only cyclo-
adducts with this ciseendo configuration were detected and iso-
lated from the reaction products. This fact induces to think of the
existence of coordination effects that favor the coupling dien-
eedienophile across a compact transition state.
4. Experimental section
4.1. General methods
Unless otherwise noted, all reactions were conducted under an
atmosphere of dry nitrogen or argon in oven-dried glassware. Raw
materials were obtained from commercial suppliers and used as
received. All solvents were purified using standard techniques be-
fore use: ether, tetrahydrofuran, hexane, and pentane were distilled
under nitrogen from sodium/benzophenone. Acetonitrile was dis-
tilled under nitrogen from CaH2. Infrared spectra were recorded on
a FT-IR NICOLET 510 spectrophotometer as thin films over NaCl
plates. NMR spectra were obtained in CDCl3 on spectrometers at
400 MHz (MERCURY-400) and/or 500 MHz (UNITY-500) for 1H
NMR, and at 100 MHz for 13C NMR. For 1H NMR tetramethylsilane
was used as internal standard. 13C NMR spectra were referenced to
This coordination effect could be taken into consideration by
synthetic chemists when designing retrosynthetic pathways and

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
steric repulsion
O
H3C
CH3
Cis-endo product
(favoured but in a lesser extent)
Compact TS
CH3
O
M
H3C
Steric repulsion
No coordinating
properties
These phenomena propitiate
an extended approach and
also an stepwise mechanism
O
Cis-endo product
Compact TS
(f avoured)
O
ZnLn
The two-bonds link
f acilitates the
approach
coordination >> steric repulsion
X
Steric repulsion
Coordination
X = O, N
Fig. 8. Different interaction of the furan diene, having coordinating and non-coordinating substituents, with the oxyallyl dienophile.
Fig. 9. 1H NMR spectra signal pattern of the four possible diastereoisomers.
the 77.0 ppm resonance of chloroform. When necessary, assign-
ments were established by DEPT, 1He1HeCOSY and HMBC, gHMQC
or HSQC 13Ce1H correlation experiments. Mass spectra were
measured on a HEWLETT-PACKARD 5890 mass spectrometer using
the chemical ionization technique and ammonia as ionizing gas. GC
analyses were performed on HP-8790 gas chromatograph equipped
with a HEWLETTePACKARD-crosslinked MePheeSilicone capillary
and nitrogen was determined by evaluation of the combustion
gases by gas chromatography using a FID detector.
4.2. Experimental conditions for the X-ray diffraction analy-
sis of a single crystal of cycloadduct 20a
A prismatic crystal (0.1ꢂ0.1ꢂ0.2 mm) was selected and mounted
column (L¼25 m,
F
¼0.2 mm,
d
¼2.5
m
m) using helium as gas carrier
on a MAR345 diffractometer with image plate detector. Unit-cell
and a FID detector (T¼250 ꢁC, PH ¼4.2 psi, Pair¼2.1 psi). The ele-
parameters were determined from 1418 reflections (3<
and refined by least-squares method. Intensities were collected
with graphite monochromatized Mo K radiation, using 4 scan-
technique. 4636 reflections were measured in the range
q
<31ꢁ)
2
mental analyses were obtained in a FISONS elemental analyzer,
Model Na-1500. The samples were previously pyrolyzed at 1000 ꢁC
under oxygen atmosphere and the content of carbon, hydrogen,
a

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9991
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
4.3. Cycloaddition reaction methodologies
2,4-Dibromo-3-pentanone and 2,4-diiodo-3-pentanone, used as
precursors of oxyallyl cation, have been prepared according to
procedures described in the literature.19,20
In the process of optimization of the [4þ3] cycloaddition, several
reaction conditions have been used, which are quoted in Table 3.
Table 3
Cycloaddition procedures depending on the used reagents
Reaction
Reducing metal
Dihaloketone
Other
procedure
reagents
Fig. 10. ORTEP Representation for crystal structure of cycloadduct 20A with ciseendo
configuration.
1-Cu
2-Cu
3-Cu
4-Cu
1-Zn
2-Zn
3-Zn
4-Zn
5-Zn
6-Zn
Cu (powder, bronze or submicron) Dibromoketone
Cu (powder, bronze or submicron) Diiodoketone
Cu (powder, bronze or submicron) Dibromoketone
Cu (powder, bronze or submicron) Diiodoketone
d
d
NaI
NaI
d
Table 2
Crystal data and structure refinement for 20a
Zn or metallic couples Zn (Metal)
Zn or metallic couples Zn (Metal)
Zn or metallic couples Zn (Metal)
Zn or metallic couples Zn (Metal)
Zn or metallic couples Zn (Metal)
Zn or metallic couples Zn (Metal)
Dibromoketone
Diiodoketone
Dibromoketone
Diiodoketone
Dibromoketone
Diiodoketone
d
Empirical formula
Formula weight
C14H21NO3
251.32
NaI
NaI
TMSCl
TMSCl
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
293(2) K
ꢂ
0.71073 Aꢀ
Triclinic, P1
ꢂ
a¼9.032(8) A
a
b
¼94.74(6)ꢁ
¼108.64(5)ꢁ
ꢂ
b¼9.421(6) A
ꢂ
4.3.1. Experimental procedures using copper as reducing agent
c¼10.180(7) A
g
¼117.58(4)ꢁ
3
ꢂ
Volume
Z
Calculated density
Absorption coefficient
F(000)
699.6(9) A
2
4.3.1.1. Experimental procedure 1-Cu: cycloaddition by reduction
of a dibromoketone with copper powder. In a double necked flask,
fitted with magnetic stirring and nitrogen atmosphere, freshly acti-
vated copper (210 mg, 3.32 mmol) was added and suspended in
acetonitrile (11 mL). The mixture was cooled down to 0 ꢁC and
1.193 Mg/m3
0.083 mmꢀ1
272
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta¼25.00
Absorption correction
Max. and min transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
0.1ꢂ0.09ꢂ0.08 mm
2.20 to 29.79ꢁ.
the furan derivative (300 mL, 4.24 mmol) was added at once using
ꢀ11ꢃhꢃ11, ꢀ12ꢃkꢃ11, ꢀ13ꢃlꢃ12
4636/2749 [R(int)¼0.0614]
90.7%
amicrosyringe. Then, 2,4-dibromo-3-pentanone(258mg,1.06mmol)
was added dropwise. The reaction mixture was homogenized by
stirring and maintained at the temperature of work by using a heat-
ing/cooling bath with a temperature stabilizing system. The reaction
is controlled by both TLC and GC. The reaction is considered finished
after observing a constant conversion in successive analyses.
Empirical
0.99 and 0.98
Full-matrix least-squares on F2
2749/4/163
1.142
Final R indices [I>2
R indices (all data)
Largest diff. peak and hole
s
(I)]
R1¼0.0692, wR2¼0.2041
The isolation of products from the reaction mixture, in experi-
ments in which the reducing agent is copper, is carried out in the
following way: the mixture was cooled to 0 ꢁC and methylene chlo-
ride was added under constant stirring. The mixture was added over
a 1:1 mixture of water/ice (30 mL approx.) and it was filtered through
a porous sintered plate (filtering plate number 4) under vacuum to
remove excess of copper powder. The phases were decanted and the
aqueous phase was extracted with methylene chloride until discol-
oration of the organic phase (4ꢂ30 mL) is observed. The organic
phases are combined together and washed successively with a 3%
water solution of NH3 (3ꢂ20 mL) until no blue color (due to tet-
raamminecopper(II) complex) was observed in the washing aqueous
extracts, followed by ice-water (2ꢂ20 mL). Finally, the organic phase
was dried with anhydrous MgSO4, filtered, and concentrated to
dryness, obtaining a product consisting of a unique structure or
a mixture of diastereoisomers, depending on the furan substrate. The
obtained oil was submitted to a flash column chromatography on
silica gel, using mixtures of hexane and ethyl acetate of increasing
polarity, eluting bywith hexane/ethyl acetate (95:5) and(90:10) (and
generally in this order) the endo, trans and exo stereoisomers.
R1¼0.0872, wR2¼0.2231
ꢂꢀ3
0.197 and ꢀ0.301 e A
2.20ꢃ
[Rint(on I)¼0.061]. 2132 reflections were assumed as observed
applying the condition I>2 (I). Lorentz-polarization and absorp-
tion corrections were made.
qꢃ29.79. 2749 of which were non-equivalent by symmetry
s
The structure was solved by Direct methods, using SHELXS
computer program and refined by full-matrix least-squares method
with SHELX97 computer program,17 using 4636 reflections, (very
negative intensities were not assumed). The function minimized
was Sw jjFoj2ꢀjFcj2j2, where w¼[
s
2(I)þ(0.1269P)2þ0.0096P]ꢀ1, and
P¼(jFoj2þ2jFcj2)/3, f, f0 and f00 were taken from International Tables
of X-ray Crystallography.18 All H atoms were computed and refined,
using a riding model, with an isotropic temperature factor equal to
1.2 times the equivalent temperature factor of the atom, which are
linked. The final R(on F) factor was 0.069, wR(on jFj2)¼0.204 and
goodness of fit¼1.142 for all observed reflections. Number of re-
fined parameters was 163. Max. shift/esd¼0.00, Mean shift/
esd¼0.00. Max. and min. peaks in final difference synthesis was
ꢂꢀ3
0.197 and ꢀ0.301 e A , respectively.
4.3.1.2. Experimental procedure 2-Cu: cycloaddition by reduction
of the diiodoketone with copper powder. The melting point of 2,4-
diiodo-3-pentanone is close to 0 ꢁC, and in many cases it is not
possible the addition of this reagent at working temperature, in the
liquid state. Therefore, the procedure of addition was modified in
the following way:
The main X-ray data are quoted in Table 2. For additional in-
formation regarding bond lengths and bond angles for compound
20a, as well as the hydrogen coordinates and the anisotropic
thermal parameters see the CIF file deposited as Supplementary
data. The file CCDC-92874 for compound 20a, contains the

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9992
ꢄ Purification method 2. Once the substrate was converted, water
In a double necked flask fitted with magnetic stirring and ni-
was added (5 mL), in order to quench the reaction process, and
the solid was filtrated through a porous plate (filter plate
number 4). Then, the liquid phase was extracted with methy-
lene chloride (5ꢂ15 mL). The organic phases were combined
together and washed with brine (2ꢂ25 mL), dried with anhy-
drous MgSO4, and concentrated to dryness. The obtained oil was
submitted to flash column chromatography on SiO2, eluting
with mixtures of hexane and ethyl acetate of increasing polarity.
trogen atmosphere, freshly activated copper (210 mg, 3.32 mmol)
was placed and suspended in acetonitrile (5 mL). The suspension
was cooled down to 0 ꢁC and the furan derivative (300
mL,
4.24 mmol) was added at once using a microsyringe. Then, 2,4-
diiodo-3-pentanone (360 mg, 1.06 mmol) dissolved in 6 mL of
acetonitrile was added dropwise. The total volume of solvent used
was the same than in the procedure 1-Cu, so that, the total dilution
of the system remains invariable. The work-up and the purification
procedure of products is identical to the one described in experi-
mental procedure 1-Cu.
4.3.2.2. Experimental procedure 5-Zn. Cycloaddition by re-
duction of dibromoketones with Zn and ZneCu couple, in the
presence of trimethylsilyl chloride.
Only in the case of using zinc (or a couple zincecopper) as re-
ducing agent, in some experiments trimethylsilyl chloride has been
added, in order to accelerate the reaction.21
4.3.1.3. Experimental procedure 3-Cu: cycloaddition by reduction
of a dibromoketone with copper powder, in the presence of sodium
iodide. Basically, this procedure is analogous to the one described
in 1-Cu, however, it is worth noting the presence of insoluble salts
in the medium, which provoke changes of color in the crude of
reaction.
In a two necked flask fitted with magnetic stirring and nitrogen
atmosphere, freshly prepared zincecopper couple (217 mg,
3.32 mmol) was suspended in the used solvent (i.e., acetonitrile,
In a double necked flask fitted with magnetic stirring and ni-
trogen atmosphere, freshly activated copper (210 mg, 3.32 mmol)
and sodium iodide (957 mg, 6.36 mmol) were added and sus-
pended in acetonitrile (11 mL). The mixture was cooled down to
11 mL). At the working temperature (i.e., 0 ꢁC), furan (300
mL,
4.24 mmol), trimethylsilyl chloride (135
mL, 1.06 mmol) and 2,4-
0
ꢁC and the furan derivative (300
once using
m
L, 4.24 mmol) was added at
dibromo-3-pentanone (258 mg, 1.06 mmol) were sequentially
added using a microsyringe. The reaction mixture was kept in a bath
stabilized at working temperatureand the course of the reactionwas
periodically controlled by gas chromatography. The reaction was
considered finished after observing a constant conversion in several
successive analyses. The work-up and the isolation of product by CC
were carried out as described in the previous section.
a
microsyringe. Then, 2,4-dibromo-3-pentanone
(258 mg, 1.06 mmol) was added dropwise. Immediately, a yellow-
ish solid was formed and the reaction mixture became turbid. The
mixture got opaque and acquired a brown color. The reaction
mixture was homogenized by stirring and maintained at the work
temperature by using a heating/cooling bath with a temperature
stabilizing system. The reaction was controlled by both TLC and GC.
The reaction was considered finished after observing a constant
conversion in successive analyses. The isolation of products was
performed as described in previous procedures.
4.3.2.3. Experimental procedures 6-Zn: cycloaddition by reduction
of diiodoketones with Zn in the presence of trimethylsilyl chlor-
ide. Procedure similar to 5-Zn, but using the modification de-
scribed in the 2-Cu addition.
4.3.1.4. Experimental procedure 4-Cu: cycloaddition by reduction
of the diiodoketones with copper powder in the presence of sodium
iodide. Procedure similar to 3-Cu, but using the modification of
addition described in 2-Cu.
4.4. Synthesis of furan substrates substituted on C-3
4.4.1. Synthesis of 3-methyl-2-furoic acid, 5. Commercial methyl 3-
methyl-2-furoate, 4, (2.0 g, 14.3 mmol) was reacted under reflux
with 3.8 mL of 30% sodium hydroxide aqueous solution
(28.5 mmol) and 3.6 mL of methanol (88.8 mmol) for 3.5 h. The
solvent was removed and the resulting crude mixture was dis-
solved in 10 mL of water and acidified with concentrated hydro-
chloric acid until pH 1, and extracted with diethyl ether (4ꢂ3 mL).
The organic phases were combined together, dried over magne-
sium sulfate, filtrated, and concentrated to dryness, giving 1.7 g of
3-methyl-2-furoic acid (13.6 mmol, yield 95%). MP: 135 ꢁC (ether).
4.3.2. Experimental procedures using zinc or metallic couples of zinc
as reducing agents
4.3.2.1. Experimental procedures 1e4 Zn. In the same way as
described for procedures using copper as a reducing agent (pro-
cedures 1-Cu to 4-Cu), it is possible to establish four different pro-
cedures for the cycloaddition reaction in the presence of zinc
powder (procedures 1-Zn to 4-Zn). The only difference among these
four procedures is the isolation method of products from the re-
action crude. Thus, due to copper salts have not been generated (not
evenwhen the reducing agent is a zincecopper couple), the washing
process with an aqueous solution of ammonia is not necessary. Next,
two work-up procedures are described for this type of experiments.
The first one, has been used in the cases in which the final product is
labile and could result altered under an aqueous treatment (during
work-up), whereas the second one, has been the procedure chosen
in those cases in which the zinc byproducts were so finely divided
that they pass through percolation columns.
1H NMR (400 MHz, CDCl3,
d, ppm): 2.40 (3H, s, CH3), 6.41 (1H, d,
J4,5¼1.6 Hz, H4), 7.52 (1H, d, J5,4¼1.6 Hz, H5). 13C NMR (100 MHz,
CDCl3, d, ppm): 170.2 (COO), 150.1 (C5), 139.9 (C2), 125.3 (C3), 112.0
(C4), 13.3 (Me). IR (film, n
, cmꢀ1): 1102 (st. CeO), 1136 (st. CeO),
1189 (st. CeO), 1488 (def. CeH), 1599 (st. C]C Ar.), 1670 (st. C]O),
2200e3200 (st. OeH). MS (EI, m/z, %): 126.03 (Mþ, 100); 127.03 (7);
109.03 (MþꢀOH, 20); 81.03 (40, MþꢀCHO2). EA. Calculated for
C6H6O3: C (57.14), H (4.80). Found: C (57.11), H (4.83).
4.4.2. Synthesis of 3-methylfuran, 6.22 A mixture of 3-methyl-2-
furoic acid, 5, (1.7 g, 13.5 mmol), quinoline (5.7 mL, 27 mmol), and
copper powder (0.33 g, 5.2 mmol) was heated in a one-piece
microdistillation setup (fitted with a condenser with an ice-water
circulating system) during 2.5 h at 165e180 ꢁC. As a result, 0.75 g
(9.2 mmol, 68% yield) of 3-methylfuran vapor was condensed in the
ꢄ Purification method 1. Once the reaction was complete, as ob-
served by GC, ethyl acetate (100 mL) was added, in order to
stop the progress of the reaction, and it was submitted to
percolation across a column packed with a small amount of
silica and alumina. Mixtures of ethyl acetate/dichloromethane
were used as eluents. Then, the organic phase was concen-
trated to dryness, and the obtained oil was submitted to flash
column chromatography on silica gel, eluting with mixtures of
hexane and ethyl acetate of increasing polarity.
receiving flask cooled with an ice bath. 1H NMR (400 MHz, CDCl3,
ppm): 2.04 (3H, br s, CH3), 6.23e6.25 (1H, m, H4), 7.19e7.21 (1H, m,
H2), 7.32e7.34 (1H, m, H5).13C NMR (100 MHz, CDCl3,
, ppm): 142.7
(C5), 139.3 (C2), 119.8 (C3), 112.2 (C4), 9.6 (Me). IR (film,
, cmꢀ1):
d,
d
n

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9993
1100 (st. CeO), 1130 (st. CeO), 1200 (st. CeO), 1480 (def. CeH), 1588
(st. C]C Ar.). MS (DIP, EI, m/z, %): 82.04 (Mþ, 100); 83.04 (6). EA.
Calculated for C5H6O: C (73.15), H (7.37). Found: C (73.10), H (7.41).
verified by gas chromatography, the acid chloride acid disappeared
and converted into ethyl 3-furoate. Diethyl ether (100 mL) was
added to the reaction mixture and it was successively extracted
with an aqueous saturated solution of NaHCO3 (2ꢂ25 mL) and
water (2ꢂ25 mL). The aqueous phases were extracted with diethyl
ether (2ꢂ25 mL) and all the organic phases were combined to-
gether and dried with anhydrous MgSO4. The solvent was evapo-
rated under vacuum affording pure ethyl 3-furoate (2.34 g,
4.4.3. Synthesis of 3,4-dimethyl-2-butenolide, 8.23 A mixture of
NaBH4 (0.60 g, 15.9 mmol) in anhydrous THF (3 mL) was stirred and
cooled in an ice bath while 2.0 g (15.9 mmol) of 2,3-dimethyl-
maleic anhydride, 7, dissolved in 19.3 mL of THF anhydrous was
added slowly. The ice bath was removed and the stirring was
continued for 1.5 h. The solution was cooled in an ice bath and
acidified with 2 M aqueous HCl down to pH 5e6. The resulting
mixture was concentrated, dissolved in 30 mL of water and
extracted three times with 10 mL of diethyl ether. The organic
phases were combined, dried over anhydrous magnesium sulfate,
and concentrated to dryness, affording 0.90 g (8.0 mmol) of 2,3-
yield¼95%) as a lightly yellowish oil. IR (film,
n
, cmꢀ1): 3080, 3000,
2975, 2960, 1730 (C]O, st), 1580, 1520, 1410, 1370, 1315, 1170, 1080,
1030, 1010. 1H NMR (200 MHz, CDCl3,
d
, ppm): 1.35 (3H, t, J¼7.0 Hz,
H200), 4.30 (2H, d, J¼7.0 Hz, H100), 6.737 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz,
H40), 7.41 (1H, dd, J1¼1.8 Hz, J2¼0.4 Hz, H50), 8.00 (1H, dd, J1¼1.8 Hz,
J2¼0.2 Hz, H20). 13C NMR (50 MHz, CDCl3,
d
, ppm): 14.3 (C200), 60.4
(C100), 109.7 (C40), 119.5 (C30), 143.5 (C50), 147.5 (C20), 163.0 (C1). MS
[DIP-EI, 70 eV, 150 ꢁC, m/z (%)]: 140 (1, M), 111 (42, MꢀC2H5), 95 (17,
MꢀC2H5O). GC (50 ꢁC,1 min,10 ꢁC/min, 250 ꢁC,15 min): tR¼8.1 min.
EA. Calculated for C7H8O3: C (59.99%), H (5.75%). Found: C (60.01%),
H (5.73%).
dimethyl-2-butenolide (yield 50%). 1H NMR (300 MHz; CDCl3;
d,
ppm) 1.83 (3H, br s, CH3), 2.02 (3H, br s, CH3), 4.63 (2H, q,
J5,7¼0.8 Hz, H5). 13C NMR (100 MHz, CDCl3,
d
, ppm): 175.7 (C2),
157.1 (C4), 122.8 (C3), 73.4 (C5), 15.0 (C7), 9.2 (C6). IR (film,
n
, cmꢀ1
)
1031 (st. CeO), 1081 (st. CeO), 1456 (def. CeH), 1684 (st. C]C), 1751
(st. C]O), 2927 (st. CeH). GC (50 ꢁC, 1 min, 5 ꢁC/min, 250 ꢁC,
10 min) tR¼7.8 min. MS (DIP, EI, m/z, %): 112.05 (Mþ, 100); 113.04
(8); 97.03 (MþꢀMe, 30); 68.06 (MþꢀCO2, 15). EA. Calculated for
C6H8O2: C (64.27), H (7.19). Found: C (64.29), H (7.22).
4.4.6. Synthesis of 3-furylmethanol, 12.
O1'
5'
4'
2'
OH
1
3'
4.4.4. Synthesis of 3,4-dimethylfuran, 9.24 3,4-Dimethyl-2-butenolide
(0.79 g, 7.0 mmol), 8, dissolved in dry ether (15 mL) was stirred and
cooled to ꢀ20 ꢁC in a 25 mL flask, fitted with magnetic stirring and
argon atmosphere. To this solution, diisobutylaluminum hydride
(6.4 mL, 7.9 mmol from a 25% w/w solution in hexane) was added
slowly, avoiding the temperature to increase. Once the addition was
complete, the mixture was allowed to stir at ꢀ20 ꢁC for 1 h before
quenching the reaction with 5 mL of 10% aqueous H2SO4. After
warming to ambient temperature, the aqueous and organic phases
were separated. The aqueous phase was extracted with ether
(3ꢂ10 mL) and the ether extracts were combined with the organic
phase, washed with brine (2ꢂ10 mL) and 5% NaHCO3 solution
(2ꢂ10 mL) and dried over MgSO4 and filtered. The solvents of the
resulting mixture were removed by controlled simple distillation in
a one-piece distillation setup and then by a Kugelrohr distillation ap-
paratus at atmospheric pressure (oven temperature 42e54 ꢁC, for the
removal of solvents; oven temperature 91e100 ꢁC, for the distillation
of 3,4-dimethylfuran). 0.21 g (2.2 mmol) of the product was obtained
A suspension of LiAlH4 (516 mg, 13 mmol) in dry diethyl ether
(10 mL) was placed in an oven-dried two-necked flask, fitted with
a condenser, magnetic stirring and nitrogen atmosphere. Then, a so-
lution of ethyl 3-furoate (2 g, 13.6 mmol) in dry diethyl ether (10 mL)
was added, at room temperature. Immediately, generation of H2 was
observed. The reaction mixture was kept under these conditions for
45 min (control by gas chromatography). The excess of hydride was
quenched byaddingethyl acetate (50 mL). Then, the reaction mixture
was washed with water (5ꢂ20 mL). The aqueous phase was extracted
with ethyl acetate (2ꢂ20 mL) and all organic phases were combined
together, dried with anhydrous MgSO4, and concentrated to dryness.
The residue was submitted to a flash column chromatography (SiO2,
eluting it with mixtures of hexane and ethyl acetate of increasing
polarity) obtaining, with hexane/ethyl acetate (8:2), 3-furylmethanol
(850 mg, yield¼65%) as a transparent oil. The resulting product was
very volatile, so, the process of concentration in the rotary
evaporator must be carried out at 0 ꢁC or by simple distillation. IR
(film, n
, cmꢀ1): 3350 (HeO, st), 3080, 2980, 1610, 1520, 1460, 1400,
1160, 1030, 970, 880. 1H NMR (200 MHz, CDCl3,
d, ppm): 4.55 (2H, s,
in this way (yield 30%). 1H NMR (400 MHz; CDCl3;
J2,6¼J5,7¼0.4 Hz, CH3, H6 and H7), 7.14 (2H, q, J2,6¼J5,7¼0.4 Hz, H2 and
d, ppm) 1.95 (6H, d,
H1), 6.43 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz, H40), 7.40 (2H, dd, J1¼1.8 Hz,
J2¼0.8 Hz, H20 and H50). 13C NMR (50 MHz, CDCl3,
d, ppm): 56.6
H5). 13C NMR (100 MHz, CDCl3,
d, ppm): 138.3 (C2, C5), 121.3 (C3, C4),
(C1), 109.7 (C40), 125.0 (C30), 139.8 (C20), 143.3 (C50). MS [GCeMS
(CI), NH3, 70 eV, 150 ꢁC, m/z, (%)]: 132 (100, MþN2H6), 115 (14,
MþNH3), 98 (13, Mþ). GC (50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 15 min):
tR¼5.6 min. TLC (SiO2, hexane/ethyl acetate, 1:1): Rf¼0.55 (black
color, developed with anisaldehydeeH2SO4 reagent). EA. Calculated
for C5H6O3: C (61.22%), H (6.16%). Found: C (61.19%), H (6.20%).
8.7 (Me). GC (35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min) tR¼1.6 min. MS
(DIP, EI, m/z, %): 96.06 (Mþ, 100); 97.06 (5); 81.03 (MþꢀMe, 25). EA.
Calculated for C6H8O: C (74.97), H (8.39). Found: C (75.01), H (8.37).
4.4.5. Synthesis of ethyl 3-furoate, 11.
O1'
5'
4'
2'
4.4.7. Isolation of 3-furylmethyl acetate, 120.
O
1
2''
3'
O1''
1''
5''
4''
2''
O
2
1
O
1'
3''
In a two-necked oven dried 50 mL flask, fitted with magnetic
stirring and nitrogen atmosphere, 3-furoic acid (2 g, 17 mmol) was
placed at room temperature and thionyl chloride (12.9 mL,
177 mmol) was added through the condenser. Then, the mixture
was warmed up to reflux, maintaining this temperature for 4 h in
order to get complete conversion of 3-furoic acid into 3-furoyl
chloride. The excess of thionyl chloride was separated by distilla-
tion. Next, ethanol (10.3 mL, 177 mmol) was added to the resulting
residue and the solution was warmed up to reflux. After 1 h, as
O
In the before-described reaction, 3-furylmethyl acetate was ob-
tained as a by-product and it was isolated by flash column chro-
matography (SiO2, eluting with mixtures of hexane and ethyl acetate
of ethyl of increasing polarity), affording with hexane/ethyl acetate
(95:5) 410 mg (yield¼10%) of this acetylated product as a yellowish
oil. IR (film,
1370, 1240, 1170, 1030, 960. 1H NMR (200 MHz, CDCl3,
n
, cmꢀ1): 3080, 2980, 1750 (C]O, st), 1510, 1460, 1380,
d, ppm): 2.07

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9994
(3H, s, H2), 4.98 (2H, s, H10), 6.43 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz, H400),
4.4.9. Synthesis of N,N-diethyl-3-furylmethylamine, 14.
7.40 (1H, t, J¼1.8 Hz, H500), 7.47 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz, H200).13
C
2''
O1
NMR (50 MHz, CDCl3, d
, ppm): 170.3 (C1), 142.7 (C500), 139.4 (C200),
1''
5
2
118.5 (C300), 110.7 (C400), 57.6 (C10), 20.8 (C2). MS [GCeMS (CI), NH3,
70 eV, 150 ꢁC, m/z, (%)]: 174 (40, MþN2H6), 158 (100, M1þNH4), 140
(11, Mþ). GC (50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 15 min): tR¼7.96 min.
TLC (SiO2, hexane/ethyl acetate, 8:2): Rf¼0.60 55 (black color, de-
veloped with anisaldehydeeH2SO4 reagent). EA. Calculated for
C7H8O3: C (59.99%), H (5.75%). Found: C (59.98%), H (5.77%).
N
1'
4
3
2''
1''
A suspension of LiAlH4 (796 mg, 21 mmol) in dry diethyl ether
(7 mL) was placed in an oven-dried two-necked flask, fitted with
a condenser, magnetic stirring and nitrogen atmosphere. Then,
a solution of N,N-diethyl-3-furamide (4 g, 21 mmol) in dry diethyl
ether (10 mL) was added, at room temperature. Immediately,
generation of H2 was observed. The reaction mixture was stirred
under reflux of solvent for 15 h. The excess of hydride was
quenched by adding ethyl acetate (50 mL). The solid was separated
4.4.8. Synthesis of N,N-diethyl-3-furamide, 13.25
2''
O1'
1''
2'
5'
N
€
1
by filtration through a Buchner funnel and washed with ether
4'
3'
2''
1''
(100 mL) and brine (5ꢂ20 mL). The aqueous phase was extracted
with ethyl acetate (2ꢂ20 mL) and all organic phases were com-
bined together, dried with anhydrous MgSO4, and concentrated to
dryness, obtaining pure product (1.78 g, yield¼50%), which does
O
In a two-necked oven dried 50 mL flask, fitted with magnetic
stirring and nitrogen atmosphere, 3-furoic acid (5 g, 44.3 mmol)
was placed at room temperature and thionyl chloride (12.9 mL,
177 mmol) was added through the condenser. Then, the mixture
was heated up to reflux, maintaining this temperature for 4 h in
order to get complete conversion of 3-furoic acid into 3-furoyl
chloride. The excess of thionyl chloride was separated by simple
distillation. In another flask, a solution of diethylamine (13.88 mL,
133 mmol) in dry tetrahydrofuran (10 mL) is prepared. Over this
solution, the crude 3-furoyl chloride of the previous step dissolved
in dry tetrahydrofuran (2ꢂ10 mL) was added, at 0 ꢁC and dropwise.
Then, the reaction mixture was kept at room temperature for 19 h,
observing the formation of a white solid (diethylammonium chlo-
ride). The reaction mixture was concentrated to dryness and the
resulting crude oil was diluted with diethyl ether (100 mL) and
washed with water (50 mL). The aqueous (basic) phase was acidi-
not need further purification. IR (film, n
, cmꢀ1): 3040, 2990, 2980,
2800, 1510, 1450, 1400, 1200, 1150, 1030, 880. 1H NMR (200 MHz,
CDCl3,
d
, ppm): 1.06 (6H, t, J¼7.0 Hz, H200), 2.51 (4H, q, J¼7.0 Hz,
H100), 3.49 (2H, s, H10), 6.37 (H1, d, J¼0.8 Hz, H4), 7.32 (1H, dd,
J1¼1.8 Hz, J2¼0.8 Hz, H2), 7.37 (1H, t, J¼1.8 Hz, H5). 13C NMR
(50 MHz, CDCl3, d
, ppm): 11.84 (C200), 46.46 (C100), 46.90 (C10), 111.38
(C4), 121.80 (C3), 140.49 (C2), 142.65 (C5). MS [GCeMS (CI), NH3,
70 eV, 150 ꢁC, m/z, (%)]: 154 (100, MþHþ). EA. Calculated for
C9H15NO: C (70.55%), H (9.87%). Found: C (70.57%), H (9.85%).
4.5. Synthesis of cycloadducts. Physical and spectroscopic
characterization
4.5.1. Synthesis of 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one.
O
O
O
O
9
9
9
9
10
10
10
10
3
3
3
3
2
2
2
2
4
4
4
4
8
O
8
O
8
O
8
O
1
5
1
1
1
5
5
5
7
6
7
6
7
6
7
6
15b
15a
15d
15c
Enantiomers
fied with concentrated hydrochloric acid (up to pH <4) and it was
extracted with ethyl acetate (3ꢂ100 mL). All organic phases were
combined, dried with anhydrous MgSO4, filtered, and concentrated
under vacuum in a rotary evaporator, affording pure product
(5.86 g, yield¼72%) as a colorless oil, which does not need further
In the cycloaddition reactions in which a mixture of cyclo-
adducts 15aed are formed, the diastereoisomers 15a, 15b and 15cd
can be separated by successive flash column chromatographies on
silica gel, eluting with mixtures of hexane and ethyl acetate of in-
creasing polarity. The elution order is 15a, then 15cd and finally
15b, by using hexane/ethyl acetate 95:5 and 90:10 as eluents. The
assignment of configuration has been carried out on the basis of 1H
NMR and 13C NMR correlations by 1D and 2D experiments (COSY,
HMBC, HSQC, HETCOR, etc.).
purification. IR (film, n
, cmꢀ1): 3060, 2990, 2970, 1630 (amide I),
1510 (amide II), 1420, 1390, 1370, 1320, 1300, 1220, 1160, 1120, 1070,
1020. 1H NMR (200 MHz, CDCl3,
d
, ppm): 1.21 (6H, t, J¼7.0 Hz, H200),
3.47 (4H, q, J¼7.0 Hz, H100), 6.58 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz, H40),
7.40 (1H, t, J¼1.8 Hz, H50), 7.69 (1H, dd, J1¼1.8 Hz, J2¼0.8 Hz, H20). 13C
Isomer 15a: IR (KBr, n
, cmꢀ1): 3080, 2974, 2950, 2885,1715 (C]O,
st), 1590 (C]C, st), 1460e1450 (CeC, d), 1380 (CeH, d), 1340, 1160,
NMR (50 MHz, CDCl3,
d
, ppm): 13.80 (C200), 41.69 (C100), 90.22 (C30),
110.17 (C40), 142.64 (C50), 142.68 (C20), 164.09 (C1). MS [GCeMS (þCI),
NH3, 70 eV, 150 ꢁC, m/z, (%)]: 185 (100, MþNH4), 168 (79 (MþH )).
GC (50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 15 min): tR¼13.84 min. CCF
(SiO2, hexane/ethyl acetate, 1:1): Rf¼0.46 (developed with ani-
1085, 920. 1H NMR (200 MHz, CDCl3,
d
, ppm): 0.97 (6H, d, J¼7.0 Hz,
H9 and H10), 2.80 (2H, dq, J1¼7.0 Hz, J2¼4.4 Hz, H2 and H4), 4.85 (2H,
d, J¼4.4 Hz, H1 and H5), 6.34 (2H, s, H6 and H7). 13C NMR (50 MHz,
CDCl3, d, ppm): 10.0 (C9 and C10), 50.3 (C2 and C4), 82.6 (C1 and C5),
saldehydeeH2SO4 reagent). EA. Calculated for C9H13NO3:
C
133.5 (C6 and C7), 208.9 (C3). MS [GCeMS (CI), NH3, 70 eV, 150 ꢁC,
m/z, (%)]: 187 (100, MþN2H5), 170 (82, MþNH4), 153 (2, MþH), 152
(64.65%), H (7.84%). Found: C (64.67%), H (7.81%).

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A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9995
(1, Mþ). EA. Calculated for C9H12O2: C (71.03%), H (7.95%). Found: C
(71.42%), H (8.02%). GC (50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 1 min):
tR¼11.80 min.
br.d, J1,2¼4.5 Hz, H1), 5.86e5.88 (1H, m, H7). 13C NMR (400 MHz;
CDCl3; d, ppm): 10.1,10.3 (C9, C10),15.2 (C11), 48.8 (C4), 51.0 (C2), 83.4
(C5), 85.7 (C1), 126.6 (C7), 145.1 (C6), 209.5 (C3). MS [GCeCIeNH3,
tR¼8.08 min, 70 eV, 200 ꢁC, CHCl3, m/z (%)]: 184 (14, MþNH4), 167
(100, MþH), 166 (36, M), 109 (8, MꢀC3H5O), 95 (12, MꢀC4H7O). EA.
Calculated for C10H14O2: C (72.26), H (8.49%). Found: C (72.29), H
(8.51%). GC (35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min): tR¼6.4 min.
Isomer 15b: IR (KBr, n
, cmꢀ1): 3080, 2960, 2925,1885,1715 (C]O,
st),1630 (C]C, st),1450,1375,1320,1240,1175,1085,1040, 960, 815.
1H NMR (200 MHz, CDCl3,
, ppm): 1.36 (6H, d, J¼7.5 Hz, H9 and
H10), 2.28 (2H, q, J¼7.5 Hz, H2 and H4), 4.65 (2H, s, H1 and H5), 6.27
(2H, s, H6 and H7). 13C NMR (50 MHz, CDCl3,
, ppm): 17.7 (C9 and
d
d
cis-Diaxial isomer, 16b: IR (film, n
, cmꢀ1): 1005 (st. CeO),1060 (st.
C10), 49.8 (C2 and C4), 81.9 (C1 and C5),133.6 (C6 and C7), 213.7 (C3).
MS [GCeMS (CI), NH3, 70 eV, 150 ꢁC, m/z, (%)]: 187 (100, MþN2H5),
170 (30, MþNH4), 153 (52, MþH), 152 (5, Mþ). EA. Calculated for
C9H12O2: C (71.03%), H (7.95%). Found: C (71.21%), H (7.86%). GC
(50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 1 min): tR¼11.46 min.
CeO),1149 (st. CeO),1450 (def. CeH),1648 (st. C]C),1705 (st. C]O),
2940 (st. CeH). 1H NMR (500 MHz, CDCl3,
d, ppm): 1.33 (3H, d,
J10,4¼7.5 Hz, H10), 1.36 (3H, d, J2,9¼7.5 Hz, H9), 1.79 (3H, br s, H11),
2.22 (1H, q, J10,4¼7.5 Hz, H4), 2.34 (1H, q, J2,9¼7.5 Hz, H2), 4.31 (1H, s,
H5), 4.56 (1H, s, H1), 5.78e5.80 (1H, m, H7). 13C NMR (400 MHz;
Isomers 15cd (racemic mixture): IR (KBr,
n
, cmꢀ1): 3060, 2965, 2945,
CDCl3; d, ppm) 12.8 (C11),17.8,18.0 (C9, C10), 49.1 (C4), 50.3 (C2), 82.7
2885, 1707 (C]O, st), 1600 (C]C, st), 1460, 1450, 1370, 1240, 1165,
(C5), 85.0 (C1), 127.3 (C7), 143.9 (C6), 214.3 (C3). MS [GCeCIeNH3,
tR¼7.80 min, 70 eV, 200 ꢁC, CHCl3, m/z (%)]: 184 (40, MþNH4), 167
(100, MþH), 166 (92, M),109 (12, MꢀC3H5O), 95 (26, MꢀC4H7O). EA.
Calculated for C10H14O2: C (72.26), H (8.49%). Found: C (72.31), H
(8.47%). GC (35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min): tR¼6.1 min.
trans Diastereoisomers, 16c,d. Only isomer 16d has been formed
or detected in very small amount. Isomer 16c was not formed or if
formed it has been in such a small amount that it was not detected
by high field 1H NMR, GC and GCeMS on the reaction crude mix-
1085, 920. 1H NMR (200 MHz, CDCl3,
d, ppm): 0.96 (3H, d, J¼7.0 Hz,
H9),1.35 (3H, d, J¼7.2 Hz, H10), 2.36 (1H, q, J¼7.2 Hz, H4), 2.85 (1H, dq,
J1¼7.0 Hz, J2¼4.4 Hz, H2), 4.67 (1H, s, H1), 4.80 (1H, d, J¼4.4 Hz, H5),
6.31 (1H, d, J¼2.0 Hz, H6) 6.33 (1H, d, J¼2.0 Hz, H7).13C NMR (50 MHz,
CDCl3, d, ppm): 10.1 (C9),16.1 (C10), 48.6 (C4), 50.3 (C2), 81.9 (C5), 82.9
(C1), 132.0 (C6), 135.1 (C7), 213.7 (C3). MS [GCeMS (CI), NH3, 70 eV,
150 ꢁC, m/z, (%)]: 187 (100, MþN2H5),170 (85, MþNH4),153 (2, MþH).
EA. Calculated for C9H12O2: C (71.03%), H (7.95%). Found: C (71.10%), H
(7.99%). GC (50 ꢁC, 1 min, 10 ꢁC/min, 250 ꢁC, 1 min): tR¼11.61 min.
ture. IR (film,
n
, cmꢀ1): 998 (st. CeO), 1058 (st. CeO), 1155 (st. CeO),
1449 (def. CeH), 1650 (st. C]C), 1707 (st. C]O), 2938 (st. CeH). 1H
4.5.2. Synthesis of 2,4,6-trimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one.
NMR (500 MHz; CDCl3;
d, ppm): 0.82 (3H, d, J¼7.5 Hz, H9), 1.23 (3H,
O
O
O
O
9
9
9
9
10
10
10
10
3
3
3
3
2
2
2
2
4
4
4
4
8
O
8
O
8
O
8
O
1
5
1
1
1
5
5
5
7
6
7
6
7
6
7
6
16b
16a
16d
16c
Diastereoisomers were separated after successive flash column
chromatographies on silica gel, eluting with mixtures of hexane and
diethyl ether of increasing polarity.
d, J¼7.5 Hz, H10),1.82 (3H, s, H11), 2.37e2.47 (4H, m, H4), 2.50e2.61
(1H, m, H2), 4.35 (1H, s, H5), 4.71 (1H, brd, J1,2¼4.5 Hz, H1),
5.82e5.84 (1H, m, H7). MS [GCeCIeNH3, tR¼8.50 min, 70 eV,
200 ꢁC, CHCl3, m/z (%),]: 184 (45, MþNH4), 167 (100, MþH), 166
(90, M), 109 (8, MꢀC3H5O), 95 (20, MꢀC4H7O). EA. Calculated for
C10H14O2: C (72.26), H (8.49%). Found: C (72.23), H (8.52%). GC
(35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min): tR¼5.9 min.
4.5.2.1. cis-Diequatorial Isomer, 16a. IR (film,
CeO), 1053 (st. CeO), 1151 (st. CeO), 1448 (def. CeH), 1644 (st. C]C),
1706 (st. C]O), 2935 (st. CeH). 1H NMR (500 MHz, CDCl3,
, ppm):
n
, cmꢀ1): 999 (st.
d
0.94 (3H, d, J4,10¼7.5 Hz, H10),1.04 (3H, d, J2,9¼7.5 Hz, H9),1.85 (3H, br
s, H11), 2.79 (1H, dq, J4,5¼4.5 Hz, J4,10¼7.5 Hz, H4), 2.90 (1H, dq,
J1,2¼4.5 Hz, J2,9¼7.5 Hz, H2), 4.57 (1H, d, J4,5¼4.5 Hz, H5), 4.73 (1H,
4.5.3. Synthesis of 2,4,6,7-tetramethyl-8-oxabicyclo[3.2.1]oct-6-en-3-
one.
O
O
O
O
9
9
9
9
10
10
10
10
3
3
3
3
2
2
2
2
4
4
4
4
8
O
8
O
8
O
8
O
1
5
1
1
1
5
5
5
7
6
7
6
6
6
7
7
12
11
11
12
11
12
12
11
17c
17d
17b
17a
Enantiomers

ꢀ
~
A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9996
cis-Diequatorial isomer, 17a: IR (ATR,
n
, cmꢀ1): 1028 (st. CeO),
Found: C (64.50%), H (7.12%). GC (50 ꢁC, 1 min, 10 ꢁC/min, 290 ꢁC,
1152 (st. CeO), 1223 (st. CeO), 1456 (def. CeH), 1653 (st. C]C), 1709
(st. C]O), 2876 (st. CeH), 2933 (st. CeH), 2972 (st. CeH), 3418
15 min): 12.03 min. TLC (SiO2, hexane/ethyl acetate, 9:1): Rf¼0.20
(developed with vanillinesulfuric acid reagent).
(harmonic C]O). 1H NMR (500 MHz, CDCl3,
d, ppm): 1.02 (6H d,
CH3; J2,9¼J4,10¼7.3 Hz, H9 and H10), 1.71 (6H, s, H11 and H12), 2.88
4.5.5. Synthesis of (1R*,2S*,4R*,5R*)-6-hidroximethyl-2,4-dimethyl-
8-oxabicyclo[3.2.1]oct-6-en-3-one, 19a.
(2H, dq, J1,2¼J4,5¼4.0 Hz, H2 and H4), 4.55 (2H, d, J1,2¼J4,5¼4.0 Hz,
H1 and H5). 13C NMR (100 MHz; CDCl3;
d, ppm): 10.1 (C9, C10), 12.5
O
(C11, C12), 50.8 (C2, C4), 87.0 (C1, C5), 134.8 (C6, C7), 209.7 (C3). MS
[GCeCIeNH3, 70 eV, 200 ꢁC, CHCl3, m/z (%)]: 182 (19, MþH), 181
(100, M), 123 (4, MꢀC3H5O), 109 (4, MꢀC4H7O). EA. Calculated for
C11H16O2: C (73.30), H (8.95%). Found: C (73.33), H (8.98%). GC
(35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min) tR¼7.0 min.
9
10'
3
2
4
8
O
cis-Diaxial isomer, 17b: IR (ATR, n
, cmꢀ1) 1030 (st. CeO), 1150 (st.
1
5
CeO),1225 (st. CeO),1460 (def. CeH),1655 (st. C]C),1710 (st. C]O),
2901 (st. CeH), 2935 (st. CeH), 2980(st. CeH), 3420(harmonic C]O).
7
6
1H NMR (500 MHz, CDCl3,
d
, ppm): 1.35 (6H, d, J2,9¼J4,10¼7.5 Hz, H9
and H10), 1.65 (6H, s, H11 and H12), 2.27 (2H, q, J2,9¼J4,10¼7.5 Hz, H2
and H4), 4.32 (2H, s, H1 and H5). 13C NMR (100 MHz; CDCl3;
, ppm):
11
OH
d
(cis-endo isomer)
10.1 (C11, C12),17.8 (C9, C10), 47.7(C2, C4), 86.1 (C1, C5),135.7 (C6, C7),
214.5 (C3). MS [GCeCIeNH3, 70 eV, 200 ꢁC, CHCl3, m/z (%)]: 199 (2,
MþNH4), 181 (84, MþH), 180 (100, M), 123 (6, MꢀC3H5O), 109 (5,
MꢀC4H7O). EA. Calculated for C11H16O2: C (73.30), H (8.95%). Found: C
(73.28), H (8.89%). GC (35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min):
tR¼6.6 min.
The experimental method 2-Zn was used to prepare compound
19a from furan 12, but modified by stirring at 0 ꢁC (see the General
methods section for experimental details).
Results: Yield¼70%. Diastereoselectivity: cis/trans¼100:0, endo/
exo¼100:0.
Isomer ciseendo: IR (film, n
, cmꢀ1): 3448 (OeH, st), 2932, 1734
trans Isomers, 17c,d (racemic mixture): IR (ATR, n
, cmꢀ1) 1029 (st.
(C]O, st), 1684, 1653, 1559, 1456, 1375, 1150, 1051, 928. 1H NMR
(200 MHz, CDCl3,
CeO),1155 (st. CeO),1220 (st. CeO),1458 (def. CeH),1651 (st. C]C),
d
, ppm): 0.96 (3H, d, J¼7.0 Hz, H9), 1.03 (3H, d,
1708 (st. C]O), 2890 (st. CeH), 2930 (st. CeH), 2978 (st. CeH). 1H
J¼7.0 Hz, H10), 2.88 (2H, m, H2 and H4), 4.21 (2H, d, J¼12 Hz, H11),
4.31 (1H, dd, J1¼5.0 Hz, J2¼1.8 Hz, H1), 4.81 (1H, d, J¼4.4 Hz, H5),
NMR (500 MHz, C5D5N,
d
, ppm): 1.01 (3H, d, J4,10¼7.5 Hz, H10), 1.35
6.16 (1H, d, J¼1.8 Hz, H7). 13C NMR (50 MHz, CDCl3,
d, ppm): 10.5
(9H, d, J2,9¼7.5 Hz, H9),1.66 (3H, s, H11),1.75 (3H, s, H12), 2.32e2.39
(2H, q, J4,10¼7.5 Hz, J2,9¼7.5 Hz, H2 and H4), 4.47e4.49 (2H, m, H1
and H5). MS [GCeCIeNH3, 70 eV, 200 ꢁC, CHCl3, m/z (%)]: 181 (70,
MþH), 180 (100, M), 123 (4, MꢀC3H5O), 120 (3, MþNH4), 109 (5,
MꢀC4H7O). EA. Calculated for C11H16O2: C (73.30), H (8.95%). Found:
C (73.35), H (8.90%). GC (35 ꢁC, 1 min, 20 ꢁC/min, 250 ꢁC, 10 min):
tR¼6.4 min.
(C9), 10.9 (C10), 47.3 (C4), 50.8 (C2), 64.3 (C11), 80.2 (C5), 87.4 (C1),
127.3 (C7), 148.1 (C6), 210.2 (C3). MS [GCeMS (CI), NH3, 70 eV,
150 ꢁC, m/z, (%)]: 200.1 (100, MþNH4), 183.2 (5, MþH), 164 (30,
MꢀOH). EA. Calculated for C10H14O3: C (65.91%), H (7.74%). Found:
C (65.87%), H (7.79%). CCF (SiO2, hexane/ethyl acetate, 9:1):
Rf¼0.26 (blue color developed with anisaldehydeesulfuric acid
reagent).
4.5.4. Synthesis of ethyl (1R*,2S*,4R*,5R*)-2,4-dimethyl-8-oxabicyclo
[3.2.1]oct-6-en-3-oxo-6-carboxilate, 18a.
4.5.6. Synthesis of (1R*,2S*,4R*,5R*)-N,N-diethyl-2,4-dimethyl-3-
oxo-8-oxabicyclo[3.2.1]oct-6-en-6-carboxamide, 20a.
O
9
10
O
3
9
2
10
3
4
2
8
O
4
8
O
1
5
1
5
7
6
1'
2'
11
O
6
7
11
N
O
2'
1'
O
2'
1'
(cis-endo isomer)
Product 18a has been prepared from furan 11 under different
reaction conditions, which are quoted in Table 1 (see also the
General methods section for the synthetic procedures).
(cis-endo isomer)
Product 20a has been prepared from furan 13, under different
reaction conditions, which are quoted in Table 1 (see also the
General methods section for the synthetic procedures).
Isomer ciseendo: IR (film,
n
, cmꢀ1): 2977, 2938, 2878,1715 (C]O,
st),1458, 1379, 1277, 1250, 1001, 1032, 933. 1H NMR (200 MHz,
Isomer ciseendo: IR (film,
n
, cmꢀ1): 2980, 2920, 1700 (C]O, st),
CDCl3,
d
, ppm): 1.00 (3H, d, J¼7.4 Hz, H9),1.01 (3H, d, J¼7.4 Hz, H10),
1460, 1430, 1350, 1310, 1210, 1090, 1030, 930. 1H NMR (200 MHz,
1.28 (3H, t, J¼7.4 Hz, H20), 2.93 (2H, m, H2 and H4), 4.21 (2H, m,
CDCl3,
d
, ppm): 0.93 (3H, d, J¼7.2 Hz, H9), 1.10 (3H, d, J¼7.2 Hz, H10),
H10), 4.97 (1H, dd, J1¼5.2 Hz, J2¼1.8 Hz, H1), 5.11 (1H, d, J¼4.4 Hz,
1.14 (6H, br t, J¼7.0 Hz, H20 and H200), 2.93 (2H, dq, J1¼4.4 Hz,
J2¼7.0 Hz, H2 and H4), 3.20 (4H, m, H10 and H100), 4.96 (1H, dd,
J1¼4.4 Hz, J2¼1.8 Hz, H1), 5.19 (1H, d, J¼4.4 Hz, H5), 6.68 (1H, d,
H5), 7.16 (1H, d, J¼1.8 Hz, H7). 13C NMR (50 MHz, CDCl3,
d, ppm):
10.02 (C9), 10.5 (C10), 14.1 (C20), 50.2 (C2), 50.9 (C4), 60.9 (C10), 82.0
(C1), 83.9 (C5), 140.8 (C6), 143.4 (C7), 168.2 (C11), 209.2 (C3). MS
[GCeMS (CI), NH3, 70 eV, 150 ꢁC, m/z, (%)]: 242 (100, MþNH4), (225
(2, MþH)). EA. Calculated for C10H16O4: C (64.27%), H (7.19%).
J¼1.8 Hz, H7). 13C NMR (50 MHz, CDCl3,
d, ppm): 9.4 (C9), 10.4 (C10),
12,3 and 14.5 (C20 and/or C200), 42.6 and 39.6 (C10 and/or C100), 50.6
(C2), 50.9 (C4), 84.2 (C1), 84.7 (C5), 131.4 (C7), 142.1 (C6), 163.1

ꢀ
~
A.M. Montana et al. / Tetrahedron 68 (2012) 9982e9998
9997
(C11), 208.7 (C3). MS [GCeMS (CI), NH3, 70 eV, 150 ꢁC, m/z, (%)]: 269
References and notes
(45, MþNH4), 262 (100, MþH). EA. Calculated for C14H21NO3: C
(66.91%), H (8.42%). Found: C (67.04%), H (8.25%). GC (50 ꢁC, 1 min,
10 ꢁC/min, 290 ꢁC, 15 min): 15.78 min. TLC (SiO2, hexane/ethyl ac-
etate, 1:1): Rf¼0.17 (blue color developed with anisaldehy-
deesulfuric acid reagent).
1. (a) Hoffmann, H. M. R. Angew. Chem.1973, 20, 877e894; (b) Noyori, R.; Hayakawa,
Y. Org. React. 1983, 29, 163e344; (c) Joshi, N. N.; Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 1e88; (d) Pavzda, A.; Schoffstall, A. Adv. Cycloaddit. 1990, 2,
1e89; (e) Hosomi, A.; Tominaga, Y. Comprehen. Org. Synth. 1995, 5, 593e615; (f)
West, F. G. Adv. Cycloaddit. 1995, 4, 1e40; (g) Harmata, M. Tetrahedron 1997, 53,
6235e6280; (h) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351e478; (i) Harmata,
M. Recent Res. Dev. Org. Chem. 1997, 1, 523e535; (j) Harmata, M. Adv. Cycloaddit.
1997, 4, 41e86; (k) Cha, J. K.; Oh, J. Curr. Org. Chem.1998, 2, 217e231; (l) El-Wareth,
A.; Sarhan, A. A. O. Curr. Org. Chem. 2001, 5, 827e844; (m) Harmata, M. Acc. Chem.
Res. 2001, 34, 595e605; (n) Schall, A.; Reiser, O. Chemtracts 2004, 17, 436e441; (o)
Huang, J.; Hsung, R. P. Chemtracts 2005, 18, 207e214; (p) Hartung, I. V.; Hoffmann,
H. M. R. Angew. Chem. 2004, 43, 1934e1949; (q) Harmata, M. Adv. Synth. Catal.
2006, 348, 2297e2306; (r) Harmata, M. Chem. Commun. 2010, 8886e8903; (s)
Lohse, A. G.; Hsung, R. P. Chem.dEur. J. 2011, 17, 3812e3822.
4.5.7. Synthesis of (1R*,2S*,4R*,5R*)-6-(N,N-diethylaminomethyl)-
2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one, 21a.
O
9
10
3
2
~
2. (a) Montana, A. M.; Ribes, S.; Grima, P. M.; García, F. Chem. Lett. 1997, 847e848;
4
~
(b) Montana, A. M.; Ribes, S.; Grima, P. M.; García, F. Acta Chem. Scand. 1998, 52,
8
~
453e460; (c) Montana, A. M.; García, F.; Batalla, C. Lett. Org. Chem. 2005, 2,
O
~
475e479; (d) Montana, A. M.; García, F.; Batalla, C. Lett. Org. Chem. 2005, 2,
1
5
~
480e484; (e) Montana, A. M.; Grima, P. M.; Batalla, C. Targets Heterocycl. Syst.
1'
~
2'
2009, 13, 231e251; (f) Montana, A. M.; Ribes, S.; Grima, P. M.; García, F.; Solans,
~
X.; Font-Bardia, M. Tetrahedron 1997, 53, 11669e11684; (g) Montana, A. M.;
6
7
~
11
García, F.; Grima, P. M. Tetrahedron 1999, 55, 5483e5504; (h) Montana, A. M.;
N
~
García, F.; Grima, P. M. Tetrahedron Lett. 1999, 40, 1375e1378; (i) Montana, A.
~
M.; García, F.; Batalla, C. Tetrahedron Lett. 2004, 45, 8549e8552; (j) Montana, A.
€
M.; Barcia, J. A.; Kociok-Kohn, G.; Font-Bardía, M. Tetrahedron 2009, 65,
2'
1'
~
5308e5321; (k) Montana, A. M.; Barcia, J. A. Tetrahedron Lett. 2005, 46,
8475e8478.
(cis-endo isomer)
~
3. (a) Montana, A. M.; Grima, P. M. Tetrahedron Lett. 2002, 43, 2017e2021; (b)
~
Montana, A. M.; Grima, P. M. Tetrahedron 2002, 58, 4769e4786.
4. (a) Noyori, R.; Shimizu, F.; Fukuta, K.; Takaya, H.; Hayakawa, Y. J. Am. Chem. Soc.
1977, 99, 5196e5198; (b) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P.
Natural Products Synthesis through Pericyclic Reactions; ACS Monograph 180:
Washington DC, 1983, pp 254e261; (c) Mann, J.; Holland, H. J. Tetrahedron 1987,
43, 2533e2542; (d) Mann, J.; Overton, H. J. Tetrahedron Lett. 1985, 26,
6133e6136; (e) Chaves, F. C.; Barbosa, L. C. A.; Demuner, A. J.; Silva, A. A.
Compound 21a has been prepared according to the experi-
mental method 2-Zn, under stirring at 0 ꢁC (see the General
methods section for experimental details).
Results: Yield¼81%. Diastereoselectivity: cis/trans¼100:0, endo/
exo¼100:0.
€
Zeitschrifrt fur Naturforschung 2006, 1285e1294; (f) Shimizu, N.; Tanaka, M.;
Isomer ciseendo: IR (film, n
, cmꢀ1): 2950,2800, 2750, 1725 (C]O,
Tsuno, Y. J. Am. Chem. Soc. 1982, 104, 1330e1340; (g) Paquete, L. A.; Kravetz, T.
M. J. Org. Chem. 1985, 50, 3781e3787; (h) Hoffmann, H. M. R. Angew. Chem.
1973, 12, 819e835; (i) Hoffmann, H. M. R. Angew. Chem. 1984, 23, 1e19; (j)
Ishizu, T.; Mori, M.; Kanematsu, K. J. Org. Chem. 1981, 46, 526e531; (k) Walter,
M. A.; Arcand, H. R.; Lawrie, D. J. Tetrahedron Lett. 1995, 36, 23e26; (l) Hosomi,
A.; Tominaga, Y. In [4þ3] Cycloadditions in Comprehensive Organic Synthesis;
Trost, B., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 593e613.
5. (a) Hoffmann, H. M. R.; Chidgey, R. Tetrahedron Lett. 1978, 85e88; (b) Sakurai,
H.; Shirahata, A.; Hosomi, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 163e164; (c)
st), 1460, 1445, 1380, 1200, 1150, 1040, 925. 1H NMR (200 MHz,
CDCl3,
d
, ppm): 0.94 (3H, d, J¼6.8 Hz, H9), 0.98 (6H, t, J¼7.2 Hz, H20
and H200), 1.04 (3H, d, J¼7.4 Hz, H10), 2.40 and 2.56 (4H, m, H10 and
H100), 2.80 (1H, dq, J1¼4.7 Hz, J2¼7.0 Hz, H4), 2.91 (1H, dq, J1¼4.6 Hz,
J2¼7.0 Hz, H2), 3.02 and 3.21 (2H, d, J¼14, H11), 4.78 (1H, brd,
J¼4.4 Hz, H5), 4.80 (1H, d, J¼4.8 Hz, H1), 6.06 (1H, br s, H6). 13C NMR
€
€
(50 MHz, CDCl3, d
, ppm): 9.7 (C9), 10.1 (C10), 11.7 (C20 and C200), 47.0
Fohlisch, B.; Flogaus, R.; Oexle, J.; Schadel, A. Tetrahedron Lett. 1984, 25,
1773e1776.
(C10 and C100), 47.1 (C2), 51.0 (C4), 52.2 (C11), 83.1 (C1), 83.3 (C5),
127.8 (C6), 148.5 (C7), 209.4 (C3). MS [GCeMS (CI), NH3, 70 eV,
150 ꢁC, m/z, (%)]: 238 (97, MþH), 237 (14, Mþ). EA. Calculated for
C14H23NO2: C (70.85%), H (9.77%). Found: C (70.65%), H (6.69%). TLC
(SiO2, hexane/ethyl acetate, 1:1): Rf¼0.08 (blue color developed
with anisaldehydeesulfuric acid reagent).
6. Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1979, 101,
1786e1793.
7. Mann, J. Tetrahedron 1986, 42, 4611e4659.
8. Sargent, M. V.; Cresp, T. M. In Comprehensive Organic Chemistry; Barton, D., Ollis,
W. D., Eds.; Pergamon: London, 1979; Vol. 4, pp 693e744.
9. Barbosa, L. C. A.; Pereira, U. A.; Teixeira, R. R.; Maltha, C. R. A.; Fernandes, S. A.;
Forlani, G. J. Agric. Food Chem. 2008, 56, 9434e9440.
10. Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163e344 (Especially pages
309e314 and data and references from tables in these pages).
11. Beck, H.; Stark, C. B. W.; Hoffmann, M. R. Org. Lett. 2000, 2, 883e886.
Acknowledgements
ꢀ
12. (a) Arman, H. D.; Biella, S.; Bruce, D. W.; Fourmigue, M.; Hanks, T. W.; Karpfen,
A.; Kochi, J. K.; legon, A. C.; Metrangolo, P.; Pennington, W. T.; Pilati, T.; resnati,
G.; Rosokha, S. V. Halogen Bonding, Fundamentals and Applications; Springer:
Berlin, Germany, 2008; Vol. 126; (b) Ritter, S. K. Chem. Eng. News 2009 Sep-
tember 21, 39e42; (c) Legon, A. C. Phys. Chem. Chem. Phys. 2010, 12,
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We thank the University of Barcelona for financial support (UB-
VRR/2012: AR000126).
Supplementary data
Digital copies of IR and 1H- and 13C NMR spectra of compounds
described in this work are available on line from the publisher.
The main X-ray data for compound 20a are quoted in Table 2 of
this paper. The CIF file has been deposited as Supplementary data
with The Cambridge Crystallographic Data Centre as file CCDC-
92874, which contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.ca-
m.ac.uk/data_request/cif. For additional information regarding
bond lengths and bond angles for compound 20a, as well as the
hydrogen coordinates and the anisotropic thermal parameters see
also Tables 4e7 of the Supplementary data available on line from
the publisher. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2012.09.070.
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