Diastereoselective synthesis of tetrahydrofurans from Aryl 3-chloropropylsulfoxides and aldehydes

Article abstract of DOI:10.1021/jo1002196

Carbanions of aryl 3-chloropropylsulfoxides react with nonenolizable aldehydes to give 2,3-disubstituted tetrahydrofurans. Deprotonation of the sulfoxides carried out in the presence of aldehydes results in the addition of the carbanions to the carbonyl group of the aldehydes, followed by 1,5-intramolecular substitution of the resulting aldol-type anion to produce the tetrahydrofuran ring. The 2-aryl and 3-arylsulfinyl substituents are always in trans relation, and the reaction proceeds with high diastereoselectivity also in respect to the chiral sulfur atom. The diastereoselectivity is attributed to the cyclic transition state of the aldol addition and increases when the aromatic ring of the sulfoxide contains electron-withdrawing substituents, whereas that of the aldehyde has electron-donating groups.

Full text of DOI:10.1021/jo1002196

pubs.acs.org/joc
Diastereoselective Synthesis of Tetrahydrofurans from Aryl
3-Chloropropylsulfoxides and Aldehydes‡
Zofia Komsta, Michaz Barbasiewicz,† and Mieczyszaw Ma-kosza*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
†Current address: Department of Chemistry, Warsaw University, Pasteura 1, 02-089 Warsaw, Poland.
icho-s@icho.edu.pl
Received February 10, 2010
Carbanions of aryl 3-chloropropylsulfoxides react with nonenolizable aldehydes to give 2,3-disub-
stituted tetrahydrofurans. Deprotonation of the sulfoxides carried out in the presence of aldehydes
results in the addition of the carbanions to the carbonyl group of the aldehydes, followed by 1,5-intra-
molecular substitution of the resulting aldol-type anion to produce the tetrahydrofuran ring. The
2-aryl and 3-arylsulfinyl substituents are always in trans relation, and the reaction proceeds with high
diastereoselectivity also in respect to the chiral sulfur atom. The diastereoselectivity is attributed to
the cyclic transition state of the aldol addition and increases when the aromatic ring of the sulfoxide
contains electron-withdrawing substituents, whereas that of the aldehyde has electron-donating
groups.
Introduction
acceptors to form tetrahydrofurans,5-7 pyrrolidines,8 and cyclo-
pentanes,9 respectively. These processes resemble to some extent
the Darzens and aza-Darzens reactions, where R-halocarbanions
add to electron-deficient CdO and CdN bonds to form aldol-
type anion intermediates that subsequently undergo intramo-
lecular substitution to produce three-membered rings. Simi-
larity of these reactions is based on the fact that the carbanions
containing leaving groups such as halogen, upon addition to
the electron-deficient double bonds, form anions in which
nucleophilic and electrophilic centers are separated by two
more atoms. Thus, R-halocarbanions in which nucleophilic
and electrophilic centers are at the same atom, upon addition
to electron-deficient double bonds form anions with 1,3-relation
to these centers, whereas γ-halocarbanions with 1,3-relation
to nucleophilic and electrophilic centers form systems with
1,5-relation to such centers (Scheme 1).
γ-Halocarbanions are short-lived intermediates that enter
rapid intramolecular substitution to produce three-membered
rings. This reaction is a valuable process for the synthesis of
cyclopropanes1 and also a key step for such important processes
as the Favorsky, Ramberg-Backlund, and related transfor-
mations.4 Recently we have shown that despite the fast intra-
molecular 1,3-substitution, often called γ-elimination, γ-halo-
carbanions can be trapped by aldehydes, imines, and Michael
2
3
€
‡ Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday.
(1) (a) Zwanenburg, B.; De Kimpe, N. In Carbocyclic Three-Membered Ring
Compounds, 4th ed.; de Meijere, A., Ed.; Georg Thieme Verlag: Stuttgart, 1996;
Vol. E17a, pp 29-40. (b) Gronert, S.; Azizian, A.; Friedman, M. A. J. Am. Chem.
Soc. 1998, 120, 3220. (c) Habusha, U.; Rozental, E.; Hoz, S. J. Am. Chem. Soc.
2002, 124, 15006.
(2) Guijarro, D.; Yus, M. Curr. Org. Chem. 2005,9, 1713 and references therein.
(3) Clough, J. M. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, p 861.
(4) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Carson, C. A.; Kerr, M. A.
Chem. Soc. Rev. 2009, 38, 3051.
Despite their similarities, γ-halocarbanions differ mark-
edly from R-carbanions because of the fast intramolecular
substitution, which competes with the intermolecular addi-
tion to electrophiles. While R-carbanions are relatively stable
species and their potential side processes (such as dimeriza-
tion or R-elimination to carbenes) are generally suppressed,
(5) Shibata, I.; Yamasaki, H.; Baba, A.; Matsuda, H. J. Org. Chem. 1992,
57, 6909.
(6) (a) For a preliminary communication of the synthesis of tetrahydro-
furans from 4-chlorobutyronitrile and aldehydes under basic phase transfer
catalysis conditions, see: Ma-kosza, M.; Przyborowski, J.; Klajn, R.; Kwast,
A. Synlett 2000, 1773. (b) For a review of reactions of γ-halocarbanions, see:
Barbasiewicz, M.; Judka, M.; Ma-kosza, M. Russ. Chem. Bull., Int. Ed. 2004,
53, 1846.
(7) Ma-kosza, M.; Judka, M. Chem.;Eur. J. 2002, 8, 4234.
(8) Ma-kosza, M.; Judka, M. Helv. Chim. Acta 2005, 88, 1676.
(9) Ma-kosza, M.; Judka, M. Synlett 2004, 717.
DOI: 10.1021/jo1002196
r
Published on Web 04/21/2010
J. Org. Chem. 2010, 75, 3251–3259 3251
2010 American Chemical Society

Komsta et al.
JOCArticle
SCHEME 1. Reactions of R- and γ-Halocarbanionsa
reactions of 4-bromobutyl phenyl sulfone, methyl 5-bromo-
pentanoate, and δ-bromovalerophenone with aldehydes
gave substituted tetrahydropyranes in good to excellent
yields.15 In turn, oxygen analogues of γ- and δ-halocarba-
nions, i.e., anions of 2-chloroethanol and 3-chloropropanol,
react with aldehydes to form cyclic acetals (1,3-dioxolanes
and 1,3-dioxanes) under kinetically controlled basic condi-
tions; the method is complementary to an acid-catalyzed
(equilibrated) acetalization of aldehydes with glycols.16
An important aspect of the discussed methodology is the
stereochemistry of the products and methods of its control.
In the model reactions of carbanions of 3-chloropropyl
phenyl sulfone, alkyl 4-chlorobutyrates, and 4-chlorobutyro-
nitrile with aldehydes, two new stereogenic centers are created.
In most cases the predominant products of the reactions are
trans isomers of 2,3-disubstituted tetrahydrofurans, and only
when EWG is of a minimal steric demand is formation of the cis
isomer observed.7,12 This high stereoselectivity may be attri-
buted to the selective, kinetically controlled formation of the
predominant trans isomer or, alternatively, to thermodynami-
cally controlled base-catalyzed epimerization of the cis product
at the C-3 position, in the vicinity of the electron-withdrawing
group. Although reliable mechanistic data is available for only a
few systems,7,12 the first possibility seems to be more plausible. A
more complicated situation can be considered for systems where
asymmetric induction is exerted by a nonenolizable stereogenic
center present in the substrates;17 as two new stereogenic centers
are created at the five-membered ring, four diastereoisomeric
products (22=4) are expected. In our case only the stereogenic
center at C-2 position is irreversibly fixed in the cyclization step,
while the second one, at C-3, is labile and prone to epimerization
due to the presence of adjacent EWG group. Therefore in the
general case, when one of the substrates possesses a non-
enolizable stereogenic center, the product selectivity at C-2
derives from induction by this center, while the configuration
at C-3 could be established by base-induced epimerization of the
product (Scheme 2).18
aDeprotonation of the precursors with base gives carbanions that in the
presence of electrophile (aldehydes, imines, or Michael acceptors) can be
trapped into aldol-type adducts and then cyclized to three- and five-
membered rings, respectively. The mechanistic scheme is of general
character and is similar for a few reactions, such as Darzens, Corey-
Chaykovsky, etc.
γ-halocarbanions rapidly cyclize to cyclopropanes, and the
competition between intra- and intermolecular reactions is
controlled by numerous factors. In attempts to favor the
bimolecular reaction nature of the leaving group,7,10,11 the
electron-withdrawing group,8 substituents in the chain of the
γ-halocarbanion precursor, various bases and solvents,11,12
concentration of the reactants,7 the temperature, and the reac-
tion time11,13 were studied. For a variety of structures the
optimized conditions provided high yield and selectivity of the
desired products resulting from the intermolecular reactions.
Manipulation of leaving groups,10 for instance, exchanging
a halogen for trimethylammonium and diphenylphosphi-
noxy groups, was partially successful. Nucleophilic replace-
ment of the trimethyl ammonium group is known to proceed
more slowly than replacement of the chlorine; however,
carbanions of 3-(trimethylammonium)propyl phenyl sul-
fone and 4-trimethylammonium butyronitrile do not cyclize
to cyclopropane derivatives. These carbanions add to benz-
aldehyde, but so-formed aldol-type adducts do not cyclize
either.10a On the other hand the diphenylphosphinoxy group
in carbanion of 3-diphenylphosphinoxypropyl phenyl sul-
fone behaved as expected.10b Cyclization of the carbanion
was a slow process, so formation of tetrahydrofurans via its
reaction with aldehydes proceeded smothly.
Finally, we should consider that the mechanism of the process
consists of two steps: the aldol-type addition and the subsequent
cyclization via intramolecular nucleophilic substitution; both
steps can control the stereochemistry of the products with
respect to the nonlabile C-2 position. When the aldol-type
addition is a stereoselective process, the intermediate adduct is
formed as a predominant isomer that subsequently cyclizes
(Scheme 3, path a). On the other hand, when the addition is
faster than 1,5-substitution, then the composition of the diaste-
reoisomeric products can be governed by the relation between
rates of the cyclization of the isomeric adducts (providing that
the addition step is reversible and the aldol-type adducts may
quickly equilibrate)19 (Scheme 3, path b).
In further studies the methodology was extended to reac-
tions of δ-halocarbanions14,15 and anions of 2-haloalco-
hols16 taking advantage of the same mechanistic scheme as
presented for the reactions of γ-halocarbanions. δ-Halocar-
banions are relatively long-lived species as a result of much
slower competing intramolecular 1,4-substitution, and thus
their facile addition to a carbonyl group is expected. In fact
(17) For reactions of γ-halocarbanions with chiral imines, see: (a)
Baricordi, N.; Benetti, S.; Biondini, G.; De Risi, C.; Pollini, G. P. Tetrahedron
Lett. 2004, 45, 1373. (b) Hassner, A.; Usak, D.; Kumareswaran, R.; Friedman,
O. Eur. J. Org. Chem. 2004, 2421. For reactions of γ-halocarbanions with
chiral Michael acceptors, see: (c) Hassner, A.; Ghera, E.; Yechezkel, T.;
Kleiman, V.; Balasubramanian, T.; Ostercamp., D. Pure Appl. Chem. 2000,
72, 1671.
(18) The configurations at C-2 and C-3 of newly formed tetrahydrofurans
depend on the selectivity of the aldol addition and cyclization process.
However, in the end proportion of trans and cis isomers (relative C-2 to C-3
configuration) approaches the thermodynamic limit after the base-induced
C-3 epimerization.
(10) (a) Ma-kosza, M.; Judka, M. Synthesis 2003, 820. (b) Ma-kosza, M.;
Wojtasiewicz, A. Phosphorus, Sulfur, Silicon Relat. Elem. 2009, 184, 857.
(11) Ma-kosza, M.; Barbasiewicz, M.; Krajewski, D. Org. Lett. 2005, 7,
2945.
(12) Barbasiewicz, M.; Ma-kosza, M. Synthesis 2006, 1190.
(13) Wojtasiewicz, A.; Barbasiewicz, M.; Ma-kosza, M. Eur. J. Org.
Chem. 2010, 1885.
(14) Fleming, F. F.; Gudipati, V.; Steward., O. W. J. Org. Chem. 2003, 68,
3943.
(15) Barbasiewicz, M.; Brud, A.; Ma-kosza, M. Synthesis 2007, 1209.
(16) Barbasiewicz, M.; Ma-kosza, M. Org. Lett. 2006, 8, 3745.
(19) Alternatively, aldol-type adducts may isomerize by epimerization.
For some hint that it actually involves a dissociation-addition sequence see
note 17 in ref 15.
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SCHEME 2. Reaction of a Chiral Precursor of γ-Halocarba-
groups that act as “chiral auxiliaries”20 at the first, irrever-
sible step of the reaction, the aldol addition, and we therefore
expect that this step shall control the overall stereochemistry
of the product formation.
nion with an Aldehydea
Results and Discussion
Although for the aldol-type processes a wealth of chiral
auxiliaries is available,21 strong basic conditions and the
presence of weakly coordinating potassium cations, as re-
quired for the one-pot synthesis of tetrahydrofurans, limit
their number to few.22 Taking into account our earlier
observations of stereochemical course of the tetrahydrofur-
an synthesis7,11 we have chosen 4-chlorobutyrates of chiral
alcohols and aryl 3-chloropropyl sulfoxides as γ-halocarb-
anion precursors for the reaction with aldehydes. We be-
lieved that, in the same way as achiral tert-butyl 4-chloro-
butyrate and 3-chloropropyl phenyl sulfone, also esters of
the chiral alcohols and sulfoxides upon deprotonation in the
presence of the aldehydes should give tetrahydrofurans with
ring substituents in trans relation, and the stereogenic center
present in the molecule will control the stereochemistry of the
addition step.
aThis reaction may lead to four distereoisomers of the product. How-
ever, two of them are prone to epimerization and only trans-2,3-
disubstituted tetrahydrofurans can be isolated from the reaction
mixture.
SCHEME 3. Mechanistic Considerations of the Asymmetric
Induction in a Two-Step Reactiona
Synthesis of Substrates. 4-Chlorobutyrates of (-)-menthol,
(-)-8-phenylmenthol, and 1,2:5,6-diisopropylidene-D-gluco-
furanose were obtained in the reaction of the chiral alcohols
with 4-chlorobutyric acid chloride. Aryl 3-chloropropyl sulf-
oxides were synthesized in two steps starting from commer-
cially available thiophenols. Thiophenol and 4-chlorothio-
phenol were reacted with 1,3-dichloropropane under phase
transfer catalysis conditions (NaOH and catalytic amount of
NBu4Cl) and purified by vacuum distillation. Under such
conditions 2-mercaptopyridine reacted with 1,3-dichloropro-
pane nonselectively and substantial amounts 1,3-bis(2-thio-
pyridyl)propane were formed. The reaction with 1-bromo-3-
chloropropane in the presence of KOH in ethanol gave the
desired sulfide, which was purified by column chromatogra-
phy. Aryl 3-chloropropyl sulfides were subsequently oxidized
to sulfoxides with bromine under a simple two-phase aqueous
KHCO3/CH2Cl2 system described by Mikozajczyk.23 Again,
the pyridine derivative gave under the above-mentioned con-
ditions unsatisfactory yields and required periodate oxidation
followed by column chromatography. In all cases, yields of the
desired sulfoxides (1-4) were moderate to good and purity of
the products was uncompromised.
aSelectivity is gained in the first (a) or in the second step, providing that
the first step is reversible (b).
Recently we demonstrated that 2,3,5-trisubstituted tetra-
hydrofurans are produced in the aldol-type addition of
γ,δ-epoxycarbanions to aldehydes and subsequent Lewis
acid catalyzed intramolecular substitution via opening of
the oxirane ring acting as a leaving group.11 Diastereoselec-
tivity of the reaction is controlled by the stereocenter present
in the carbanion precursor; the first step is nonstereoselective
but reversible, and what controls distribution of the stereo-
isomers (according to the Curtin-Hammett postulate) is the
difference between rates of the subsequent irreversible cycli-
zation of the diastereoisomeric adducts. Having in mind the
results of the above-mentioned reaction, where the cycli-
zation step determines the stereoselectivity, we took up the
idea of the diastereoselective aldol-type reaction (Scheme 3,
path b). In this report we present and discuss reactions of
γ-halocarbanions containing chiral electron-withdrawing
Reactions of 4-Chlorobutyrates of Chiral Alcohols with
Aldehydes. In the first attempts toward the asymmetric
synthesis of tetrahydrofurans via the reaction of γ-halocar-
banions with aldehydes, we used 4-chlorobutyrates of chiral
alcohols: menthol, 8-phenylmenthol, and 1,2:5,6-diisopropy-
lidene-D-glucofuranose. Treatment of a mixture of menthyl
and 8-phenylmenthyl 4-chlorobutyrates and benzaldehyde
(21) For a recent review, see: Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
(22) As lifetimes of typical γ-halocarbanions are on the order of only
seconds or shorter at -78 °C, to avoid cyclization to cyclopropanes, base is
added to a mixture of an aldehyde and γ-halocarbanion precursor (so-called
Barbier conditions). Under these conditions many strong bases such as
n-BuLi or LDA add preferentially to the carbonyl group (see, for example
Commins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078) of non-
enolizable aldehyde rather than deprotonate γ-halocarbanion precursor, and
thus t-BuOK remains a reagent of choice for this one-pot process. See refs 7,
8, and Judka, M.; Wojtasiewicz, A.; Danikiewicz, W.; Ma-kosza, M.
Tetrahedron 2007, 63, 8902.
(20) By definition, a chiral auxiliary is a unit that is temporarily incorpo-
rated into the molecule, so that the synthesis can be carried out in an
asymmetric manner. A chiral auxiliary is capable of being recycled, and
therefore we refer to sulfoxides as formal chiral auxiliaries.21 Our attempts to
synthesize the pure enantiomer of 1 by oxidation of 3-chloropropyl phenyl
sulfide (Brunel, J.-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J. Org. Chem.
1995, 60, 8086) failed (ee <15%).
(23) Drabowicz, J.; Midura, W.; Mikozajczyk, M. Synthesis 1979, 39.
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TABLE 1. Reactions of Alkyl 4-Chlorobutyrates with Arylaldehydes in the Presence of t-BuOK in Hexanes Gives Tetrahydrofuran Derivatives
in High Yields
R1
R2
isolated yield (%)
trans:cis isomer ratioa
yield (%) in THF
61b
t-Bu
t-Bu
t-Bu
t-Bu
Me
H
97
88
91
86
86:14
93:7
88:12
88:12
Me
MeO
Cl
H
H
62b
c
44b
31b
38
46 (þ18)d
50:50
trans onlye
menthyl
8-phenyl-menthyl
96
80
H
67e:33
50
aAccording to 1H NMR, trans-cis isomerization is limited in hexanes. bData taken from ref 7. cNo data available. dTransesterification product with
t-BuOK. eAs a 50:50 mixture of trans isomers.
SCHEME 4. Unsuccessful Attempts To Isolate Protonated
with t-BuOK under various conditions gave the expected
substituted tetrahydrofurans in moderate yields, but with
low or negligible induction by stereogenic centers of the
alcohols (however, good trans:cis selectivity was observed
in most cases). The reaction of the ester of 1,2:5,6-diisopro-
pylidene-D-glucofuranose under the identical conditions
resulted in decomposition. The only interesting observation
was a high yield of the tetrahydrofurans when reactions of
ester 4-chlorobutyrates were performed in hexane (Table 1).
For aromatic aldehydes yields of tetrahydrofurans reached
80-95%, much superior to those obtained in a t-BuOK/
THF system.7 (For broader comparison several reactions
with achiral precursors of γ-halocarbanions with aldehydes
were performed in hexane.) The detailed experimental results
of the reactions are presented in Supporting Information.
Reactions of Aryl 3-Chloropropyl Sulfoxides with Alde-
hydes. In the following studies a model reaction of 3-chloro-
propyl phenyl sulfoxide 1 with benzaldehyde was investigated.
In the preliminary experiment 1 mmol of 1 and 1.5 mmol of
benzaldehyde were dissolved in THF and cooled to -50 °C,
and a solution of t-BuOK (2 mmol) was added slowly. In
contrast to the results obtained with more acidic γ-chlorocar-
banion precursors such as sulfones, esters and nitriles, which are
deprotonated immediately upon treatment with potassium
t-BuOK even at low temperatures,7 the sulfoxide exhibited only
moderate acidity. The reaction carried out for 1 h resulted in
substantial substrate recovery. The same experiment repeated at
-25 °C for 1 h gave the expected tetrahydrofuran derivative 5 in
good yield of 77% (as a 6:1 mixture of diastereoisomers 5a:5b,
Intermediate Aldol Anionsa
aThe kinetic pattern of the process consists of a rate-determining
deprotonation step, followed by fast aldol-type addition and subsequent
cyclization.
stitution of the produced aldol-type anion. Once the carba-
nion is generated, it reacts immediately with the aldehyde,
and this addition process is much faster than the competing
cyclization to the cyclopropane. In the next step the aldol-
type anion cyclizes immediately, so its concentration in the
reaction mixture is negligible, and hence acidic quenching
of the mixture does not produce protonated aldol inter-
mediates. This reasoning also gives a hint concerning the
source of the diastereoselectivity observed in the reaction.
Under these conditions equilibration of the addition is hardly
possible, and the kinetic composition of the diastereoisomeric
aldol adducts is probably fixed by the fast cyclization to
tetrahydrofurans.
In the course of optimization of the reaction conditions,
manipulation with solvents appeared unsuccessful. Reaction
of 1 with benzaldehyde in the presence of t-BuOK carried out
at -25 °C in THF for 1 h gave only traces of 5 accompanied
by large amounts of unreacted sulfoxide. In turn the reaction
carried out in DMF gave 5 in moderate yield (46%), but
stereoselectivity was negligible (5a:5b=1:1.4), whereas cyclo-
propane 14 was produced as a main product (50%, see the
next section for details).
1
based on H NMR), cyclopropyl phenyl sulfoxide 14 (10%),
and small amounts of unchanged substrate 1. Interestingly,
when the mixtures of reaction performed at low tempera-
tures were quenched after a short time, we were able to
isolate only unreacted 1, cyclopropane 14, and the final
product 5 (as a mixture of isomers), whereas intermediate
aldol-type adducts could neither be isolated nor detected
by 1H NMR of the crude reaction mixtures (Scheme 4). All
attempts to isolate the intermediate adducts when the
reaction mixture was quenched with aqueous NH4Cl after
1 min at -78 °C, -50, and -25 °C failed.
The experiment revealed that the deprotonation of 1 is a
rate-determining step followed by fast aldol-type addition of
the carbanion to the aldehyde and 1,5-intramolecular sub-
To overcome the difficulties with the conversion and
reduce the side reactions observed at the higher temperatures
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TABLE 2. Reactions of Aryl 3-Chloropropyl Sulfoxides (1-4) with Aldehydes
aAryl cyclopropyl sulfoxides (e10%) were not isolated in routine preparative experiments. bThe ratio corresponds to proportion of isomers denoted
in the text as “a” and “b” respectively. c2-Bromobenzaldehyde, 4-chlorobenzaldehyde, 2-pirydylaldehyde, and furfural failed to react (see the
explanation below). d4-Chlorophenyl cyclopropyl sulfoxide 15 (25%) and two products of secondary transformations (23%) were observed in the
reaction mixture (see Supporting Information for details).
when longer reaction times were necessary, we have tested
sulfoxides that exhibit higher C-H acidity due to the pre-
sence of electron-withdrawing groups in the aromatic rings.
Thus 3-chloropropyl 4-chlorophenyl (2), 2-pirydyl (3), and
3,4-dichlorophenyl (4) sulfoxides were subjected to reactions
with aldehydes in the presence of t-BuOK in THF.24
t-BuOK, the only product was the cyclopropane 15 in
moderate yield (<20%), whereas a majority of 2 was recov-
ered. The unexpected behavior can be rationalized by our
earlier findings that nonenolizable aldehydes react with
potassium alkoxides to form hemiacetal-type adducts. The
addition is a reversible process and equilibrium of the addi-
tion depends on substituents present in the aromatic ring.16
The electron acceptors and the coordinating sites of pyridine
and furane stabilize adducts and force the equilibrium to the
right (Scheme 5). In the investigated system t-BuOQ anion is
presumably trapped in a form of the hemiacetal anion, the
alkoxide of much lower basicity that cannot efficiently
deprotonate the sulfoxide. Both the base and the aldehyde
are consumed in a competitive but reversible process, and
thus in the system there is a weaker base, whereas concentra-
tion of an electrophile is reduced. As a result only formation
of minor amounts of the cyclopropane 15, the product of an
intramolecular process, is observed. After the reaction mix-
ture is quenched with aqueous NH4Cl, hemiacetal anion is
decomposed into the alcohol and the aldehyde, whereas the
sulfoxide is mostly recovered. Strong support for the hypo-
thesis was derived from comparative experiments performed
on the model sulfoxide (2) in the presence and absence of an
aldehyde (Scheme 5).
In the routine experiments, crude reaction mixtures were
1
analyzed with H NMR to determine the ratio of isomers.
The products were then isolated by chromatography as
mixtures of isomers, whereas minor amounts of cyclopro-
pane derivatives were not isolated in preparative experi-
ments. From the mixtures of diastereoisomers analytical
samples of only the main isomers (“a”) were isolated. The
pure main isomers were characterized with 1H and 13C
NMR, MS, IR and elemental analysis. Only product 6 was
fully resolved, and full analysis also of minor isomer 6b was
made. The results are presented in Table 2.
As expected, conversion of these more acidic sulfoxides at
low temperatures was higher in comparison with 1, and even
the ratio of isomers was slightly improved.25 Surprisingly the
four aldehydes 2-bromobenzaldehyde, 4-chlorobenzalde-
hyde, 2-pirydylaldehyde, and furfural failed to react. When
the sulfoxide 2 was subjected to the reaction with these
aldehydes under standard conditions with an excess of
Treatment of 4-chlorophenyl 3-chloropropyl sulfoxide (2)
with t-BuOK at low temperature resulted in formation of the
substituted cyclopropane 15 (80%), while under the same
conditions in the presence of 4-chlorobenzaldehyde mainly
unreacted 2 and the aldehyde was recovered. Thus in the
latter case the aldehyde consumed reversibly the base and
(24) Pentachlorophenyl 3-chloropropyl sulfoxide was synthesized but
decomposed when subjected to reaction with benzaldehyde in the presence
of t-BuOK at low temperature (see Supporting Information for details).
(25) We assume that the selectivity derives from decreased reactivity of
more stabilized carbanions and less electrophilic aldehydes in agreement with
common reactivity-selectivity principle. For some criticizm on reactivity-
selectivity principle see: Mayr, H.; Ofial, A. R. Angew. Chem., Int. Ed. 2006,
45, 1844.
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SCHEME 5. Reaction of 2 with t-BuOK Gives Substituted
SCHEME 6. Oxidation of Diastereoisomeric Tetrahydrofurans
(6a and 6b) Leads to the Same Product
Cyclopropane 15a
solvent dimethylformamide (DMF), the two diastereo-
isomers were formed in almost equal quantities, with a slight
preference for the minor isomer that was produced earlier in
THF (Scheme 7).28
aThe presence of electrophilic aldehydes results in substrate recovery.
This discrepancy can be explained by formation of the hemiacetal anion,
the process that consumes both the base and electrophile.
On the basis of the literature data,29 we assumed that the
transition state of the addition process has a cyclic structure,
where potassium cation chelates the oxygen atoms of the
sulfoxide and aldehyde and forms a six-membered, chair-
like transition state. Potassium cations are generally more
weakly coordinating than, e.g., Liþ; however, the disparate
distributions of isomeric products produced in reactions
carried out in THF and DMF suggest that in the latter case
donor solvent associates with potassium cations and the
transition state has no longer organized structure. To confirm
this assumption, we retracted the structure of the transition
state of the aldol addition in THF, which after cyclization
should give the characterized main isomer of the product
(Scheme 8).
The geometry was perfectly consistent with expectations
that sterically demanding aryl groups should occupy the
equatorial positions, giving preference to the observed con-
figurations at the sulfur atom and nonepimerizable C-2
position. In turn, the configuration at C-3 may still arise
from direct cyclization of the anti adduct or cyclization of the
syn isomer followed by base-catalyzed isomerization; both
possibilities are in agreement with the observed data
(Scheme 8).11 However, the first structure of the transition
state has all substituents in a favored equatorial orientation,
and the second possibility, where the 2-chloroethyl group is
oriented axially, must not be disregarded. In contrary to the
bulky aryl groups, which may suffer from considerable 1,3-
diaxial repulsive forces with hydrogen atom and solvent
molecules coordinated to potassium cation, a 2-chloroethyl
group located axially is influenced only slightly by the
hence “protected” the substrate from deprotonation and
subsequent reactions.26
Determination of the Stereochemistry of the Product. To
verify the hypothesis that substituents at positions C-2 and
C-3 in the obtained tetrahydrofurans are always in trans
relation and the diastereoisomers differ only in configuration
on the sulfur, both diasteroisomeric tetrahydrofurans 6a and
6b were oxidized with m-CPBA in CH2Cl2. In both of the
experiments the same sulfone was formed, proving that
diastereoisomers a and b differ only by configuration on
the sulfur atom (Scheme 6).
Finally, to unambiguously determine a relative configura-
tion of the stereogenic centers, the X-ray structure of the
main crystalline isomer of tetrahydrofuran (7a) was obtained
(Figure 1).
Discussion of Mechanism of the Reaction. Taking into
account the results presented above, we analyzed the mecha-
nism of the reaction from a viewpoint of stereochemistry. As
we assumed previously, deprotonation of the sulfoxide with
t-BuOK is a rate-determining step, and all subsequent steps
are fast and generally irreversible. Thus, the very short
lifetimes of the γ-halocarbanions and relatively high rate of
the cyclization step of the aldol-type adducts suggested that
there is no equilibration at the addition step. On the other
hand, when the reaction was carried out in the more polar
(26) The situation can be alternatively explained by the formation of
intermediate aldol-type adducts that decompose when quenched with
aqueous NH4Cl to release the substrate (when their cyclization is a rate-
determining step). The possibility is less plausible because under the similar
conditions (1) adducts with less electrophilic aldehydes cyclize to tetra-
hydrofurans in high yield, (2) average rates of cyclization of adducts of
sulfones, esters, and nitriles under similar conditions range from seconds to
minutes (see Supporting Information for details), and (3) cyclization of the
sulfoxide 2 in the absence of an aldehyde is a slow process in contrast to the
behavior of more acidic precursors such as sulfones, nitriles, and esters.
(27) We wish to acknowledge the use of a free version of Ortep-3 for
Windows program: Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(28) The same observation was made when 2 was reacted with benzalde-
hyde in DMF to give tetrahydrofurans (6, 45%; 6a:6b=1:1.4) and cyclopro-
pane (15, 51%).
~
(29) (a) Barros, D.; Carreno, M. C.; Garcıa Ruano, J. L.; Maestro, C.
´
Tetrahedron Lett. 1992, 33, 2733. (b) Sato, T.; Itoh, T.; Fujisawa, T.
Tetrahedron Lett. 1987, 28, 5677. (c) Casey, M.; Mukherjee, I.; Trabsa, H.
Tetrahedron Lett. 1992, 33, 127. (d) Kingsbury, C. A. J. Org. Chem. 1972, 37,
102.
3256 J. Org. Chem. Vol. 75, No. 10, 2010

Komsta et al.
JOCArticle
FIGURE 1. ORTEP representation of X-ray structure of 7a (the main isomer).27
SCHEME 7. Distribution of Diastereoisomeric Tetrahydrofurans 5a and 5b and Cyclopropane 14 for the Reaction Carried
out in THF and DMF27
SCHEME 8. Proposed Geometry of the Transition State
Leading to the Main Isomer of the Product
At the same time, the bulky groups are located in the
preferred antiperiplanar orientation around the newly
formed carbon-carbon bond. Thus the conformations of
the isomeric adducts are not only stabilized by chelation with
the potassium cation arranged in the transition state of the
addition but also biased against unfavorable gauche orienta-
tion of the substituents after the addition is completed.
In turn anti orientation of the aryl and arylsulfinyl groups
forces the reacting centers of the alkoxide and β-chloroethyl
group to 60° and 180° angles for anti and syn isomers,
respectively, and the latter situation strongly disfavores
cyclization to the tetrahydrofurane ring (Scheme 9). As
was demonstrated by us11,15 and Hassner17b for five-mem-
bered rings and supported by data for Darzens31 and Corey-
Chaykovsky32 cyclizations to oxiranes, only anti-configured
intermediates may feasibly cyclize and syn isomers are much
less prone to cyclize or do not cyclize at all. The phenomena is
common to the “gem-dimethyl effect” and applicable for
systems where bulky substituents located on a cyclizing chain
alter the energy of its conformers33 and thus control orienta-
tion of the reacting centers. The conformational origin of
the effect34 is still supported by observation that the rate of
the 1,5-intramolecular substitution in the model reactions of
presence of the oxygen lone pairs. The same phenomena
demonstrated in 5-substituted-1,3-dioxanes30 is attributed to
the reduced bulkiness of the lone electron pairs of the oxygen
as compared to the hydrogen atoms present in the parent
cyclohexane system that expel substituents from axial posi-
tions by repulsive 1,3-interactions. Thus energetic preference
for equatorial orientation of the 2-chloroethyl group is ex-
pectedly limited. However, the key argument for the anti
transition state stems from the ability of the isomeric aldol-
type anions to undergo 1,5-intramolecular substitution of
chlorine atom. Both anti and syn aldol-type adducts are
stabilized in the form of cyclic structures, where the potassi-
um cation is chelated by oxygen atoms and sterically de-
manding aryl groups occupy favorable equatorial positions.
(31) Zimmerman, H. E.; Ahramjian, L. J. Am. Chem. Soc. 1960, 82, 5459.
(32) (a) Aggarwal, V. K.; Hynd, G.; Picoul, W.; Vasse, J.-L. J. Am. Chem.
Soc. 2002, 124, 9964. (b) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.;
Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.;
Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2006, 128, 2105.
(33) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
(34) The modern explanation of the gem-dimethyl effect for increased
rates of cyclizations of medium size rings is based on the “reactive rotamer”
idea, associated with changes in conformer populations as clarified in the
text.33 The alternative concept of a valence distortion posed by substituents,
the so-called Thorpe-Ingold effect, would be too small to rationalize the
observed differences.
(30) Eliel, E. L.; Knoeber, M. C., Sr. J. Am. Chem. Soc. 1968, 90, 3444.
J. Org. Chem. Vol. 75, No. 10, 2010 3257

Komsta et al.
JOCArticle
SCHEME 9. Conformational Equilibria of the Intermediate
Aldol-Type Adducts
electrophilic aldehydes react more selectively. In turn, the
electrophilic aldehydes fail to react with precursors of car-
banions, because base is consumed in the reaction with the
carbonyl group of the aldehyde in a form of hemiacetal
anion. In the one-pot synthesis of substituted tetrahydrofur-
ans deprotonation with t-BuOK is a rate-determining step
followed by diastereoselective aldol-type addition and sub-
sequent cyclization of the adducts. We postulate that the
latter step consists of anti aldol-type adducts that are prone
to cyclize to the tetrahydrofurane ring.
Experimental Section
General. All reactions were carried out under an atmosphere
of argon in dried glassware using standard Schlenck techniques.
THF was distilled from K/benzophenone ketyl, and hexanes,
toluene, and EtOAc were distilled. Benzaldehyde was distilled
and stored under argon, while other aldehydes for preparative
reactions were used as freshly obtained from commercial
sources. H and 13C NMR spectra were recorded on 200, 400,
1
γ-halocarbanions with aldehydes varies greatly with the size
of the electron-withdrawing group: sulfones rapidly cyclize
to tetrahydrofurans and only aldol-type adducts of esters
and nitriles can be isolated in high yields after the reaction
mixtures are quenched with aqueous NH4Cl at low tempera-
ture (see Supporting Information for details).
and 500 MHz spectrometers. Chemical shifts are reported in
ppm from the solvent resonance (CDCl3 as 7.26 ppm). Data are
reported as follows: chemical shift, multiplicity, (s=singlet, d=
doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants, and number of protons. All crude reaction
mixtures were analyzed with 1H NMR. Isomer ratio was
determined by integration of signals of characteristic doublets
of protons present at position 2 of the tetrahydrofuran ring.
Finally, the cyclic structure of the transition state of the
aldol addition offers a simple explanation for the observed
correlation between activity of the reactants and selectivity
of the formation of the isomeric tetrahydrofurans.25 On the
basis of the assumption that reactions of more stabilized
carbanions and less electrophilic aldehydes are characterized
by higher energy barriers, the transition state of the reaction
is reached later and has a more compact structure, in which
1,3-diaxial interactions of bulky substituents disfavoring
formation of the minor isomers of tetrahydrofurans are more
pronounced if compared with the loose, early variant in the
case of the more reactive substrates. Thus difference between
energy barriers leading to diasteroisomers is larger and
manifests itself in an increased ratio of the isomers. The
same phenomena was observed earlier for aldol reactions of
nitriles35 and other systems described in the literature.36,37
Thus the distribution of the diastereoisomeric tetrahydro-
furans suggests again that the addition step is responsible for
the observed selectivity.
1
Peak assignments of 5-13 are based on H, (1H-1H) COSY,
and NOE NMR spectra of trans and cis isomers of analogous
2-phenyl-3-tetrahydrofurancarboxylic acid tert-butyl ester (see
page S-82 and spectra reproductions on pages S-84 to S-98 in
Supporting Information). Melting points are uncorrected.
General Procedure for the Synthesis of Sulfoxides 5-13. A
Schlenk flask was charged withsulfoxide (1-4, 1 mmol), aldehyde
(1.5 mmol), andTHF(4mL) andcooledtolowtemperatureunder
argon. A solution of potassium tert-butoxide (2 mL, 2 mmol, 1 M
in THF) was added slowly with stirring. After 3 h the cooling bath
was removed, and an aqueous solution of NH4Cl was added. The
mixture was extracted with ethyl acetate (3 ꢀ 60 mL), and the
combined organic phases were washed with brine and dried with
Na2SO4. Solvent was evaporated, and the residue was analyzed
with 1H NMR and then separated with column chromatography
on silica gel with hexanes/ethyl acetate or toluene/ethyl acetate.
Minor amounts of aldehydes, cyclopropane derivatives, and
unreacted sulfoxides were observed in each case but were rejected
in routine preparative experiments. See Supporting Information
for details.
Characterization data for 5a. Oil. 1H NMR (500 MHz,
CDCl3): δ 7.58-7.63 (m, 2H, Harom), 7.50-7.55 (m, 3H, Harom),
Conclusions
We have found that carbanions of aryl 3-chloropropyl
sulfoxides react with nonenolizable aldehydes to give 2,3-
disubstituted tetrahydrofurans. The products are formed as
mixtures of two diastereoisomers (one predominant) that
differ in the configuration at the sulfur atom, whereas
substituents in the ring are always in the trans relation. The
observed stereochemistry stems from the organized cyclic
transition state of the aldol-type addition of the sulfoxide
carbanions to aldehydes and correlates with their electro-
nic properties, i.e., more stabilized carbanions and less
3
7.27-7.38 (m, 5H, Harom), 5.09 (d, JHH =6.7 Hz, 1H, H-2),
4.16-4.21 (m, 1H, H-5), 3.97-4.03 (m, 1H, H-5), 3.18-3.23 (m,
1H, H-3), 2.59-2.66 (m, 1H, H-2), 1.91-2.00 (m, 1H, H-2). 13
C
NMR (125 MHz, CDCl3): δ 142.5, 140.2, 131.2, 129.2, 128.6,
128.0, 125.7, 124.3, 80.3, 71.9, 68.2, 24.1. IR (neat): 3059, 2874,
1603, 1582, 1494, 1477, 1443, 1307, 1086, 1047, 912, 751, 698,
522, 471 cm-1. MS (ESI) calcd for C16H16O2SNa 295.1, found
295.1. Anal. Calcd for C16H16O2S: C, 70.56; H, 5.92; S, 11.77.
Found: C, 70.50; H, 5.95; S, 11.63.
Characterization data for 6a. Oil. 1H NMR (500 MHz,
CDCl3): δ 7.37-7.50 (m, 4H, Harom), 7.23-7.36 (m, 5H, Harom),
3
5.02 (d, JHH = 6.9 Hz, 1H, H-2), 4.08-4.16 (m, 1H, H-5),
(35) Carlier, P. R.; Lo, K. M.; Lo, M. M.-C.; Lo, P. C.-K.; Lo, C. W.-S.
J. Org. Chem. 1997, 62, 6316.
3.87-3.95 (m, 1H, H-5), 3.07-3.17 (m, 1H, H-3), 2.45-2.56 (m,
1H, H-4), 1.81-1.93 (m, 1H, H-4). 13C NMR (100 MHz,
CDCl3): δ 140.8, 139.8, 137.2, 129.4, 128.6, 128.0, 125.6,
125.5, 80.1, 71.6, 68.1, 23.7. IR (neat): 3061, 2946, 2874, 1576,
1475, 1454, 1391, 1081, 1054, 1011, 824, 760, 742, 700, 518,
ꢀ
(36) Mzynarski, J.; Rakiel, B.; Stodulski, M.; Suszczynska, A.; Frelek, J.
Chem.;Eur. J. 2006, 12, 8158.
(37) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
1993, 4, 1783.
3258 J. Org. Chem. Vol. 75, No. 10, 2010

Komsta et al.
JOCArticle
431 cm-1. MS (ESI) calcd for C16H15ClO2SNa 329.0, found
329.0. Anal. Calcd for C16H15ClO2S: C, 62.64; H, 4.93; Cl,
11.56; S, 10.45. Found: C, 62.71; H, 5.02; Cl, 11.44; S, 10.27.
Characterization data for 6b. Mp: 126-127 °C. 1H NMR (400
MHz, CDCl3): δ 7.52-7.56 (m, 2H, Harom), 7.41-7.45 (m, 2H,
1364, 1083, 1036, 1010, 826, 740, 508 cm-1. HRMS (ESI) calcd
for C14H1935ClO2SNa 309.06865, found 309.06952. Anal. Calcd
for C14H19ClO2S: C 58.63; H, 6.68; Cl, 12.36; S, 11.18. Found:
C, 58.89; H, 6.84; Cl, 12.12; S, 10.93.
Characterization data for 11a. Oil. 1H NMR (200 MHz,
CDCl3): δ 8.51-8.60 (m, 1H, Harom), 7.87-8.02 (m, 2H, Harom),
H
arom), 7.16-7.24 (m, 3H, Harom), 6.99-7.03 (m, 2H, Harom),
3
3
5.23 (d, JHH = 4.6 Hz, 1H, H-2), 4.12-4.18 (m, 1H, H-5),
3.94-4.02 (m, 1H, H-5), 3.29-3.35 (m, 1H, H-3), 2.24-2.38 (m,
2H, H-4). 13C NMR (100 MHz, CDCl3): δ 140.9, 140.8, 137.6,
129.5, 128.4, 127.6, 126.1, 125.7, 78.5, 70.3, 68.3, 28.9. IR (in
CH2Cl2): 2955, 2878, 1452, 1390, 1048, 1034, 954, 818, 768, 716,
698, 505, 428 cm-1. HRMS (ESI) calcd for C16H1535ClO2SNa
329.03735, found 329.03764. Anal. Calcd for C16H15ClO2S: C,
62.64; H, 4.93. Found: C, 62.63; H, 4.93.
7.26-7.48 (m, 6H, Harom), 5.26 (d, JHH =7.3 Hz, 1H, H-2),
4.06-4.18 (m, 1H, H-5), 3.88-4.01 (m, 1H, H-5), 3.56-3.68 (m,
1H, H-3), 2.38-2.55 (m, 1H, H-4), 1.67-1.87 (m, 1H, H-4). 13
C
NMR (50 MHz, CDCl3): δ 163.7, 149.6, 139.9, 137.9, 128.6,
128.1, 126.0, 124.6, 120.3, 80.5, 68.9, 68.3, 23.6. IR (neat): 3490,
3059, 2978, 2876, 1576, 1562, 1494, 1452, 1423, 1054, 769, 700,
470 cm-1. MS (ESI) calcd for C15H15NO2SNa 296.1, found
296.2.
Characterization data for 7a. Mp: 88-91 °C. 1H NMR (200
MHz, CDCl3): δ 7.48-7.64 (m, 4H, Harom), 7.24-7.36 (m, 2H,
Characterization data for 12a. Oil (87%). 1H NMR (500
4
MHz, CDCl3): δ 7.65 (d, JHH =2.0 Hz, 1H, Harom), 7.55 (d,
H
arom), 6.89-6.99 (m, 2H, Harom), 5.03 (d, 3JHH=7.2 Hz, 1H,
3JHH=8.3 Hz, 1H, Harom), 7.29-7.39 (m, 6H, Harom), 5.05 (d,
3JHH=7.2 Hz, 1H, H-2), 4.13-4.18 (m, 1H, H-5), 3.92-3.98 (m,
1H, H-5), 3.09-3.15 (m, 1H, H-3), 2.49-2.56 (m, 1H, H-4),
1.86-1.95 (m, 1H, H-4). 13C NMR (125 MHz, CDCl3): δ 142.7,
139.6, 135.7, 134.2, 131.3, 128.8, 128.4, 126.2, 125.9, 123.3, 80.5,
71.8, 68.3, 23.6. IR (neat): 3059, 2875, 1455, 1368, 1139, 1058,
1030, 809, 760, 699, 673, 581, 459 cm-1. MS (ESI) calcd for
C16H1435Cl2O2SNa 363.0 found 363.3. Anal. Calcd for
C16H14Cl2O2S: C, 56.31; H, 4.14; Cl, 20.78; S, 9.40. Found: C,
56.99; H, 4.07; Cl, 19.92; S, 8.96.
H-2), 4.12-4.27 (m, 1H, H-5), 3.90-4.06 (m, 1H, H-5), 3.86 (s,
3H, OCH3), 3.08-3.25 (m, 1H, H-3), 2.50-2.70 (m, 1H, H-4),
1.86-2.12 (m, 1H, H-4). 13C NMR (50 MHz, CDCl3): δ 159.5,
140.9, 137.3, 131.5, 129.4, 127.2, 125.6, 114.0, 80.1, 71.7, 68.0,
55.2, 23.8. IR (KBr): 3050, 2929, 2877, 2838, 1611, 1511, 1391,
1306, 1246, 1064, 1027, 845, 830, 816, 742, 537, 512, 423 cm-1
.
HRMS (ESI) calcd for C17H1735ClO3SNa 359.04791, found
359.04963. Anal. Calcd for C17H17ClO3S: C, 60.62; H, 5.09;
Cl, 10.53; S, 9.52. Found: C, 60.67; H, 5.17; Cl, 10.65; S, 9.57.
Characterization data for 8a. Mp: 66-68 °C. 1H NMR (400
MHz, CDCl3): δ 7.50-7.54 (m, 2H, Harom), 7.46-7.50 (m, 2H,
Characterization data for 13a. Oil (92%). 1H NMR (500
4
MHz, CDCl3): δ 7.64 (d, JHH =2.0 Hz, 1H, Harom), 7.55 (d,
H
arom), 7.24-7.29 (m, 1H, Harom), 6.80-6.88 (m, 3H, Harom),
3JHH =8.3 Hz, 1H, Harom), 7.35 (dd, JHH =8.3, 2.1 Hz, 1H,
Harom), 7.23-7.28 (m, 2H, Harom), 6.88-6.92 (m, 2H, Harom),
3
5.02 (d, JHH = 6.7 Hz, 1H, H-2), 4.13-4.19 (m, 1H, H-5),
3.92-4.00 (m, 1H, H-5), 3.79 (s, 3H, OCH3), 3.10-3.17 (m, 1H,
H-3), 2.50-2.59 (m, 1H, H-4), 1.86-1.97 (m, 1H, H-4). 13C
NMR (100 MHz, CDCl3): δ 159.9, 141.6, 140.9, 137.5, 129.9,
129.6, 125.7, 117.9, 113.7, 111.1, 80.1, 71.9, 68.3, 55.2, 23.9. IR
(in CH2Cl2): 2942, 1724, 1602, 1475, 1391, 1264, 1157, 1080,
1048, 1011, 825, 781, 742, 697, 518 cm-1. HRMS (ESI) calcd for
C17H1735ClO3SNa 359.04791, found 359.04932. Anal. Calcd for
C17H17ClO3S: C, 60.62; H, 5.09; Cl, 10.53; S, 9.52. Found: C,
60.36; H, 4.94; Cl, 10.40; S, 9.38.
3
4.97 (d, JHH = 7.5 Hz, 1H, H-2), 4.12-4.17 (m, 1H, H-5),
3.89-3.96 (m, 1H, H-5), 3.81 (s, 3H, OCH3), 3.07-3.13 (m, 1H,
H-3), 2.49-2.57 (m, 1H, H-4), 1.87-1.97 (m, 1H, H-3). 13C
NMR (125 MHz, CDCl3): δ 159.7, 142.8, 135.6, 134.2, 131.2,
127.4, 126.2, 123.3, 114.2, 80.4, 71.7, 68.0, 55.3, 23.8. IR (neat):
3077, 2948, 2868, 1612, 1512, 1458, 1366, 1305, 1243, 1048, 922,
829, 814, 673, 576, 449 cm-1
C17H1635Cl2O3SNa 393.0, found 393.7.
. MS (ESI) calcd for
Characterization data for 9a. Oil. 1H NMR (400 MHz,
CDCl3): δ 7.44-7.51 (m, 4H, Harom), 6.75-6.79 (m, 3H, Harom),
Acknowledgment. Part of this work is the subject of the
M.Sc. thesis of Z.K. at the Faculty of Chemistry, Warsaw
University of Technology. The authors would like to thank
Prof. Janusz Jurczak and Dr. Piotr Kwiatkowski (IChO
PAN) for a generous gift of (-)-8-phenylmenthol. M.B.
thanks the Foundation for Polish Science (HOMING pro-
gram funded from European Economic Area Financial
Mechanism) for support while writing this manuscript. The
X-ray measurements were undertaken in the Crystallo-
graphic Unit of the Physical Chemistry Laboratory at the
Faculty of Chemistry, University of Warsaw.
3
5.93-5.96 (m, 2H, Harom), 4.92 (d, JHH =7.3 Hz, 1H, H-2),
4.08-4.15 (m, 1H, H-5), 3.87-3.94 (m, 1H, H-5), 3.02-3.09 (m,
1H, H-3), 2.47-2.56 (m, 1H, H-4), 1.82-1.93 (m, 1H, H-4). 13
C
NMR (100 MHz, CDCl3): δ 148.0, 147.5, 140.9, 137.4, 133.4,
129.5, 125.6, 119.6, 108.3, 106.1, 101.1, 80.3, 71.7, 68.1, 23.7. IR
(in CH2Cl2): 2926, 1724, 1577, 1504, 1489, 1476, 1445, 1391,
1249, 1079, 1038, 1011, 932, 821, 742, 516, 433 cm-1. HRMS
(ESI) calcd for C17H1535ClO4SNa 373.02718, found 373.02902.
Characterization data for 10. Mp: 102-105 °C. 1H NMR (500
MHz, CDCl3): δ 7.44-7.47 (m, 2H, Harom), 7.48-7.42 (m, 2H,
3
Harom), 3.80-3.86 (m, 1H, H-5), 3.76 (d, JHH =5.8 Hz, 1H,
H-2), 3.61-3.68 (m, 1H, H-5), 2.88-2.91 (m, 1H, H-3),
2.31-2.38 (m, 1H, H-4), 1.59-1.69 (m, 1H, H-4), 0.80 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 141.1, 137.1, 129.3, 125.5, 86.6,
68.1, 65.3, 34.3, 25.6, 24.7. IR (KBr): 2956, 1575, 1474, 1392,
Supporting Information Available: Lengthy experimental
procedures, analytical and spectral characterization data, crys-
tallographic information, and peripheral findings. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 10, 2010 3259