Synthesis of C3-substituted enantiopure 2-(p-tolylsulfinyl)-furans: The sulfoxide group as a chiral inductor for furan dienes as precursors of a wide variety of chiral intermediates

Article abstract of DOI:10.1016/j.tetasy.2014.03.013

(-)-(1R,2S,5R)-Menthyl (S_S)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulfoxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyloxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the inclusion of this organic function into numerous substrates, with defined stereochemistry and high enantiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this synthetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which π-facial selectivity should be induced in order to obtain enantioselective reactions.

Full text of DOI:10.1016/j.tetasy.2014.03.013

Tetrahedron: Asymmetry 25 (2014) 677–689
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Tetrahedron: Asymmetry
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Synthesis of C3-substituted enantiopure 2-(p-tolylsulfinyl)-furans:
the sulfoxide group as a chiral inductor for furan dienes as
precursors of a wide variety of chiral intermediates
b
a
c
Ángel M. Montaña a, , Pedro M. Grima , Consuelo Batalla , Gabriele Kociok-Köhn
⇑
a Unidad de Química Orgánica Industrial y Aplicada, Departamento de Química Orgánica, Facultad de Química, Universidad de Barcelona, c/Martí i Franquès, 1-11, 08028
Barcelona, Spain
b Medicinal Chemistry Department, Laboratorios Ferrer Internacional, c/Juan de Sada, 28-32, 08028 Barcelona, Spain
c Department of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 February 2014
Accepted 10 March 2014
(ꢀ)-(1R,2S,5R)-Menthyl (SS)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulf-
oxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyl-
oxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the
inclusion of this organic function into numerous substrates, with defined stereochemistry and high enan-
tiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this syn-
thetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can
be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which
p-facial selectivity should be induced in order to obtain enantioselective reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
non-shared electron pair, and a bulky and flat tolyl group. These
big differences between these three ligands both on steric and elec-
tronic levels, allow the induction of asymmetry.
The configurationally stable asymmetric sulfoxide group has
been widely used as a chiral inductor in many chemical processes.1
Thus it has been used for the induction of enantioselectivity in
nucleophilic additions,2,3 in the reduction of carbonyls (with the
In addition, the presence in the diene substrate of the oxygen
atom of the sulfoxide, together with the oxygen atom of the furan
ring, favors the formation of bidentated chelating structures in
such a way that the conformation of the chiral auxiliary group
could be fixed in the reaction intermediate or in the transition
state, thus increasing the effectiveness of the asymmetric induc-
tion by coordination, when there is a metallic ion or a Lewis acid
involved in the reaction process. It should be noted that all of the
examples shown in Scheme 1 have a carbonyl group located at a
suitable distance to coordinate in a bidentate manner to the Lewis
acid used as a catalyst in the coupling reaction (see also Fig. 1). A
clear case of this effect is highlighted in example (b) of Scheme 1
(reaction conditions b and b0), in which coordination with a Lewis
acid changes the sense of the asymmetric induction of the carbonyl
group reduction reaction, since this reaction occurs via the less sta-
ble conformation in the absence of a Lewis acid.
sulfinyl group at the
a
position)4 as well as in Diels–Alder cycload-
ditions,5,6 amongst other chemical transformations.7,8 In Scheme 1
some of these enantioselective processes are illustrated.
Since the resolution of (ꢀ)-menthyl (SS)-p-tolylsulfinate and its
enantiomer in 1925, these two compounds have been the most
common source for a chiral sulfoxide group in organic synthesis.9
The replacement of the methoxy group with complete inversion
or total retention of the configuration at the sulfur center of chiral
sulfoxide, allows for the inclusion of this organic function in
numerous substrates, with a defined stereochemistry and with
high enantiomeric purity. For this reason the p-tolylsulfinyl group
has been chosen for our studies.
In order to understand the role and efficiency of this chiral aux-
iliary, it is necessary to take into account that the stereogenic
center is located at the sulfur atom and the three ligands linked
to it are different: an oxygen atom with high electron density, a
Our objective was to use the configurationally stable p-tolylsul-
finyl group as a chiral inductor in stereoselective [4+3] cycloaddi-
tion reactions in order to obtain enantiomerically pure
polyfunctionalized oxabicyclic systems (Scheme 2), strategically
functionalized at C1 in order to allow the opening of the
oxygen bridge, and also to perform further derivatizations and/or
⇑
Corresponding author. Tel.: +34 93 402 16 81; fax: +34 93 339 78 78.
E-mail address: angel.montana@ub.edu (Á.M. Montaña).
http://dx.doi.org/10.1016/j.tetasy.2014.03.013
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

678
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
OH
OH
O
O
S
S
a)
S
a)
SnPh3
H
-
+
I >> II
-
-
+
+
+
O
O
S
S
S
II
I
Tol
Tol
Tol
-
-
-
O
O
O
OH
O
OH
b)
c)
O
O
b)
O
b')
S
S
+
S
Tol
Tol
Tol
+
+
O
-
O
O
O
-
-
c)
N
I >> II
Tol
O
O
S
+
+
Tol
+
N
N
S
S
Tol
+
+
II
I
O
O
O
OMe
O
O
O
d)
H
-
O
d)
O
+
+
I >> II
-
-
O
O
O
S
+
S
S
+
+
TMSO
II
Tol
I
Tol
Tol
a) TiCl4, -80ºC; b) DIBALH, -78ºC; b') DIBALH, ZnCl2;
c) AlCl3, 25oC; d) Yb(OTf)3, -20oC
Scheme 1. Examples of the application of chiral sulfoxides to asymmetric versions of different organic reactions.
H
We consider that the synthesis and physical and spectroscopic
O
characterization of these chiral furans could be of interest to syn-
thetic chemists who may use these substrates for a wide variety
of stereoselective reactions.
O
+
M
+
-
S
O
The use of cycloheptane synthons as precursors of natural and
unnatural products with biological activity has been an objective
of many chemists. We have also made contributions to this field
over the past few years.12,13 When five-membered cyclic dienes
are used as starting materials, it is possible to further functionalize
the cycloadducts, in a regio- and stereoselective manner, due to the
lack of conformational freedom, in the resultant bicyclic system
because of the presence of a carbocyclic or heterocyclic bridge.14,15
Herein our main aim was to synthesize C3-substituted
2-p-tolylsulfinylfuran derivatives in order to evaluate the effects
of steric hindrance, and the inductive and coordination capabilities
of those substituents attached to C3 of the furan ring, which have
been shown to be important with regard to the stereochemical
outcome of cycloaddition reactions.16 For this purpose nine chiral,
enantiomerically pure, sulfinylfurans (Fig. 2) were prepared so that
they could be evaluated under the [4+3] cycloaddition reaction
conditions.11 However, these enantiopure furan derivatives may
also be used as substrates for other types of reactions.1–8
An added value of this methodology is the commercial
availability of both enantiomeric forms of the precursor menthyl
p-toluenesulfinate, making the obtention of both enantiomers of
2-(p-toluenesulfinyl)furan derivatives possible.17
Nine furan derivatives, all of them functionalized at the C2
position by the (S)-p-tolylsulfinyl group (see Fig. 2) and substituted
at the C3 position by a chelating function, were prepared. The bro-
minated derivative 2 was synthesized in order to analyze the effect
of steric hindrance on the conformational freedom and also the
influence of its inductive effect. The other dienes, all of them
Figure 1. Bidentate coordination of a sulfoxide group and a carbonyl group to a
Lewis acid or a metallic ion.
O
-
-
O
O
-
O
[4+3] cycloaddition
Zn
O
S
+
+
O
Tol
+
S
+
Tol
R
R
Scheme 2. C3 substituted 2-sulfinylfurans as substrates in [4+3] cycloaddition
reactions.
functionalizations. These cycloadducts were intended to be pre-
pared in a stereoselective manner, by starting from C2, C3, and/
or C5 functionalized furans as dienes and 2,4-dihalo-3-pentanones
as precursors of oxyallyl cations.10 The substitution at C3 of furans
as dienes is thought to decrease the conformational freedom of the
p-tolylsulfinyl group attached to C2, which in turn would deter-
mine a preferential stereochemical approach between the diene
and dienophile in the cycloaddition process, due to a different
accessibility of both faces of the furan diene. Herein we report
the synthesis of C3 substituted 2-sulfinylfurans, which will be used
as substrates for enantioselective [4+3] cycloaddition reactions.11

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
679
O
O
lithium derivative generated from the furyl substrate and LDA
(Scheme 3).
2
7
R = Br
15 R =
2.2. Synthesis of (S)-3-bromo-2-(p-tolylsulfinyl)furan
-
O
R
R = CH2OH
O
10 R = CH2NEt2
11 R = COOH
R = COOMe
R = COOEt
R = CONEt2
S
+
Tol
Bromosulfinylfuran 2 was prepared for a comparative study in
order to evaluate the possible stereoelectronic effects exerted by
the bromine atom, especially steric, inductive, and coordinating
effects. The synthesis of (ꢀ)-2 was carried out by starting from
3-bromofuran 1a via intermediate 10, followed by a nucleophilic
substitution of (ꢀ)-menthyl (SS)-p-tolylsulfinate. Compound 2
was also prepared from dibromoderivative 1b via a bromine-lith-
ium exchange (Scheme 4).
12
13
16
O
17
R =
HN
Ph
Figure 2. Derivatives of (S)-2-(p-tolylsulfinyl)furan, resulting from substitution at
the C3 position.
-
O
O
Li
O
c)
O
a)
S
+
substituted at the C3 position by groups containing chelating het-
eroatoms, were designed in order to analyze the potential effects of
bidentate coordination to metal ions or a Lewis acid, present in the
reaction medium (see Figs. 1 and 3), or hydrogen bonding effects
(as in the case of sulfinylfuran 7) (Fig. 3).
Tol
Br
Br
Br
1a
1'
2
(-)-
b)
Y = 60% (from 1a)
1b
O
Br
2. Results and discussion
Y = 58% (from
)
Br
2.1. Introduction of the (S)-2-p-tolylsulfinyl group at the C2
position of the furan ring
1b
a) LDA, THF, -78 ºC; b) MeLi, Et2O, -44oC;
c) menthyl (-)-(S)-p-toluenesulfinate, THF, -78 to 20oC
The replacement of the menthyloxy group, from (ꢀ)-(1R,2S,5R)-
menthyl (SS)-p-toluenesulfinate, by means of nucleophilic substi-
tution with complete inversion of the configuration at the sulfur
center of chiral sulfoxide, allowed the insertion of this chiral aux-
iliary into numerous substrates, with a defined stereochemistry
and with high enantiomeric purity.
In the literature, there are examples concerning the use of
nucleophiles with a furan structure or similar, in this type of reac-
tion.18 They all confirm that the SN2 reaction is carried out with to-
tal inversion of configuration at the sulfur asymmetric center when
the nucleophile used is the corresponding Grignard reagent or the
Scheme 4. Synthesis of (S)-3-bromo-2-(p-tolylsulfinyl)furan 2.
The synthesis of compound 2 was carried out by starting from
commercially available 3-bromofuran 1a and using LDA as a base
in THF at ꢀ78 °C,19 to give a 60% yield with complete enantiomeric
purity as checked by GC on a chiral stationary phase. An alternative
synthesis of 2 was accomplished by starting from commercially
available 2,3-dibromofuran and using MeLi in diethyl ether at
ꢀ44 °C to generate intermediate 10, by bromine–lithium
exchange,20,21 followed by reaction with (ꢀ)-menthyl (SS)-p-tolyl-
-O
O
O
S+
S+
Tol
Tol
O-
monosubstituted furan: high conformational freedom
metal coordinating effects
M+
-O
R
O-
Tol
O
O
O
O
S+
Tol
S+
O-
S+
O-
S+
Tol
Tol
H
R
XH
hydrogen bonding
electronic stabilizing interactions
steric
and/or
X
steric repulsion
inductive effects
C2,C3-disubstituted furans: restricted conformational freedom
Figure 3. Modification of the conformational freedom of the 2-(p-toluenesulfinyl)furan by insertion of a functional group at the C3 position.
-
-
O
O
SN
2
O
O
S
+
+
+
MgBrH
S
+
MgBr
O
Tol
O
Scheme 3. Synthesis of (S)-2-(p-tolylsulfinyl)furan from (ꢀ)-(1R,2S,5R)-menthyl (SS)-p-toluenesulfinate.

680
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
O
in ether at rt; however, these reaction conditions afforded a com-
O
O
plex reaction mixture.
OH
X
X'
This chemical behavior led us to believe that in the case of
substituted furans with C3-coordinating groups, the use of Grig-
nard reagents as intermediates in the SN2 reaction is not essential
in order to achieve complete enantioselectivity, due to the stabiliz-
ing coordinating effects of these C3-groups in the lithium interme-
diate. A confirmation of this hypothesis could also be found in the
preparation of 15 and/or 17.
X
O
O
O
-
O
-
O
-
O
O
S
+
O
S
+
Tol
O
S
+
X
Tol
O
X
OH
2.3. Synthesis of C3-substituted (S)-2-(p-tolylsulfinyl)furan
X
derivatives from 3-furoic acid
Figure 4. Strategies for the synthesis of 2-(p-tolylsulfinyl)furan derivatives substi-
tuted at the C3 position.
The other sulfinylfuran derivatives mentioned in Figure 2 were
synthesized from available starting materials such as 3-furoic acid,
already functionalized at the C3 position. Bearing in mind that the
introduction of the sulfoxide group is expected to be performed via
an SN2 reaction in which an organometallic compound is involved,
the synthesis of derivatives with an ester or an amide function
(compounds 11–17) was conducted by derivatization of the car-
boxylic acid after the sulfoxide group had been introduced into
the molecule (Fig. 4). The hydroxymethyl and N,N-diethylamino-
methyl groups were generated by reduction with LiAlH4 of the cor-
responding carboxylic derivatives (ester and amide, respectively).
This derivatization was performed before the introduction of the
sulfoxide group (otherwise the reduction conditions used would
sulfinate, which afforded compound 2 with a similar yield (58%)
and enantiomeric purity to that of the previous method. In this last
method, no reaction of the bromine atom at C3 was observed when
using equimolar ratios of reagents. The temperature was seen to be
an important factor with regard to the conversion and chemoselec-
tivity; the use of MeLi at ꢀ78 °C produced a low conversion (30%).
Increasing the reaction temperature to ꢀ44 °C improved the con-
version to 68% and afforded a 58% yield (the remaining 32% of
starting material was isolated and identified spectroscopically).
In an attempt to improve the conversion, n-BuLi was tested, but
O
O
O
O
c)
b)
a)
OH
COCl
COOH
COOEt
4
3
5
6
Y = 72 %
g)
O
O
c)
NEt2
CONEt2
8
9
Y = 36 %
Br
-
O
O
O
O
Li
Mg
O
e)
f)
d)
S
+
Tol
O
OH
Mg
Br
Li
OH
Y = 51%
6
7
(+)-
-
O
Br
Mg
NEt2
O
O
O
S
+
O
Li
NEt2
i)
f)
Tol
h)
NEt2
NEt2
Y = 40%
9
(-)-10
a) SOCl2 (excess), reflux; b) abs. EtOH, reflux; c) LiAlH4, anh. ether, r.t.; d) 2 eq. n-BuLi, Et2O, 0oC to 34oC;
e) 2 eq. MgBr2, Et2O, 0oC to 20oC; f) Menthyl (-)-(S)-p-toluenesulfinate, Et2O, -78oC to 20oC; g) NHEt2, 0oC;
h) 1 eq. n-BuLi, Et2O, 0oC to 34oC; i) 1 eq. MgBr2, Et2O, 0oC to 20oC
Scheme 5. Synthesis of sulfoxides 7 and 10.

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
681
-
O
O
O
Li
a)
O
b)
S
+
O
Tol
OH
O
Li
O
O
OH
11
3
(+)-
Y = 90% C = 100%
a) 2 eq LDA, THF, -78ºC; b) menthyl (-)-(S)-p-toluenesulfinate, Et2O, -78oC to 20oC
Scheme 6. Synthesis of acid 11.
evolve toward the formation of the corresponding p-tolylsulfenyl
derivatives, thus losing the chirality of the initial sulfinyl group).
Alcohol 6 and amine 9 were used as key intermediates for the
synthesis of sulfinylfurans 14 and 17 respectively, (Scheme 5). In
the first case, using two equivalents of n-BuLi as the base, the hy-
droxyl group was converted into the corresponding alkoxide, while
a second deprotonation at the more acidic neighboring position, in
this case the C2 position, afforded the lithium 2-furyllithium-3-
alkoxide intermediate.22 This dilithium intermediate was trans-
metallated into the corresponding Grignard reagent with MgBr2
and in this way a single product 7 was obtained in a regioselective
manner. In the case of N,N-diethylaminomethyl derivative 10,
using a single equivalent of base, the anion in the neighboring C2
position was obtained selectively by chelation effects, although
the steric hindrance exerted by the Et2N-group should be also ta-
ken in consideration (Scheme 5) to explain the lower yield.
The synthesis of esters and amides derived from acid 11 was
carried out in various methods. The synthesis of esters of volatile
alcohols (methyl and ethyl esters 12 and 13, respectively) was con-
ducted by esterification under acidic catalysis (Fischer conditions).
Total conversions were obtained by this procedure while the per-
formance in the first case (Y = 96%) was higher than in the second
(Y = 53%) (see Scheme 7).
-
-
O
O
O
O
S
+
O
S
+
Tol
Tol
R
OH
+ H2O
+
O
OH
11
OR
(+)-
12
(-)- , R = Me, Y = 96%, C = 100%
13
(-)- , R = Et, Y = 53%, C = 100%
The same principle of directed deprotonation used for the syn-
thesis of 10 was applied to the synthesis of carboxylic acid 11, a
precursor of the esters and amides. The use of two equivalents of
base, in this case LDA, regioselectively generated the anion at the
C2 position of the furan ring (Scheme 6). Taking into account
precedents in which nucleophilic substitution occurs with total
inversion of the configuration at the asymmetric sulfur atom of
the menthyl (ꢀ)-(S)-p-toluenesulfinate, by using similar nucleo-
philes, generated with LDA, the Li–Mg exchange was not consid-
ered essential in this strategy.18 Unlike all other previous cases,
the reaction was conducted in THF as a solvent due to the insolu-
bility of the dilithium derivative intermediate in diethyl ether.
Scheme 7. Synthesis of methyl and ethyl esters, 12 and 13, respectively.
The synthesis of esters from bulkier and chiral alcohols, such as
(ꢀ)-(1S,2R,5S)-myrtanol was addressed by esterification under
acidic catalysis in an inert solvent and shifting the esterification
equilibrium by distilling off the water formed (by azeotropic distil-
lation), or by activation of the carboxylic acid as an acid chloride or
as a mixed carbonic-carboxylic acid anhydride (compound 14).
The application of the Fischer esterification, under stoichiome-
tric conditions, resulted in the decomposition of the starting acid
11, without obtaining the desired product. Likewise, the activation
-
-
-
O
O
-
O
O
O
O
O
S
+
O
S
+
O
O
S
+
O
S
+
O
Tol
Tol
Tol
O
Tol
+
a)
b)
O
O
O
OH
Et
Myrt
15
11
(+)-
14
(-)-
Y = 75%
13
OEt
(-)-
Y = 11%
EtO- + CO2
c)
-
O
O
S
+
Tol
O
NRR'
16
(-)- , R = Et, R' = Et, Y = 80%
17
(+)- , R = H, R' = CH(CH3)Ph, Y = 64%
a) TEA, ClCOOEt, THF, 0oC; b) TEA, (1S,2R,5S)-(-)-myrtanol, THF, 20oC; c) NHRR', THF, 20oC
Scheme 8. Formation of esters by reaction of alcohols with the mixed anhydride 14.

682
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
Table 1
Crystal data and structure refinement for 7
Chemical formula
Formula Mass
C12H12O3S
236.28
Crystal system, Space group
Monoclinic, P 21/a
8.6744(5)
10.8606(7)
12.1615(8)
90
100.777(4)
90
1125.52(12)
150(2)
a/Å
b/Å
c/Å
a
/°
b/°
/°
c
Unit cell volume/Å3
Temperature/K
Space group
P21/a
No. of formula units per unit cell, Z
Density (Calcd) g cmꢀ3
Radiation type
4
1.394
MoK
0.275
a
Absorption coefficient,
l
/mmꢀ1
No. of reflections measured
No. of independent reflections
Rint
19236
1987
0.1249
0.0464
0.1011
0.0870
0.1165
1.034
Final R1 values (I > 2r(I))
Final wR(F2) values (I > 2
Final R1 values (all data)
r(I))
Final wR(F2) values (all data)
Goodness of fit on F2
The reaction was conducted under conditions analogous to those
of the synthesis of the myrtanyl ester 15, obtaining the corre-
sponding amides in moderate to good yields.
A possible alternative to this reaction, based on the replacement
of the methoxy group from the methyl ester 12 by these amines,
via an addition–elimination mechanism, did not give the expected
results for either of the two evaluated amines. On the other hand, it
is worth noting that the chiral amine (1-methylbenzylamine) and
the chiral alcohol (mirtanol) used were enantiomerically pure
and that by this amidation/esterification process a second chiral
subunit was inserted into compounds 17 and 15, respectively.
Since these compounds were obtained as pure diastereoisomers
(confirmed by GC and 1H NMR), it was possible to confirm that
the synthesis of acid 11, by using LDA instead of the organomagne-
sium intermediate, occurred with total inversion of configuration
at the stereogenic sulfur atom, without racemization of the sulfox-
ide group.24 Thus, as mentioned in the Introduction, commercially
available (ꢀ)-(1R,2S,5R)-menthyl (SS)-p-toluenesulfinate precursor
was used to prepare enantiomerically pure sulfinylfurans with an
(SS)-configuration, via an SN2 reaction, with complete inversion
of configuration (see Scheme 3). Due to the availability of the other
enantiomer of the precursor, (+)-(1S,2R,5S)-menthyl (RS)-p-tolu-
enesulfinate, the enantiomers of the sulfinylfurans prepared here
could also be obtained by applying the same chemistry described
herein.
Figure 5. X-ray structure of 7. Ellipsoid diagram at 50% probability level for 7.
of the carboxylic acid in the form of an acid chloride was useless for
the synthesis of esters, since acid 11 in the presence of thionyl
chloride, underwent multiple side reactions: chlorination of the
acid group, chlorination of the C5 position of the furan ring and
concomitant reduction of the sulfoxide group to a thioether group.
Finally, activation of acid 11 in the form of a mixed anhydride
with ethoxycarbonic acid, by using ethyl chloroformate, and subse-
quent in situ reaction with (ꢀ)-(1S,2R,5S)-myrtanol gave the de-
sired ester in 75% yield. In this process, one equivalent of
ethoxide anion was formed, as a byproduct of the esterification
reaction. This anion, although in a low extent, came into competi-
tion with (ꢀ)-(1S,2R,5S)-myrtanol, generating ethyl ester 13 in 11%
yield (Scheme 8). Alternative mixed anhydrides to obviate this side
reaction could be considered.23
Taking into account the previous synthesis of the esters of acid
11, the preparation of amides 16 and 17 of this acid was addressed
through activation of the acid in the form of mixed anhydride 14.
Chiral amine (ꢀ)-(S)-1-methylbenzylamine was used for this pur-
pose and also diethylamine as an achiral amine (see Scheme 8).
Figure 6. (a) Hydrogen bonds between the hydroxyl group and the oxygen atom of the sulfoxide group of a neighbor molecule. (b) Crystal cell packing of 7.

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
683
Table 2
Modification of the reaction condition in the preparation of 11
a
Entry 3-Furoic acid
(mmol)
LDA
(mmol)
Reaction conditions
(1st step)
MgBr2
Reaction conditionsa
(2nd step)
Menthyl sulfinate
(mmol)
Reaction condition
(3rd step)
Conversion
(%)
Yield
(%)
(mmol)
1
2
2
2
4.2
4.2
2 h, 20 °Cb
4.2
2 h, 20 °Cb
2
2
2 h, ꢀ78 °C; then
0
0
0
0
16 h, 20 °Cb
2 h, 20 °Cb
—
—
2 h, ꢀ78 °C; then
16 h, 20 °Cb
3
4
0.9
0.9
1.8
1.8
1 h, 20 °Cc
—
—
—
—
0.9
0.9
16 h, 20 °Cc
48
32
25
28
45 min, ꢀ78 °Cc
1 h, ꢀ78 °C; then
1 h, 20 °Cb
5
0.9
3
45 min, ꢀ78 °Cc
—
—
0.9
1 h, ꢀ78 °C; then
1 h, 20 °Cb
50
22
6
7
8
1.8
1.8
8.9
3.7
3.7
17.8
45 min, ꢀ78 °Cc
45 min, ꢀ78 °Cc
45 min, ꢀ78 °Cc
—
3.7
—
—
0.9
0.9
4.5
1 h, ꢀ78 °Cc
100
0
100
90
0
77
2 h, ꢀ78 °Cc
1 h, ꢀ78 °Cc
—
1 h, ꢀ78 °Cc
a
b
c
Transmetallation process according to the procedure described for the preparation of compound 2.
Diethyl ether as the solvent.
THF as a solvent.
The structure of 7 was confirmed by X-ray diffraction analysis
4. Experimental
4.1. General
on a single crystal (Fig. 5). All of the bond lengths and angles are
within the normal ranges. In the crystal packing, the molecules
are arranged parallel to each other along the c axis as shown in
Figure 6. Hydrogen bonding between the hydroxyl group and the
oxygen of sulfoxide is also observed in the crystal cell. Crystal data
and structure refinement for enantiopure furan 7 are quoted in
Table 1. The molecular illustrations (Figs. 5 and 6) were made by
using MERCURY software.25
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 tech-
niques before use: ether, tetrahydrofuran, hexane, and pentane
were distilled under nitrogen from sodium/benzophenone. Ace-
tonitrile was distilled 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 VARIAN spectrometers at 200 MHz (GEMINI 200), 300 MHz
(INOVA-300), and/or 400 MHz (MERCURY-400) for 1H NMR and
at 50 and/or 100 MHz for 13C NMR. For 1H NMR tetramethylsil-
ane was used as internal standard. 13C NMR spectra were refer-
enced to the 77.0 ppm resonance of chloroform. When
necessary, assignments were established by DEPT, 1H–1H–COSY,
and HMBC or gHMQC 13C–1H 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 HEWLETT-PACK-
ARD-crosslinked MePhe-silicone capillary column (L = 25 m,
3. Conclusion
Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans
were prepared from (ꢀ)-(1R,2S,5R)-menthyl (SS)-p-toluenesulfi-
nate as the precursor via an SN2 reaction that took place with total
inversion of the configuration at the sulfur asymmetric center.
According to the literature, in a non-substituted furan or in C4 or
C5-substituted furans, a nucleophilic shift via an SN2 of the men-
thyloxy group could be obtained with complete inversion of the
configuration at the sulfur center of the chiral sulfoxide, when
the generated intermediate is the corresponding 2-furyl Grignard
reagent, or a 2-furyllithium intermediate, in turn generated from
the corresponding furan derivative and LDA. When the 2-furyllithi-
um nucleophile is generated by the reaction of furan and n-BuLi or
MeLi, the product obtained was a quasi-racemic mixture. However,
as deduced from the present work, in the case of substituted furans
with C3-coordinating groups, the use of Grignard reagents or LDA
is not essential to obtain complete enantioselectivity, due to the
stabilizing coordinating effects of these C3-groups in the lithium
intermediate.
UID = 0.2 mm, dfilm = 2.5 lm) using helium as the gas carrier
and an FID detector (T = 250 °C, PH2 = 4.2 psi, Pair = 2.1 psi). The
chiral GC analyses of furan derivatives and cycloadducts were
carried out by using an ALLTECH Chirasil-ValÒ capillary column
(L = 25 m, UID = 0.25 mm, dfilm = 0.16 lm) in the range of 40–
220 °C. The working conditions are specified for each compound.
The elemental analyses were obtained in a FISONS elemental
analyzer, Model Na-1500. The samples were previously pyro-
lized at 1000 °C under an oxygen atmosphere and the content
of carbon, hydrogen, sulfur, and nitrogen was determined by
evaluation of the combustion gases by gas chromatography
using an FID detector. Melting points were determined in a
GALLENKAMP apparatus Mod 5A 6797.
Herein we have reported on the synthesis of several C3-substi-
tuted 2-sulfinylfurans, which will be used as substrates for enan-
tioselective [4+3] cycloaddition reactions and other types of
reactions, whose results, will be published in due course. We antic-
ipate that the synthesis and physical and spectroscopic character-
ization of these chiral furans could be of interest to synthetic
chemists as substrates for a wide variety of reactions intended to
be stereoselective via p-facial stereodifferentiation. This stereodif-
ferentiation may be induced by the sulfinyl chiral auxiliary and fa-
vored by the C3-substituent, due to its stereoelectronic effects such
as coordination, steric hindrance, hydrogen bonding, and decrease
of the conformational freedom of the sulfinyl subunit.
Our results could also be applied to the enantiomer of the pre-
cursor (+)-(1S,2R,5S)-menthyl (RS)-p-toluenesulfinate, which is also
commercially available, in such a way that all of the enantiomers of
the furan derivatives described herein may be obtained.
4.2. X-ray crystal structure analysis of 7
3-Hydroxymethyl-2-p-tolylsulfinylfuran 7 was dissolved in the
minimum amount of ethyl acetate, at room temperature. A few
drops of hexane were then added and the saturated solution was
kept in a refrigerator at 4 °C. Suitable crystals for X-ray diffraction
studies grew over a period of two weeks.

684
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
Intensity data were collected at 150 K on a Nonius KappaCCD
diffractometer equipped with an Oxford Cryosystem, using graph-
ite monochromated MoK radiation (k = 0.71073 Å). Data were
4.3.2. Use of 2,3-dibromofuran as the starting material
In an oven-dried 50 mL round bottomed flask, fitted with a
magnetic stirrer and septum, commercially available 2,3-
dibromofuran 1b (1 g, 4.46 mmol) and dry diethyl ether (10 mL)
were placed and the system purged with argon. The system was
cooled down to ꢀ44 °C and a solution of 1.0 M MeLi in cumene
a
processed using the Nonius Software.26 A symmetry-related (mul-
ti-scan) absorption correction was applied. The structures were
solved by direct methods (SIR-97)27 and refined with full-matrix
least-squares techniques against F2 (SHELXL-2013)28 using the
program platform SHELXle.29 Non-hydrogen atoms were aniso-
tropically refined. Heteroatom and hydrogen atoms were located
in the difference Fourier map and were isotropically refined and
all others were placed onto calculated positions.
(4.50 mL, 4.50 mmol) was added portionwise by
a syringe.
The reaction mixture turned reddish and was maintained under
these conditions for 2 h. This solution of 3-bromo-2-furyllithium
was then cooled to ꢀ78 °C and transferred via cannula to another
flask containing (1R,2S,5R)-(ꢀ)-menthyl (SS)-p-toluenesulfinate
(1.31 g, 4.46 mmol) dissolved in dry THF (10 mL), and also cooled
to ꢀ78 °C. The resulting reaction mixture was maintained under
these conditions for 2 h, and then at room temperature for 16 h.
Work-up was similar to the previous method, and compound 2
was isolated in 58% yield. Also, a 32% of unchanged starting mate-
rial 1b was isolated in the nonpolar fractions of the column.
Details of crystal data and summary of the intensity data collec-
tion for 7 are summarized in Table 1. Crystallographic data
(excluding structure factors) for these structures have been depos-
ited at the Cambridge Crystallographic Data Centre (Cambridge,
UK) as a CIF file with reference no. CCDC-959635. Copies of these
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
4.4. Synthesis of (S)-[2-(p-tolylsulfinyl)-3-furyl]methanol 7
4.4.1. Synthesis of ethyl 3-furoate 5 and 3-furylmethanol 6
While 3-furylmethanol is commercially available, we synthe-
sized it from 3-furoic acid to illustrate how this synthetic route
could be used to prepare a wide variety of structurally related
derivatives (see Scheme 5).
4.3. Synthesis of (S)-3-bromo-2-(p-tolylsulfinyl)furan, 2
-
O
1
O
2'
S
1'
5
3'
4'
+
2
3
4
6'
7'
4.4.2. Synthesis of (S)-[2-(p-tolylsulfinyl)-3-furyl]methanol 7
Br
5'
-
O
1
4.3.1. Use of 3-bromofuran as the starting material
2'
O
S
+
1'
5
3'
4'
2
3
In an oven-dried 50 mL round bottomed flask, fitted with a
magnetic stirrer and septum, commercially available 3-bromofu-
ran 1a (0.68 g, 4.62 mmol) and dry diethyl ether (10 mL) were
placed and the system purged with argon. The system was cooled
down to ꢀ78 °C and a solution of 2.0 M LDA in THF (2.34 mL,
4.68 mmol) was added portionwise by a syringe. The reaction mix-
ture turned reddish and was maintained under these conditions for
2 h. This solution of 3-bromo-2-furyllithium was then transferred
via cannula to another flask containing (1R,2S,5R)-(ꢀ)-menthyl
(SS)-p-toluenesulfinate (1.36 g, 4.62 mmol) dissolved in dry THF
(10 mL), and cooled to ꢀ78 °C. The resulting reaction mixture
was maintained under these conditions for 2 h, and then left at
room temperature for 16 h. The ether reaction mixture was
washed with saturated aqueous solution of NH4Cl (30 mL), dried
over anhydrous MgSO4, filtered, and percolated through a short
pad of activated neutral alumina. The ether solution was concen-
trated to dryness in vacuo after which the resulting crude product
was submitted to flash column chromatography on silica gel, elut-
ing with mixtures of hexane and ethyl acetate of increasing polar-
ity. With hexane/ethyl acetate 50:50, pure product was eluted and
isolated as an orange solid (756 mg, yield = 60%). Mp = 97–98.5 °C
4
6'
7'
5'
6
OH
In an oven-dried 50 mL round-bottomed flask fitted with a
magnetic stirrer and a reflux condenser and purged with argon,
3-furylmethanol 6 (425 mg, 4.42 mmol), dissolved in dry diethyl
ether (10 mL) was placed. The system was cooled down to 0 °C
and BuLi, 1.6 M in hexane (6.64 mL, 10.62 mmol) was added drop-
wise. The reaction mixture was stirred at 0 °C for 2 h and then for
an additional hour at reflux, observing the formation of lithium
(furan-2-yl-lithium-3-yl)methoxide as a yellowish solid. Simulta-
neously in another reaction flask (25 mL), activated magnesium
turnings (594 mg, 10.62 mmol)30 were placed in dry diethyl ether
(10 mL) at room temperature and 1,2-dibromoethane (0.46 mL,
5.30 mmol) was added dropwise. This reaction mixture was re-
fluxed for 1 h to give MgBr2. The ether solution of magnesium
dibromide was filtered out via cannula to remove the excess mag-
nesium turnings. The resulting clear solution of MgBr2 was added
portionwise via cannula at 0 °C to the solution of the dilithium
intermediate, already prepared in the first reactor. The new reac-
tion mixture was stirred for 2 h at room temperature to give the
corresponding Grignard intermediate. Over this solution, cooled
down to ꢀ78 °C, (1R,2S,5R)-(ꢀ)-menthyl (SS)-p-toluenesulfinate
(1.49 g, 5.06 mmol), dissolved in dry diethyl ether (15 mL) was
added at once. The reaction was maintained under stirring at
ꢀ78 °C for 2 h and then 16 additional hours at room temperature.
The reaction mixture was diluted with ethyl acetate (50 mL) and
washed with a saturated aqueous solution of NH4Cl (50 mL). After-
ward, the aqueous phase was washed with ethyl acetate
(4 ꢂ 30 mL). All organic phases were combined, dried over anhy-
drous MgSO4, and concentrated to dryness in vacuo. The resulting
crude oil was submitted to flash column chromatography on silica
gel, eluting with mixtures of hexane and ethyl acetate of increasing
polarity. The elution with hexane/ethyl acetate 30:70 afforded
pure product as a white solid [533 mg, yield = 51% (with respect
(hexane/ethyl acetate). IR (film):
m = 3148, 3116, 2921, 1559,
1539, 1491, 1466, 1360, 1192, 1122, 1082, 1057 cmꢀ1.1H NMR
(200 MHz, CDCl3) d = 2.41 (3H, s, H70), 6.52 (1H, d, J = 1.8 Hz, H4),
7.33 (2H, d, J = 8.2 Hz, H50 and H30), 7.44 (1H, d, J = 1.8 Hz, H5),
7.59 (2H, d, J = 8.2 Hz, H20 and H60) ppm. 13C NMR (50 MHz, CDCl3)
d = 21.5 (C70), 106.9 (C3), 115.24 (C4), 124.5 (C20 and C60), 129.9
(C30 and C50), 137.6 (C40), 141.7 (C10), 147.0 (C5), 149.9 (C2) ppm.
MS [GC-MS(CI), NH3, 70 eV, 150 °C]: m/z (%) = 304 (100,
M+NH3+2, isotopic distribution), 302 (97, M+NH3), 287 (19, M+2,
isotopic distribution), 285 (19, M+). Anal. Calcd for C11H9BrO2S: C,
46.33; H, 3.18. Found: C, 46.12; H, 3.02. ½a D21
¼ ꢀ71:0 (c 1.5, CHCl3).
ꢁ
Chiral GC (100 °C, 1 min, 5 °C/min, 220 °C, 20 min): tR = 19.5 min.
Ee = 100. CCF (SiO2, hexane: ethyl acetate, 9:1, two elutions):
Rf = 0.21 (developed as a blue spot with anisaldehyde and sulfuric
acid).

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
685
to 3-furylmethanol), conversion = 49%]. Mp = 98–99 °C (ethyl ace-
tate/hexane). IR (film): = 3382 (H–O, st), 3059, 2925, 2875,
1647, 1595, 1485, 1389, 1157, 1128, 1043, 889 cmꢀ1 1H NMR
4.5.2. Synthesis of N,N-diethyl-3-furylmethylamine 9
m
.
2'
O1
(200 MHz, CDCl3) d = 2.41 (3H, s, H70), 3.47 (1H, br s, O–H), 4.67
(1H, d, J = 3 Hz, H6), 4.70 (1H, d, J = 3 Hz, H6), 6.47 (1H, d,
J = 1.8 Hz, H4), 7.32 (2H, d, J = 7.4 Hz, H30 and H50), 7.43 (1H, d,
J = 1.8 Hz, H5), 7.59 (2H, d, J = 7.4 Hz, H20 and H60) ppm. 13C NMR
(50 MHz, CDCl3) d = 21.3 (C70), 55.7 (C6), 112.3 (C4), 125.0 (C30
and C50), 130.0 (C20 and C60), 132.3 (C3), 138.0 (C40), 141.9 (C10),
145.9 (C5), 147.7 (C2) ppm. MS [GC-MS(CI), NH3, 70 eV, 150 °C]:
m/z (%) = 256 (7), 254 (100, M+NH4), 237 (90, M+1). Anal. Calcd
1'
2
5
N
2'
4
3
6
1'
In an oven-dried 100 mL round-bottomed flask fitted with a
condenser, an argon atmosphere, and efficient magnetic stirrer, a
suspension of LiAlH4 (796 mg, 21 mmol) in dry ether (10 mL) was
placed. A solution of N,N-diethyl-3-furamide 8 (4 g, 21 mmol) in
dry ether (10 mL) was then added slowly, at room temperature,
though the condenser tip and a CaCl2 tube were fitted to this
end. An immediate release of H2 gas from the reaction medium
was observed. The reaction mixture was stirred at reflux overnight.
The excess of hydride was quenched with ethyl acetate (50 mL).
The aluminum hydroxide was filtered off by a Büchner filter and
the solid washed with ethyl acetate and water. The aqueous phase
was extracted with ethyl acetate (2 ꢂ 25 mL). All of the organic
phases were combined together, dried over anhydrous MgSO4, fil-
tered, and concentrated by simple distillation at atmospheric pres-
sure using a Vigreux column to give a pure product (1.78 g, Y = 50%,
for
C12H12O3S: C, 61.00; H, 5.12. Found: C, 61.20; H, 5.06.
¼ þ12:1 (c 0.66, CHCl3). Chiral GC (100 °C, 1 min, 5 °C/min,
½
a 2D1
ꢁ
220 °C, 20 min): tR = 19.03 min. Ee = 100%. TLC (SiO2, ethyl ace-
tate): Rf = 0.66 (developed as a white spot that turns black with
anisaldehyde/sulfuric acid).
4.5. Synthesis of (S)-N-ethyl-N-[(2-(p-tolylsulfinyl)furan-3-yl)-
methyl]ethanamine 10
4.5.1. Synthesis of N,N-diethyl-3-furamide31
8
C = 100%), as a colorless oil. IR (film):
m
= 3040, 2990, 2980, 2800,
2'
O1
1510, 1450, 1400, 1200, 1150, 1030, 880 cmꢀ1
.
1H NMR
1'
2
5
(200 MHz, CDCl3): d = 1.06 (6H, t, J = 7.0 Hz, H20), 2.51 (4H, q,
J = 7.0 Hz, H10), 3.49 (2H, s, H6), 6.37 (H1, br d, J = 0.8 Hz, H4),
7.32 (1H, dd, J1 = 1.8 Hz, J2 = 0.8 Hz, H2), 7.37 (1H, t, J = 1.8 Hz,
6
N
2'
4
3
1'
O
13
H5) ppm. C NMR (50 MHz, CDCl3): d = 11.8 (C20), 46.5 (C10),
In a three-necked oven-dried 100 mL round-bottomed flask fit-
ted with a condenser, an argon atmosphere, and efficient magnetic
stirrer, furoic acid 3 (5 g, 44.3 mmol) was placed. Thionyl chloride
(12.9 mL, 177 mmol) was then slowly added though the condenser
tip and a CaCl2 tube was fitted to this end. The reaction mixture
was refluxed for 3 h, observing the release of HCl gas. The excess
SOCl2 was removed under atmospheric distillation using a Vigreux
column. In another flask, fitted with an addition funnel, magnetic
stirrer, and an argon atmosphere, a solution of diethylamine
(13.88 mL, 133 mmol) in dry THF (10 mL) was prepared. The furoyl
chloride 11 obtained was diluted with dry THF (20 mL) and placed
in the addition funnel. This solution was added dropwise to the
amine solution at 0 °C and with vigorous stirring. The reaction mix-
ture was stirred at room temperature overnight, which led to the
formation of a white solid (diethyl ammonium chloride). The crude
product was concentrated to dryness in vacuo at room tempera-
ture and the resulting residue diluted with ethyl acetate
(100 mL) and washed with water (2 ꢂ 25 mL). The aqueous phase
was acidified with concentrated HCl up to pH = 3 and the resulting
solution was extracted with ethyl acetate (3 ꢂ 25 mL). All organic
phases were combined, dried over anhydrous MgSO4, filtered,
and concentrated to dryness in vacuo, to give a pure product
46.9 (C6), 111.4 (C4), 121.8 (C3), 140.5 (C2), 142.6 (C5) ppm. MS
[GC-MS (CI), NH3, 70 eV, 150 °C]: m/z (%) = 154 (100, M+H+). Anal.
Calcd for C9H15NO: C, 70.55; H, 9.87; N, 9.14. Found: C, 70.61; H,
9.83; N, 9.02.
4.5.3. Synthesis of (S)-N-Ethyl-N-[(2-(p-tolylsulfinyl)furan-3-
yl)methyl]ethanamine 10
-
O
1
O
2'
1'
S
+
3'
4'
5
2
4
3
6
6'
7'
5'
N
Et
Et
In an oven-dried 50 mL round-bottomed flask fitted with a
magnetic stirrer, a reflux condenser, and purged with argon, n-
BuLi, 1.6 M in hexane (3.75 mL, 6 mmol) and dry diethyl ether
(5 mL) were placed. The system was cooled down to ꢀ24 °C and
N,N-diethyl-3-furylmethylamine 9 (850 mg, 5 mmol) dissolved in
dry diethyl ether (5 mL) was added dropwise. The cooling bath
was changed and the reaction mixture was stirred at 0 °C for 2 h
and for an additional hour at reflux, not observing the formation
of any precipitate (different from what was observed in previous
cases). Simultaneously in another reaction flask (25 mL), activated
magnesium turnings (727 mg, 13 mmol) were placed in dry diethyl
ether (10 mL) at room temperature and 1,2-dibromoethane
(0.57 mL, 6.5 mmol) was added dropwise. This reaction mixture
was refluxed for 1 h with the formation of MgBr2. The ether solu-
tion of magnesium dibromide was filtered out via cannula to re-
move the excess magnesium turnings. The resulting clear
solution of MgBr2 was added portionwise via cannula at 0 °C to
the solution of lithium intermediate, already prepared in the first
reactor. The new reaction mixture was stirred for 2 h at room
temperature to give the corresponding Grignard intermediate. To
this solution cooled down to ꢀ78 °C, (ꢀ)-(1R,2S,5R)-menthyl
(5.86 g, Y = 72%), as a colorless oil. IR (film):
2970, 1630 (amide I st.), 1510 (amide II, st.), 1420, 1390, 1370,
1320, 1300, 1220, 1160, 1120, 1070, 1020 cmꢀ1 1H NMR
m = 3060, 2990,
.
(200 MHz, CDCl3): d = 1.21 (6H, t, J = 7.0 Hz, H20), 3.47 (4H, q,
J = 7.0 Hz, H10), 6.58 (1H, dd, J1 = 1.8 Hz, J2 = 0.8 Hz, H4), 7.40
(1H, t, J = 1.8 Hz, H5), 7.69 (1H, dd, J1 = 1.8 Hz, J2 = 0.8 Hz, H2)
ppm. 13C NMR (50 MHz, CDCl3): d = 13.8 (C20), 41.7 (C10),
90.2 (C3), 110.2 (C4), 142.6 (C5), 142.7 (C2), 164.1 (C6) ppm. MS
[GC–MS(CI), NH3, 70 eV, 150 °C]: m/z (%) = 185 (100, M+NH4),
168 (79 (M+H+). Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84; N,
8.38. Found: C, 64.70; H, 7.90; N, 8.35. GC (50 °C, 1 min, 10 °C/
min, 250 °C, 15 min): tR = 13.84 min. TLC (SiO2, hexane/ethyl
acetate, 50/50): Rf = 0.46 (developed as a white spot on a pink
background, with anisaldehyde/sulfuric acid).

686
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
(SS)-p-toluenesulfinate (1.47 g, 5 mmol) dissolved in dry diethyl
ether (15 mL) was added at once. The reaction was stirred at
ꢀ78 °C for 2 h and then 16 additional hours at room temperature.
The reaction mixture was diluted with ethyl acetate (50 mL) and
washed with aqueous HCl 3% (w/w) (4 ꢂ 25 mL) to give the prod-
uct as an ammonium salt. The organic phase was washed with
water (50 mL). The resulting aqueous phase was combined with
the previous acidic phases. The organic phase was dried over anhy-
drous MgSO4, filtered, and concentrated to dryness in vacuo to re-
cover the unchanged menthyl sulfinate. Aqueous NaOH 5% (w/v)
was added to the acidic aqueous phase up until pH = 10 and then
extracted with ethyl acetate (4 ꢂ 25 mL). The organic phases were
combined, dried over anhydrous MgSO4, filtered, and concentrated
to dryness, to give a pure product as a viscous oil (583 mg,
unreacted 3-furoic acid. This crude mixture was subjected to a
flash column chromatography on silica gel (eluting with mixture
of hexane and ethyl acetate of increasing polarity). The product
was isolated by elution with hexane/ethyl acetate 60:40 as a
yellowish solid (209.5 mg, yield = 90%, respect to menthyl
p-toluenesulfinate, conversion = 100%). Mp = 94–95 °C (ethyl/ace-
tate hexane). IR (film):
m
= 3200–2000 (br, H–O, st), 2927, 1723
(C@O, st), 1489, 1173, 1024, 1007, 756 cmꢀ1
.
1H NMR (200 MHz,
CDCl3): d = 2.41 (3H, s, H70), 6.88 (1H, d, J = 1.8 Hz, H4), 7.34 (2H,
d, J = 8.0 Hz, H30 and H50), 7.53 (1H, d, J = 1.8 Hz, H5), 7.70 (2H, d,
J = 8.0 Hz, H20 and H60), 9.90 (1H, br s, O-H) ppm. 13C NMR
(50 MHz, CDCl3): d = 21.5 (C70), 112.9 (C4), 121.5 (C3), 125.0 (C30
and C50), 130.2 (C20 y C60), 137.3 (C40), 142.8 (C10), 146.0 (C5),
154.8 (C2), 163.8 (C6) ppm. MS [GC–MS(CI), NH3, 70 eV, 150 °C]:
m/z (%) = 268 (100, M+NH4), 251 (37, M+1). Anal. Calcd for: C,
yield = 40%, conversion = 40%). IR (film):
m = 2969, 2934, 2811,
1597, 1493, 1385, 1182, 1085, 1047, 1016, 810, 764, 621 cmꢀ1
.
57.59; H, 4.03. Found: C, 57.40; H, 4.12. ½a D21
¼ þ27:4 (c 0.5, CHCl3).
ꢁ
1H NMR (200 MHz, CDCl3): d = 1.05 (6H, t, J = 7.4 Hz, NCH2CH3),
2.40 (3H, s, H70), 2.55 (4H, dq, J1 = 7.4 Hz, J2 = 1.4 Hz, NCH2CH3),
3.70 (2H, d, J = 7 Hz, H6), 6.48 (1H, d, J = 1.8 Hz, H4), 7.30 (2H, d,
J = 7.4 Hz, H30 and H50), 7.43 (1H, d, J = 1.8 Hz, H5), 7.56 (2H, d,
J = 7.4 Hz, H20 and H60) ppm. 13C NMR (50 MHz, CDCl3): d = 11.7
(NCH2CH3), 21.4 (C70), 46.5 (NCH2CH3), 46.8 (C6), 112.9 (C4),
124.7 (C30 and C50), 129.7 (C20 and C60), 131.5 (C3), 138.2 (C40),
141.1 (C10), 146.4 (C5), 148.8 (C2) ppm. MS [GC–MS(CI), NH3,
70 eV, 150 °C]: m/z (%) = 299 (100, M+1), 274 (3, M-17). Anal. Calcd
Chiral GC (100 °C, 1 min, 5 °C/min, 220 °C, 20 min): tR = 19.10 min.
Ee = 100%. TLC (SiO2, ethyl acetate): Rf = 0.12.
4.6.1. Modifications and optimizations of the experimental
procedure
The reaction conditions evaluated in order to optimize this
reaction process are quoted in Table 2. When diethyl ether
was used as the solvent, the reaction did not take place (due
to the low solubility of the dilithium intermediate) (entries 1
and 2). When an excess of dilithium intermediate versus men-
thyl sulfinate was used, a great increase in yield was observed
(from moderate to quantitative yield) (entry 6). On the other
hand, a large excess of LDA led to a decrease in the yield due
to the reaction of this strong base with menthyl sulfinate (entry
5). Finally, it is worth noting that a transmetallation process
with MgBr2 afforded a null yield of the desired product (entries
1 and 7), probably due to the low reactivity of the intermediate
Grignard reagent.
for: C, 65.95; H, 7.26. Found: C, 66.03; H, 7.10. ½a D21
¼ ꢀ20:9 (c 1.0,
ꢁ
CHCl3). Chiral GC (100 °C, 1 min, 5 °C/min, 220 °C, 20 min):
tR = 25.71 min. Ee = 100%. TLC (SiO2, ethyl acetate): Rf = 0.15 (two
elutions and developed as a brown spot with anisaldehyde/sulfuric
acid).
4.6. Synthesis of (S)-2-(p-tolylsulfinyl)-3-furoic acid 11
-
O
1
O
2'
1'
4.7. Synthesis of methyl (S)-2-(p-tolylsulfinyl)-3-furoate 12
S
3'
4'
5
+
2
O 6'
4
3
7'
6
5'
-
O
OH
1
O
2'
1'
S
+
3'
4'
5
2
In a 100 mL oven-dried round-bottomed flask, fitted with a
magnetic stirrer and under an argon atmosphere, a solution of
2.0 M LDA in THF (1.86 mL, 3.72 mmol) and dry tetrahydrofuran
(5 mL) were placed. The solution was cooled down to ꢀ78 °C and
3-furoic acid 3 (200 mg, 1.78 mmol) dissolved in dry THF (9 mL)
was added dropwise. The reaction mixture was maintained at
ꢀ78 °C for 45 min and the formation of the dilithium intermediate
took place without precipitation. This solution was maintained at
O 6'
4
3
7'
6
5'
OMe
In a 100 mL round-bottomed flask, fitted with a magnetic stirrer
and a simple distillation setup, (S)-2-(p-tolylsulfinyl)-3-furoic acid
11 (250 mg, 1 mmol) was placed, and dissolved in dry methanol
(40 mL). Four drops of 96% (w/w) H2SO4 were added as a catalyst,
for the Fisher esterification to take place, and the mixture was
slowly heated up to reflux temperature. Methanol was slowly dis-
tilled (35 mL collected) to give a residue of 5 mL. It is important not
to concentrate to dryness because the yield considerably decreases.
An additional volume of dry methanol (35 mL) was added to the
reaction flask and the process was repeated. This process was car-
ried out for third time until the control by TLC showed complete
conversion (esterification). The concentrated residue was diluted
with ethyl acetate (50 mL) and washed with a saturated aqueous
solution of NaHCO3 (2 ꢂ 10 mL) in order to remove sulfuric acid.
The aqueous phase was extracted with ethyl acetate (2 ꢂ 25 mL)
and all of the organic phases were combined together, dried over
anhydrous MgSO4, filtered, and concentrated to dryness under vac-
uum, to give a pure product as a white solid (254 mg, 96% yield).
ꢀ78 °C
and
(1R,2S,5R)-(ꢀ)-menthyl
(SS)-p-toluenesulfinate
(275 mg, 0.93 mmol), dissolved in dry THF (10 mL) was added
dropwise after which the reaction mixture was stirred for 1 h, at
ꢀ78 °C. Next, the quenching was carried out by the addition of
aqueous 3% (w/w) HCl (10 mL). The reaction mixture was then ex-
tracted with ethyl acetate (3 ꢂ 50 mL). The aqueous acidic phase
(pH <1) was discarded and the organic phase extracted with aque-
ous 10% (w/v) NaOH (3 ꢂ 30 mL) in order to recover the product as
a sodium carboxylate. The aqueous basic extracts were combined
together and washed with ethyl acetate (3 ꢂ 25 mL). The organic
phases contain mainly menthol and unreacted sulfinate as by-
products. Finally, the basic aqueous phase (pH >10), containing
the product as a sodium carboxylate, was acidified by the dropwise
addition of concentrated HCl (until pH = 1) and extracted with
ethyl acetate (3 ꢂ 50 mL). The resulting organic phase was dried
over anhydrous MgSO4, filtered, and concentrated to dryness in va-
cuo, to give a solid residue containing the desired product and
Mp = 130.5–131.5 °C (ethyl acetate). IR (film):
1711 (C@O, st), 1485, 1306, 1180, 1163, 1115, 1083, 1059, 1045,
1024 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 2.40 (3H, s, H70), 3.93
m = 3158, 2952,
.

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
687
(1H, s, OCH3), 6.76 (1H, d, J = 1.8 Hz, H4), 7.32 (2H, d, J = 8.0 Hz, H30
and H50), 7.50 (1H, d, J = 1.8 Hz, H5), 7.69 (2H, d, J = 8.0 Hz, H20 and
the freezer for at least one week. A sample of this product was iso-
lated for its physical and spectroscopic characterization. IR (film):
= 3120, 2984, 1807, 1728, 1489, 1302, 1227, 1088, 1041, 989,
754 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 1.43 (3H, t, J = 7.0 Hz,
m
13
H60) ppm. C NMR (50 MHz, CDCl3): d = 21.5 (C70), 52.34 (O-CH3),
111.7 (C4), 120.7 (C3), 124.8 (C30 and C50), 129.9 (C20 and C60),
138.5 (C40), 142.0 (C10), 146.0 (C5), 154.8 (C2), 162.0 (C6) ppm.
MS [GC-MS(CI), NH3, 70 eV, 150 °C]: m/z (%) = 283 (16, MH+NH4),
282 (100, M+NH4), 265 (35, MH+). Anal. Calcd for: C, 59.08; H,
.
OCH2CH3), 2.41 (3H, s, H70), 4.33–4.47 (2H, m, OCH2CH3), 6.96
(1H, d, J = 1.8 Hz, H4), 7.31 (2H, d, J = 8.0 Hz, H30 and H50), 7.59
(1H, d, J = 1.8 Hz, H5), 7.69 (2H, d, J = 8.0 Hz, H20 and H60) ppm.
13C NMR (50 MHz, CDCl3): d = 14.3 (OCH2CH3), 21.5 (C70), 61.5
(OCH2CH3), 111.8 (C4), 118.9 (C3), 124.9 (C30 and C50), 129.9 (C20
and C60), 138.7 (C40), 142.0 (C10), 146.5 (C5), 154.6 (C2), 159.0
(OCO2), 161.0 (C6) ppm. Anal. Calcd for C15H14O6S: C, 55.89; H,
4.38; S, 9.95. Found: C, 55.92; H, 4.43; S, 10.01. MS [DIP-EI,
70 eV, 150 °C]: m/z (%) = 332 (20, M), 233 (100, MꢀOCOOEt), 231
(45, MꢀC6H4Me), 205 (20, MꢀC4H5O4). Chiral GC (100 °C, 1 min,
5 °C/min, 220 °C, 20 min): tR = 28.4 min. Ee = 100%. TLC (SiO2, ethyl
acetate): Rf = 0.45.
4.58. Found: C, 59.19; H, 4.67. ½a D21
¼ ꢀ86:7 (c 0.66, CHCl3). Chiral
ꢁ
GC (100 °C, 1 min, 5 °C/min, 220 °C, 20 min): tR = 25.80 min.
Ee = 100%. TLC (SiO2, hexane/ethyl acetate): Rf = 0.33 (7:3), 0.63
(1:1), 0.9 (0:1).
4.8. Synthesis of ethyl (S)-2-(p-tolylsulfinyl)-3-furoate 13
-
O
1
O
2'
1'
S
3'
4'
5
4.10. Synthesis of (1S,2R,5S)-myrtanyl (S)-2-(p-tolylsulfinyl)-3-
furoate 15 and the concomitant formation of by-product 13
+
2
O 6'
4
3
7'
6
5'
OEt
An esterification reaction, under conditions similar to the ones
previously described, was carried out with ethanol to obtain the
ethyl ester, but the yield was lower under all tried reaction condi-
tions. The best results obtained correspond to a 100% conversion
and a 53% yield. White solid. Mp = 93–94.5 °C (ethyl acetate). IR
-
O
1
2'
O
1'
S
3'
4'
5
+
2
O 6'
4
3
7'
6
5'
O
10''
(film):
m = 3129, 2983, 2925, 1792 (C@O, st), 1734 (C@O, st),
2''
1636, 1559, 1489, 1456, 1302, 1259, 1177, 1086, 1028,
1''
3''
4''
810 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 1.41 (3H, t, J = 7.0 Hz,
.
7''
6''
OCH2CH3), 2.40 (3H, s, H70), 4.40 (2H, q, J = 7.0 Hz, OCH2CH3),
6.76 (1H, d, J = 1.8 Hz, H4), 7.32 (2H, d, J = 8.0 Hz, H30 and H50),
7.49 (1H, d, J = 1.8 Hz, H5), 7.69 (2H, d, J = 8.0 Hz, H20 and H60)
8''
5''
9''
13
ppm. C NMR (50 MHz, CDCl3): d = 14.3 (OCH2CH3), 21.5 (C70),
In an oven-dried round-bottomed 25 mL flask, fitted with a mag-
netic stirrer and under an argon atmosphere, mixed anhydride 14
(148.3 mg, 0.46 mmol) was placed and dissolved in dry THF
(6 mL). The system was cooled down to 0 °C and triethylamine
(0.28 mL, 1.84 mmol) was added, followed by the dropwise addition
of a solution of (ꢀ)-(1S,2R,5S)-myrtanol (283 mg, 1.84 mmol) in dry
THF (3 mL). The reaction mixture was stirred at room temperature
for 4 h. Afterward, the solvent was removed under vacuum and
the resulting residue was subjected to flash column chromatogra-
phy on silica gel, eluting with mixtures of hexane and ethyl acetate
of increasing polarity. The product was isolated by elution with hex-
ane/ethyl acetate 95:5 as a thick oil (133.5 mg, yield = 75%). IR
61.6 (OCH2CH3), 111.8 (C4), 120.7 (C3), 124.9 (C30 and C500),
130.0 (C20 and C60), 138.5 (C40), 140.1 (C10), 146.0 (C5), 154.8
(C2), 161.1 (C6) ppm. MS [GC-MS(CI), NH3, 70 eV, 150 °C]: m/z
(%) = 296 (100, M+NH4), 279 (37, M+1). Anal. Calcd for: C, 60.42;
H, 5.07; S, 11.52. Found: C, 60.45; H, 5.02; S, 11.60.
½
a 2D5
ꢁ
¼ ꢀ159:1 (c 0.11, CHCl3). Chiral GC (100 °C, 1 min, 5 °C/min,
220 °C, 20 min): tR = 26.98 min. Ee = 100%. TLC (SiO2, hexane/ethyl
acetate, 1:1): Rf = 0.75.
4.9. Synthesis of the mixed anhydride from (S)-2-(p-tolylsulfi-
nyl)-3-furoic acid and ethyl hydrogencarbonate 14
(film):
m = 3118, 2917, 2869, 1723 (C@O, st), 1541, 1489, 1300,
1240, 1169, 1086, 1059, 1043, 1118, 889 cmꢀ1. 1H NMR (200 MHz,
CDCl3): d = 0.86 (3H, s, H800), 1.22 (3H, s, H900), 1.26-2.30 (9H, m,
H100, H200, H300, H400, H500, H700), 2.40 (3H, s, H70), 4.14 (2H, q,
J = 7.4 Hz, H10’’), 6.76 (1H, d, J = 1.8 Hz, H4), 7.31 (2H, d, J = 8.0 Hz,
H30 and H50), 7.50 (1H, d, J = 1.8 Hz, H5), 7.67 (2H, d, J = 8.0 Hz, H20
and H60) ppm. 13C NMR (50 MHz, CDCl3): d = 16.2 (C900), 18.2 (C800),
19.5 (C400), 21.4 (C70), 21.9 (C300), 24.6 (C700), 32.3 (C200), 37.2 (C600),
38.7 (C500), 40.3 (C100), 109.8 (C4), 119.4 (C3), 122.7 (C30 and C50),
127.9 (C20 and C60), 136.3 (C40), 139.9 (C10), 143.9 (C5), 154.8 (C2),
159.8 (C6) ppm. MS [GC-MS(CI), NH3, 70 eV, 150 °C]: m/z (%) = 404
(100, M+NH4), 387 (16, M+1), 386 (4, M+). Anal. Calcd for
-
O
1
O
2'
1'
S
3'
4'
5
+
2
O 6'
4
3
7'
6
5'
O
O
O
In a 5 mL oven-dried round-bottomed flask, fitted with a mag-
netic stirrer and in an argon atmosphere (S)-2-(p-tolylsulfinyl)-3-
furoic acid was placed (80 mg, 0.32 mmol) and dissolved in dry
THF (2 mL). To this solution and at 0 °C, triethylamine (44
0.32 mmol) and ethyl chloroformate (30 L, 0.32 mmol) were
added sequentially dropwise. The reaction mixture was stirred at
0 °C for 1 h, observing the formation of a solid (triethylammonium
chloride), which was removed by filtration via cannula at 0 °C. The
mixed anhydride, dissolved in THF, was directly used for the deriv-
atization reactions of the carboxylic group. This solution is stable in
C
22H26O4S: C, 68.37; H, 6.78; S, 8.29. Found: C, 68.41; H, 6.75; S,
lL,
8.24. ½a 2D5
¼ ꢀ158:8 (c 0.072, CHCl3). Chiral GC (100 °C, 1 min,
ꢁ
l
5 °C/min, 220 °C, 20 min): tR = 30.29 min. Ee = 100%. TLC (SiO2, hex-
ane/ethyl acetate, 1:1): Rf = 0.85.
In this reaction ethyl (S)-2-(p-tolylsulfinyl)-3-furoate 13 was
formed as a by-product. It was isolated in the same column chro-
matography purification by elution with hexane/ethyl acetate
80:20 to give a pure white solid (14 mg, yield = 11%).

688
Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
4.11. Synthesis of (S)-N,N-diethyl-2-(p-tolylsulfinyl)-3-furamide
16
NMR (200 MHz, CDCl3): d = 1.42 (3H, d, J = 7.0 Hz, H200), 2.30 (3H,
s, H70), 5.18 (1H, q, J = 7.0 Hz, H100), 6.80 (1H, t, J = 1.8 Hz, H4),
7.09-7.31 (7H, m, H30, H50, H400, H500, H600, H700, H800), 7.34 (1H, t,
J = 1.8 Hz, H5), 7.50 (2H, d, J = 8.0 Hz, H20 and H60), 8.87 (1H, br d,
-
O
1
O
2'
1'
S
3'
13
5
2
J = 7 Hz, N–H) ppm. C NMR (50 MHz, CDCl3): d = 21.4 (C70), 22.5
+
4'
(C200), 49.6 (C100), 114.4 (C4), 124.7 (C30 and C50), 126.0 (C400 and
C800) 126.5 (C3), 127.1 (C600), 128.5 (C500 and C700), 130.2 (C20 and
C60), 138.1 (C40), 142.6 (C10), 143.4 (C300), 144.5 (C5), 151.0 (C2),
159.1 (C6) ppm. MS [GC-MS(CI), NH3, 70 eV, 150 °C]: m/z
O 6'
4
3
7'
6
5'
NEt2
(%) = 355 (24, M+1), 354 (100, M+). ½a D25
¼ þ77:5 (c 0.18, CHCl3).
ꢁ
Anal. Calcd for C20H19NO3S: C, 67.97; H, 5.42. Found: C, 68.05; H,
5.34. Chiral GC (100 °C, 1 min, 5 °C/min, 220 °C, 20 min):
tR = 29.94 min. TLC (SiO2, ethyl acetate): Rf = 0.60 (developed as a
brown spot with anisaldehyde/sulfuric acid).
In an oven-dried round-bottomed 10 mL flask, fitted with a
magnetic stirrer and under an argon atmosphere, mixed anhydride
14 (128.9 mg, 0.40 mmol) was placed and dissolved in dry THF
(5 mL). The system was cooled down to 0 °C and diethylamine
(0.17 mL, 1.6 mmol) was added at once and the mixture was stir-
red at room temperature for 16 h. The solvent was removed under
vacuum and the resulting residue was subjected to flash column
chromatography on silica gel, eluting with mixtures of hexane
and ethyl acetate of increasing polarity. The product was isolated
Acknowledgments
We thank the University of Barcelona for financial support
(Grant UB-VRR-2012/AR000126).
by elution with hexane/ethyl acetate 1:1, as
(97.7 mg, yield = 80%, conversion = 100%). IR (film):
1636, 1576, 1559, 1541, 1506, 1489, 1456, 1437, 1126, 1084,
1049, 891, 812, 750 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 1.23
a
viscous oil
m
= 2977,
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(6H, q, J = 7.0 Hz, NCH2CH3), 2.39 (3H, s, H70), 3.33-3.53 (4H, m,
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and H50), 7.70 (1H, d, J = 1.8 Hz, H5), 7.71 (2H, d, J = 8.0 Hz, H20
and H60) ppm. 13C NMR (50 MHz, CDCl3): d = 12.8 and 14.5
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4.12. Synthesis of (SS,S)-N-(1-phenylethyl)-2-(p-tolylsulfinyl)-3-
furamide 17
-
O
1
O
2'
1'
S
3'
4'
5
+
2
O 6'
4
3
7'
6
5'
1'' NH
2''
4''
3''
8''
7''
5''
6''
In an oven-dried round-bottomed 25 mL flask, fitted with a
magnetic stirrer and under an argon atmosphere, mixed anhydride
14 (257.8 mg, 0.80 mmol) was placed and dissolved in dry THF
(10 mL). The system was cooled down to 0 °C and (S)-(ꢀ)-1-meth-
ylbenzylamine (414 lL, 3.2 mmol) was added at once and the mix-
ture was stirred at room temperature for 20 h. The solvent was
removed under vacuum and the resulting residue was submitted
to a flash column chromatography on silica gel, eluting with mix-
tures of hexane and ethyl acetate of increasing polarity. The prod-
uct was isolated by elution with hexane/ethyl acetate 1:1, as a
colorless oil (182 mg, yield = 64%, conversion = 100%). IR (film):
= 3309 (N–H, st), 3114, 3031, 2977, 2929, 1653, 1576, 1526,
1493, 1451, 1375, 1213, 1126, 1082, 1038, 891, 810 cmꢀ1 1H
m
.

Á. M. Montaña et al. / Tetrahedron: Asymmetry 25 (2014) 677–689
689
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