Soluble and insoluble polymeric 1,3-dithiane reagents for the synthesis of aldehydes from alkyl halides

Article abstract of DOI:10.1016/j.tet.2005.07.091

Through the synthesis and study of model systems as proper dithiane derivatives, vinyl monomers and soluble copolymeric reagents containing 2-unsubstituted 1,3-dithiane rings, we attained the key synthon 1,3-dithiane-5-methanol. Through its reaction with commercial resins, new polymeric reagents useful for supported organic synthesis and combinatorial chemistry were developed. Exploiting the reactivity of position 2 in 1,3-dithiane rings, such polymeric reagents were employed in the production of aldehydes from alkyl halides through a process entirely free from unpleasant odors.

Full text of DOI:10.1016/j.tet.2005.07.091

Tetrahedron 61 (2005) 9519–9526
Soluble and insoluble polymeric 1,3-dithiane reagents for the
synthesis of aldehydes from alkyl halides
*
Vincenzo Bertini, Francesco Lucchesini, Marco Pocci and Silvana Alfei
`
Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari Universita di Genova, Via Brigata Salerno, I-16147 Genova, Italy
Received 13 May 2005; revised 14 July 2005; accepted 28 July 2005
Available online 15 August 2005
Abstract—Through the synthesis and study of model systems as proper dithiane derivatives, vinyl monomers and soluble copolymeric
reagents containing 2-unsubstituted 1,3-dithiane rings, we attained the key synthon 1,3-dithiane-5-methanol. Through its reaction with
commercial resins, new polymeric reagents useful for supported organic synthesis and combinatorial chemistry were developed. Exploiting
the reactivity of position 2 in 1,3-dithiane rings, such polymeric reagents were employed in the production of aldehydes from alkyl halides
through a process entirely free from unpleasant odors.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
monomers and soluble copolymeric reagents containing
2-unsubstituted 1,3-dithiane rings.
In organic chemistry the great synthetic potentiality of
sulfur(II) compounds such as thiols and dithiols, precursors
of thioacetals or thioketals, is strongly handicapped by the
very unpleasant odor of such materials. In previous papers1–5
we have overcome this handicap through the fully odorless
synthesis of polymeric reagents containing 1,3-propane-
dithiol or 2-substituted 1,3-dithiane functions, which were
tested in the preparation of ketones from aldehydes and in
the reduction of ketones, and proved effective for solid-
phase synthesis exploitable in the field of combinatorial
chemistry. The utility of thioacetal functions in the solid-
phase synthesis is also reported as a way of protecting and
anchoring the carbonyl function of methylarylketones to
commercial aminomethyl polystyrene resins before carry-
ing out transformations on the benzene ring.6 Such a process
requires, however, the unattractive handling of a 1,3-
propanedithiol derivative to transform ketones into thioke-
tals, and uses secondary amide bonds, not fully inert towards
various reagents, for the immobilization of the thioketals on
the commercial resin.
2. Results and discussion
The known 1,3-dithian-5-one7 (1), obtainable from slightly
odorous pure thioglycolic acid, having a reactive carbonyl
group useful for the introduction of a linker in the position 5
of the 1,3-dithiane ring, the farthest from the thioacetalic
carbon, appeared a reasonable precursor for the preparation
of a synthon aimed to the functionalization of haloalkyl
resins. Hence, 1 was prepared according to the literature,7
reduced to the alcohol 2,8 and allowed to react with benzyl
bromide obtaining in good yield from 1 the ether 3, a model
molecule of an umpoled thioacetal equivalent of methanal.
The compound 3, allowed to react first with n-butyllithium
then with methanol-d, afforded the deuterated dithiane
derivative 4 (Scheme 1), which showed the 1H NMR
spectrum corresponding to the substitution of the high-field
proton at C(2) with deuterium, in full agreement with the
known preferred equatorial deprotonation9 and anomeric
effect10 in 1,3-dithianes. The obtained low yield (45.3%),
probably due to a concomitant elimination reaction, made 2
an unacceptable synthon.
This work reports the functionalization of commercial
chloromethylstyrene resins with the key synthon 1,3-
dithiane-5-methanol (6) and their application to the
production of aldehydes from alkyl halides, optimized
through the synthesis of model molecules, proper vinyl
Wishing to find a reliable process for further spacing the
ether linkage from sulfur atoms and preventing elimin-
ations, we considered the 1,3-dithiane-5-methanol11 (6) and
accomplished its synthesis with an overall yield of 65%
from 1, through a Wittig reaction followed by hydrolysis
and reduction with NaBH4 of the enolether 5 (Scheme 2).
Keywords: Supported reagents; Umpolung reactions; 1,3-Dithianes;
Aldehydes; Alkyl halides.
*
Corresponding author. Tel.: C39 010 3532685; fax: C39 010 3532684;
e-mail: bertini@dictfa.unige.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.091

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V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
Scheme 4.
Scheme 1.
Wittig rearrangement of the benzylic ether13 to the lithium
alcoholate metallated at C(2), followed by deuteration with
methanol-d and exchange H–D at the hydroxy group by
addition of water (Scheme 5).
Scheme 2.
The alcohol 6 was submitted to several test reactions. It was
transformed with benzyl bromide into the benzyl ether 7,
then lithiated and deuterated (Scheme 3). The process
afforded after hydrolysis the expected 8 in 76.3% yield,
together with 9 recovered in 6.2% yield.
Scheme 5.
To avoid the presence of undesired products originating
from the reactivity of the benzyl ether, 6 was transformed
into the ether 13 with a chain of three methylene groups.
After lithiation and deuteration 13 afforded 14 in
quantitative yield (Scheme 6), proving that 6 is a good
dithiane synthon for umpolung reactions, but the modest
yield (41.7%) obtained in the synthesis of the model
molecule 13 stimulated additional studies.
Scheme 3.
The structure of 9 was confirmed by preparing its non-
deuterated analogue 12 from 6 through the ketone 11, which
was obtained from the benzenesulfonate ester 10 applying
Hu¨nig’s umpolung procedure12 of aromatic aldehydes
1
(Scheme 4), then comparing the H and 13C NMR spectra
of 9 and 12.
The formation of 9 from 7 can be rationalized through a
Scheme 6.

V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
9521
It appeared reasonable to synthesize new 1,3-dithiane vinyl
monomers with or without a benzyl ether group by reacting
6 both with commercial (4-ethenylphenyl)chloromethane
and with 1-bromo-4-(4-ethenylphenyl)butane14 to reach
monomeric then polymeric models and to test if the length
of the spacer could affect the yield attained with 1-bromo-3-
phenylpropane in the synthesis of 13. The reactions reported
in Scheme 7 gave the monomers 15 and 16, respectively,
confirming a good yield for 15 comparable with 7 and a
modest yield for 16 comparable with 13.
and containing benzyl ether linkages. The use of the
copolymeric reagent P116(1:19) with diluted dithiane units
and without benzyl ether linkages gave a negligible cross-
linking (Table 1). Since a low extent of side reactions is
sufficient to produce a significant quantity of cross-linked
material, the reported percentages of the insoluble fraction
of P3 was calculated on the assumption that the soluble and
insoluble portions of P3 had the same composition. The
cleavage of the dithiane rings in P3 with periodic acid or
with mercury(II) perchlorate hydrate afforded the aldehyde
17a (Table 1). Both soluble and insoluble portions of P3
produced 17a, but the yields of 17a reported in the fifth
column of the Table 1 refer only to the soluble one.
The reaction with mercury(II) perchlorate hydrate gave pure
17a showing an aldehydic proton triplet at d 9.74 in the 1H
NMR spectrum, while the reaction with periodic acid,
besides 17a, not unexpectedly1 produced 5–10% of the
iodine derivative 18, showing an aldehydic proton doublet
at d 9.22, whose structure was deduced from the spectro-
scopic data compared with those of 2-iodohexadecanal16
and other a-iodinated aldehydes.17
On the basis of the recorded yields, the best procedure for
the obtainment of 17a uses the model copolymeric reagent
P116(1:19), characterized by a low concentration of dithiane
units and absence of benzyl ether linkages, and carries out
the cleavage of the dithiane rings with mercury(II)
perchlorate hydrate.
Scheme 7.
Under the conditions already used for the preparation of
masked 1,3-propanedithiol linear copolymers,1,2 15 and 16
were copolymerized with styrene starting from feed molar
ratios of dithiane monomer/styrene equal to 1:9 or 1:19,
recording conversions higher than 95%. All the copolymers
Under analogous conditions, the model copolymeric reagent
P115(1:19) containing benzyl ether linkages gave yields only
slightly lower than P116(1:19), in spite of the Wittig
rearrangements, which consumes n-butyllithium forming
alcoholate and produces a significant cross-linking under
lithiation.
from 15 (P115(1:9), P115(1:19)) and 16 (P116(1:9), P116(1:19)
)
were recovered in the form of easily filtered powders after
precipitation with methanol from their dioxane solutions.
Such copolymers were tested in the transformation of
1-bromo-4-phenylbutane into the stable 5-phenylpentanal
(17a), whose 1H and 13C NMR spectra are known15
(Scheme 8).
Considering that the (4-ethenylphenyl)chloromethane, pre-
cursor of P115, is commercially available, and that the
preparation of 1-bromo-4-(4-ethenylphenyl)butane, precur-
sor of P116, is rather laborious and expensive, for most
applications the recommended copolymeric reagent model
is P115 with a low concentration of dithiane units.
The lithiation was found to cause a certain amount of cross-
linking, as evidenced by the presence of variable
percentages of gelatinous insoluble material together with
the copolymeric products P3. The cross-linking was higher
with copolymers more concentrated in dithiane units (1:9)
On this basis reagents for solid phase syntheses can be
Scheme 8.

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V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
Table 1. Synthesis of the aldehyde 17a from P115 and P116 with excess of 1-bromo-4-phenylbutane
Polymer P1
% Yield of insoluble P3
% Yield of soluble P3
Cleavage reagent
% Yield of 17a from P1
P115(1:9)
P115(1:19)
P115(1:19)
P116(1:9)
P116(1:19)
32.2
11.5
11.5
15.5
0.7
63.4
86.2
86.2
79.8
98.9
H5IO6
H5IO6
Hg(ClO4)2$xH2O
H5IO6
Hg(ClO4)2$xH2O
35.2
40.1
56.6
43.4
62.7
properly prepared by anchoring 6 to commercial resins of
Merrifield type.
Table 2. Chemical modifications of the commercial resin R0 and synthesis
of aldehydes
R0 (mmol
Cl/g)a
R1
(% yield
from R0)
R3
(% yield
from R1)
RX
RCHO
(% yield
from R0)
2.1. Solid phase synthesis of aldehydes using trans-
formed Merrifield resins
0.822
0.806
0.806
96.7
97.3
98.1
98.3
95.8
97.2
C6H5(CH2)4Br
CH3(CH2)8Br
CH3(CH2)9Br
17a (61.3)
17b (48.0)
17c (57.3)
We prepared cross-linked supports with a low concentration
of well accessible 1,3-dithiane units and tested them in the
synthesis of aldehydes from alkyl halides, anchoring 6 to the
commercial Merrifield resin having a CH2Cl loading of
0.8 mmol gK1 of resin, cross-linked with 1% divinylben-
zene (DVB), which showed a good swelling in DMF and
THF and a good reactivity towards the alkoxide ions. The
nominal CH2Cl group loading was checked by addition of
excess of sodium methoxide and titration of the chloride
ions with standard silver nitrate. The commercial resin R0
was transformed into the active dithiane resin R1 through
the reaction with the sodium salt of 6 in the empirically
optimized molar ratio 1:1.5, monitoring the process by the
disappearing of the IR band at 1263 cmK1 (C–Cl) and the
appearing of that at 1092 cmK1 (C–O) (Scheme 9).
a Determined by titration.
molar ratiosZ1:1.25:1.50; no washing of R2 with anhy-
drous THF; lithiation time and temperature: 2 h between
K30 and K35 8C. Shorter lithiation times as well as the use
of R0 with high chlorine loading decreased the yields of the
aldehyde referred to the CH2Cl units. No traces of double
alkylation of the dithiane ring with formation of ketones
were found in any experiment. Table 2 collects some
characteristic data of the reaction performed. The yields of
aldehyde in the last column refer to the CH2Cl units in R0.
The resin R1, allowed to react with excess n-butyllithium in
analogy with a previous work,3 quite likely underwent the
Wittig rearrangement to a small extent, nevertheless, it
turned red owing to the deprotonation of the dithiane ring
(R2). The red colour persisted after washing the beads with
anhydrous THF to remove the excess of base that could
interfere with the successive alkylation step, and disap-
peared when an excess of alkyl halide was added to the
mixture. From the alkylated resin R3 the aldehyde was
recovered by cleavage with mercury(II) perchlorate hydrate.
Optimized conditions for preparative syntheses are as
follows: 1,3-dithiane units in R1:n-butyllithium:alkyl halide
3. Conclusions
We performed the synthesis of polymeric reagents endowed
with thioacetal reactivity for supported organic reactions
and combinatorial chemistry using commercial Merrifield
resins and a proper 1,3-dithiane synthon, obtained through
an odorless synthesis, unsubstituted at the position 2 and
carrying at the position 5 a suitable alcoholic function for
the formation of stable ether bonds.
After having examined and then discarded the 5-hydroxy-1,
3-dithiane (2) as a possible synthon, we prepared the fully
Scheme 9.

V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
9523
satisfactory 1,3-dithiane-5-methanol (6). Through synthesis
and study of the model molecules and soluble copolymers 7,
9, 12, 13, 14, 15, 16, P115 and P116, we demonstrated that 6
can be easily anchored to a polymeric material by forming
benzyl ether or alkyl ether bridges with chloromethylphenyl
or various u-bromoalkylphenyl residues, respectively.
triphenylphosphonium chloride (11.01 g, 32.1 mmol) in
anhydrous THF (50 mL) potassium t-butoxide (3.49 g,
31.1 mmol) was rapidly added under nitrogen at room
temperature. The ensuing dark red mixture was further
stirred for 1 h, cooled to K25 8C and treated in 5 min under
stirring with 1,3-dithian-5-one 17 (1.71 g, 12.7 mmol) in
THF (25 mL), further stirred at K20 to K25 8C for 8 h, then
added with water (50 mL) and Et2O (100 mL). The organic
layer was separated, washed with water and dried (Na2SO4).
Evaporation at reduced pressure left a dark oil, which was
purified by flash-chromatography (petroleum ether/Et2O
100:5) to afford 5 (1.65 g, 79.8%). Mp 85–86 8C (Et2O/
pentane, white needles). IR (KBr) nmax cmK1: 1666 (C]C),
The presence of benzyl ether groups has the handicap of
producing by treatment with n-butyllithium small amounts
of alcoholate through the Wittig rearrangement, increasing
the consumption of the lithium reagent. Nevertheless,
materials that show such handicap, like those derived
from the Merrifield resins, have the advantage of being
prepared from commercial products, while those not
containing benzyl ether groups and not undergoing the
Wittig rearrangement, require rather laborious and expens-
ive preparations and show only a slightly higher efficiency
(compare P115 and P116 in the Table 1). For these reasons
the use of reagents derived from commercial products has to
be preferred for most applications.
1
1215, 1130 (C–O). H NMR (CDCl3) dH 3.29 (d, 2H, JZ
0.6 Hz, 6-H, trans to OCH3), 3.47 (d, 2H, JZ0.6 Hz, 4-H,
cis to OCH3), 3.64 (s, 3H, OCH3), 3.95 (s, 2H, 2-H), 6.08
(quintet, 1H, JZ0.6 Hz, 10-H). 13C NMR (CDCl3) dC 27.7
(4-C), 33.3 (6-C), 33.7 (2-C), 59.8 (OCH3), 108.1 (5-C),
142.4 (10-C). m/z (EI) 162 (MC, 100%). Found: C, 44.20; H,
6.19. C6H10OS2 requires: C, 44.41; H, 6.21.
The effectiveness of 6 for the preparation from commercial
Merrifield resins of valuable polymeric reagents for solid-
phase synthesis was demonstrated with the transformation
of alkyl halides into aldehydes containing an additional
carbon atom.
4.1.2. 1,3-Dithiane-5-methanol (6). Compound 5 (2.03 g,
12.5 mmol) was dissolved in Et2O (50 mL) and carefully
added under nitrogen and magnetic stirring with 48%
aqueous tetrafluoroboric acid at 0 8C (12 mL). After
removal of the cooling bath, the homogeneous mixture
was left 3 h at room temperature, washed with saturated
aqueous solution of NaHCO3, then with water and dried
(Na2SO4). The elimination of the solvent at reduced
pressure left a residue of crude aldehyde that was taken up
into Et2O (20 mL) and treated with NaBH4 (0.30 g,
7.9 mmol) in water (4 mL). The two-phase mixture was
stirred vigorously for 2 h, the organic layer was separated
and the aqueous one extracted with Et2O (5!5 mL). The
combined organic phases were washed with water, dried
(Na2SO4) and evaporated at reduced pressure to afford 6 as
an oil that soon crystallized. Recrystallization from Et2O/
pentane at K30 8C gave pure 6 as a white solid (1.52 g,
80.8%). Mp 60–61 8C. IR (KBr) nmax cmK1: 33091 (OH),
1062 (C–O). 1H NMR (CD3OD) dH 2.00 (m, 1H, 5 -H), 2.64
(dd, 2H, J1Z13.9 Hz, J2Z9.5 Hz, 40-Haxial), 2.85–2.90 (m,
2H, 40-Hequatorial), 3.56 (d, 2H, JZ6.7 Hz, 1-H), 3.60 (dt,
1H, J1Z13.9 Hz, J2Z1.3 Hz, 20-Hequatorial), 3.92 (d, 1H,
4. Experimental
4.1. General
Melting points were determined on a Leica Galen III hot
stage apparatus and are uncorrected. 1H and 13C NMR
spectra were obtained on a Bruker Avance DPX 300
Spectrometer at 300 and 75.5 MHz, respectively, using
TMS as internal standard and were assigned with the help of
standard NOE-difference, COSY and HETCOR experi-
ments. Mass spectra were obtained with a GC-MS Ion Trap
Varian Saturn 2000 instrument (EI mode, filament current
10 mA). Infrared spectra were measured on a Perkin-Elmer
2000 FTIR spectrophotometer, using KBr discs. Commer-
cial solvents and reagents were purchased from Aldrich
unless otherwise stated. Petroleum ether refers to the
fraction with boiling point 40–60 8C. Flash-chromato-
graphic separations were performed on Merck Silica gel
(0.040–0.063 mm). Commercial 90% (4-ethenylphenyl)
chloromethane was crystallized twice from pentane at
13
JZ13.9 Hz, 20-Haxial). C NMR (CD3OD) dC 32.4 (20-C),
32.6 (40-C and 60-C), 39.4 (50-C), 66.1 (1-C). m/z (EI) 150
(MC, 100%). Found: C, 39.91; H, 6.80. C5H10OS2 requires:
C, 39.97; H, 6.71.
1
K70 8C and distilled at reduced pressure (99% pure by H
NMR). Commercial styrene was washed with a 5% NaOH
aqueous solution, dried over KOH pellets and distilled under
nitrogen at reduced pressure. Azobisisobutyronitrile
(AIBN) was crystallized from methanol. Merrifield resins
(particle size 200–400 mesh, 1% DVB, CH2Cl loading of
0.8 mmol gK1) were purchased from Fluka. The solvents for
polymer syntheses and transformations were carefully dried,
deoxygenated and distilled under nitrogen. 1,3-Dithiane-5-
one (1)7, 1,3-dithiane-5-ol (2),8 1-bromo-4-(4-ethenylphe-
nyl)butane14 and 1-bromo-4-phenylbutane18 were prepared
according to the literature.
4.2. Synthesis of dithianic ethers 3, 7, 13, 15 and 16
The appropriate solid alcohol 2 or 6 (4 mmol) was added at
0 8C under nitrogen to the suspension of pure NaH (from the
commercial 60% dispersion in oil washed with 3!5 mL of
dry Et2O) in dry DMF (9.5 mL) and left to react for 2 h at
room temperature. The mixture cooled to 0 8C was treated
with the pure alkyl halide (molar ratio, alcohol:NaH:alkyl
halideZ1:1.2:0.9 unless otherwise stated) and stirred for
20 min at 0 8C and 6 h at room temperature. Water (30 mL)
was then added, the organic products were extracted with
pentane (3!30 mL), the combined organic layers were
washed with water and dried (Na2SO4). Removal of the
solvent at reduced pressure left a residue, which was
4.1.1. 5-Methoxymethylene-1,3-dithiane (5). To a vigor-
ously stirred suspension of commercial methoxymethyl-

9524
V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
purified by flash-chromatography (petroleum ether/Et2O
100:5).
1:1.4:1.4). Oil, 40.8%. IR (film) nmax cmK1 1118 (C–O),
991, 906 (CH2]CH), 843 (benzene ring). 1H NMR
(CDCl3) dH 1.57–1.71 (m, 4H, 200-H and 300-H), 2.18 (m,
1H, 5-H), 2.61 (t, 2H, JZ7.4 Hz, 400-H), 2.62 (dd, 2H, J1Z
13.9 Hz, J2Z9.2 Hz, 4-Haxial), 2.84 (m, 2H, 4-Hequatorial),
3.40 (d, 2H, JZ6.5 Hz, 10-H), 3.42 (t, 2H, JZ6.2 Hz, 100-H),
3.56 (dt, 1H, J1Z13.9 Hz, J2Z1.4 Hz, 2-Hequatorial), 3.84 (d,
1H, JZ13.9 Hz, 2-Haxial), 5.18 (dd, 1H, J1Z10.9 Hz, J2Z
1.0 Hz, 20000-Hcis), 5.69 (dd, 1H, J1Z17.6 Hz, J2Z1.0 Hz,
20000-Htrans), 6.69 (dd, 1H, J1Z17.6 Hz, J2Z10.9 Hz, 10000-H),
7.11–7.14 (m, 2H, 2000-H0)0, 7.31–7.3400(m, 2H, 3000-H). 13C
NMR (CDCl3) dC 27.9 (3 -C), 29.2 (2 -C), 31.9 (2-C), 32.2
(4-C and 6-C), 35.4 (400-C),0300 5.6 (5-C), 71.0 (100-C), 73.7 (10-
C), 112.9 (20000-C), 126.2 (3 -C and 5000-C), 128.6 (2000-C and
6000-C), 135.2 (quaternary aromatic carbon), 136.7 (10000-C),
142.1 (quaternary aromatic carbon). Found: C, 66.26; H,
7.89. C17H24OS2 requires: C, 66.18; H, 7.84.
4.2.1. 5-Phenylmethoxy-1,3-dithiane (3). Oil, 86.4%. IR
(film) nmax cmK1: 1088, 1069 (C–O), 738, 727, 698
1
(benzene ring). H NMR (CDCl3) dH 2.72 (dd, 2H, J1Z
13.9 Hz, J2Z10.1 Hz, 4-Haxial), 2.90–2.96 (m, 2H, 4-
Hequatorial), 3.30 (dt, 1H, J1Z13.9 Hz, J2Z1.6 Hz, 2-
Hequatorial), 3.72–3.79 (m, 1H, 5-H), 3.82 (d, 1H, JZ
13.9 Hz, 2-Haxial), 4.60 (s, 2H, 10-H), 7.25–7.38 (m, 5H,
aromatic protons). 13C NMR (CDCl3) dC 30.9 (2-C), 33.8
(4-C and 6-C), 70.6 (10-C), 74.1 (5-C), 127.7, 127.9, 128.5
(protonated aromatic carbons), 137.9 (100-C). m/z (EI) 226
(MC, 31%). Found: C, 58.28; H, 6.19. C11H14OS2 requires:
C, 58.37; H, 6.23.
4.2.2. 5-Phenylmethoxymethyl-1,3-dithiane (7). Oil,
85.0%. IR (film) nmax cmK1: 1102 (C–O), 738, 719, 698
(benzene ring). H NMR (CDCl3) dH 2.25 (m, 1H, 5-H),
1
4.3. Deuteration of dithianic ethers 3, 7 and 13
2.66 (dd, 2H, J1Z13.9 Hz, J2Z9.4 Hz, 4-Haxial), 2.84–2.91
(m, 2H, 4-Hequatorial), 3.49 (d, 2H, JZ6.4 Hz, 10-H), 3.55
(dt, 1H, J1Z13.9 Hz, J2Z1.5 Hz, 2-Hequatorial), 3.85 (d, 1H,
JZ13.9 Hz, 2-Haxial), 4.51 (s, 2H, 100-H), 7.26–7.38 (m, 5H,
aromatic protons). 13C NMR (CDCl3) dC 31.9 (2-C), 32.3
(4-C and 6-C), 35.7 (5-C), 73.1 (10-C and 100-C), 127.6,
127.7, 128.4 (protonated aromatic carbons), 138.1 (1000-C).
m/z (EI) 240 (MC, 84%). Found: C, 60.07; H, 6.67.
C12H16OS2 requires: C, 59.96; H, 6.71.
A 0.1 M solution of the proper ether 3, 7 or 13 in dry THF
(1.3 mmol) was treated under stirring with a 1.6 M hexane
solution of n-butyllithium in the molar ratio 1:1.3 at K30 8C
under nitrogen. The homogenous solution was stirred
40 min at K30 to K35 8C, then quenched with methanol-
d (0.5 mL) and treated with saturated ammonium chloride
(0.5 mL). The organic layer was separated and the aqueous
phase extracted with Et2O (2!20 mL). The combined
organic layers were dried (Na2SO4), evaporated and
submitted to flash-chromatography (petroleum ether/Et2O
100:5) to obtain the products 4, 8 or 14. After the recovery
of the product 8, the column, further eluted with Et2O/
methanol 100:5, afforded 9, which was purified through a
second flash-chromatography (petroleum ether/Et2O 3:1)
4.2.3. 5-(3-Phenylpropoxy)methyl-1,3-dithiane (13). Oil,
41.7%. IR (film) nmax cmK1: 1115 (C–O), 747, 719, 700
1
(benzene ring). H NMR (CDCl3) dH 1.91 (m, 2H, 200-H),
2.23 (m, 1H, 5-H), 2.65 (m, 4H, 4-HaxialC300-H), 2.86 (m,
2H, 4-Hequatorial), 3.42 (d, 2H, JZ6.5 Hz, 10-H), 3.42 (t, 2H,
JZ6.3 Hz, 100-H), 3.58 (dt, 1H, J1Z13.9 Hz, J2Z1.4 Hz, 2-
Hequatorial), 3.85 (d, 1H, JZ13.9 Hz, 2-Haxial), 7.16–7.30 (m,
5H aromatic protons). 13C NMR (CDCl3) dC 31.2 (200-C),
31.9(2-C), 32.26 (4-C and 6-C), 32.34 (300-C), 35.6(5-C), 70.3
(100-C), 73.7 (10-C), 125.8, 128.3, 128.5 (protonated aromatic
carbons), 141.9 (1000-C). m/z (EI) 268 (MC, 100%). Found: C,
62.55; H, 7.47. C14H20OS2 requires: C, 62.64; H, 7.51.
1
giving an oily product whose H and 13C NMR data in
CDCl3 were coincident with those of the non-deuterated
derivative 12, with the exception of the absence of the signal
of 20-Hequatorial and the following variations concerning
axial proton and carbon in the position 20 dH 3.76 (br s); dC
31.4 (t, J13C–DZ22 Hz).
4.4. 2-(1,3-Dithian-5-yl)-1-phenylethanone (11)
4.2.4. 5-(4-Ethenylphenyl)methoxymethyl-1,3-dithiane
(15). (From 6:NaH:(4-ethenylphenyl)chloromethaneZ
1:1.20:1). Mp 62–63 8C (Et2O/pentane, white solid),
88.9%. IR (KBr) nmax cmK1: 1125, 1109 (C–O), 994, 922
(CH2]CH), 826 (benzene ring). 1H NMR (CDCl3) dH 2.24
(m, 1H, 5-H), 2.66 (dd, 2H, J1Z13.9 Hz, J2Z9.3 Hz, 4-
Haxial), 2.84–2.90 (m, 2H, 4-Hequatorial), 3.48 (d, 2H, JZ
6.4 Hz, 10-H), 3.57 (dt, 1H, J1Z13.9 Hz, J2Z1.2 Hz, 2-
Hequatorial), 3.85 (d, 1H, JZ13.9 Hz, 2-Haxial), 4.50 (s, 2H,
100-H), 5.24 (dd, 1H, J1Z10.9 Hz, J2Z0.9 Hz, 20000-Hcis),
5.75 (dd, 1H, J1Z17.6 Hz, J2Z0.9 Hz, 20000-Htrans), 6.71
(dd, 2H, J1Z17.6 Hz, J2Z10.9 Hz, 10000-H), 7.26–7.29 (m,
2H, 2000-H), 7.38–7.41 (m, 2H, 3000-H). 13C NMR (CDCl3) dC
31.9 (2-C), 32.20(0040 -C and 6-C),0300 5.7 (5-C), 72.9 (100-C), 73.1
(10-C), 113.9 (2 -C), 126.3 (3 -C and 5000-C), 127.8 (2000-C
and 6000-C), 136.5 (10000-C), 137.1, 137.7 (quaternary aromatic
carbons). Found: C, 63.21; H, 6.90. C14H18OS2 requires: C,
63.11; H, 6.81.
Alcohol 6 (0.366 g, 2.44 mmol) was dissolved in dry
pyridine (2 mL) and treated at K10 8C with benzenesulfo-
nyl chloride (0.38 mL, 2.98 mmol). The mixture was stirred
at K10 8C for 4 h, then treated with cold 2 M H2SO4
(50 mL) and ethyl acetate (20 mL). The organic layer was
separated, washed with 2 M H2SO4, then three times with
water and dried (Na2SO4). The solvent was removed at
reduced pressure and the residue crystallized from absolute
ethanol to afford the benzenesulfonate ester 10 as white
needles (0.503 g, 71.1%. Mp 71–72 8C. IR (KBr) nmax cmK1
:
1353, 1339, 1184, 1176 (S–O), 754, 744, 684 (benzene
ring). Found C, 44.70; H, 4.80. C11H14O3S3 requires: C,
44.49; H, 4.86). A solution of diisopropylamine (0.27 mL,
1.93 mmol) in anhydrous THF (2 mL) was treated with a
1.66 M hexane solution of n-butyllithium (1.2 mL,
1.99 mmol) at K75 8C under nitrogen, stirred at the same
temperature for 10 min and added with benzaldehyde O-
trimethylsilyl cyanohydrin (0.398 g, 1.94 mmol) in dry THF
(0.5 mL). The thick yellow suspension immediately formed
after 10 min was treated with the solution of 10 (0.401 g,
4.2.5. 5-(4-(4-Ethenylphenyl)butoxy)methyl-1,3-dithiane
(16). (From 6:NaH:1-bromo-4-(4-ethenylphenyl)butaneZ

V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
9525
1.38 mmol) in dry THF (0.5 mL). Stirring was continued 2 h
4.7. Copolymers P315 and P316
at K60 8C, then the temperature was left to rise in 2 h from
K60 to 0 8C. The orange solution was treated with 1 M HCl
(20 mL) and methanol (10 mL), stirred overnight at room
temperature and extracted with Et2O (3!20 mL). The
combined organic layers were washed twice with 1 M
aqueous NaOH, three times with water and dried (Na2SO4).
After elimination of the solvent at reduced pressure the
residue, purified by flash-chromatography (petroleum ether/
ethyl acetate 4:1), afforded the ketone 11 (0.281 g, 85.3%).
A solution of P115 or P116 in anhydrous THF (1.2 mmol of
1,3-dithiane units at 0.1 M concentration) mechanically
stirred at K40 8C under nitrogen was treated with a 1.6 M
solution of n-butyllithium in hexane and further stirred at
K30 to K35 8C for 1 h, during which a marked increase of
the viscosity was observed owing to the formation of P2.
The mixture was treated with 1-bromo-4-phenylbutane (1,3-
dithiane units:n-buthyllitium:1-bromo-4-phenylbutaneZ
1:1.25:1.50), stirred for 2 h while the temperature was left
slowly to rise from K30 to K15 8C, then it was kept at
K10 8C overnight. Water (50 mL) and dichloromethane
(100 mL) were added and the layers allowed slowly to
separate. The organic layer was cautiously removed, while
the insoluble portion of cross-linked P3 remained floating
between the two phases, then additional extractions with
dichloromethane (2!100 mL) were performed using the
same precautions. The combined organic layers were
washed with water, dried (Na2SO4) and the solvent was
removed at reduced pressure. The crumbly residue of P3
was taken up in the appropriate solvent [(toluene for
P315(1:9) (0.10 g mLK1) and P315(1:19) (0.14 g mLK1);
dioxane for P316(1:9) (0.08 g mLK1) and P316(1:19)
(0.16 g mLK1)] and slowly poured into methanol (20
times the volume of the solution). The powdery precipitate
of P3 was filtered, washed with methanol and pump-dried at
room temperature to constant weight. From the remaining
mixture of aqueous phase and cross-linked P3 any residual
dichloromethane was eliminated in vacuo, the insoluble
material was filtered, washed thoroughly with water and
methanol then pump-dried at room temperature to constant
weight.
Mp137–138 8C (ethanol, white leaflets). IR(KBr)nmax cmK1
:
1682 (C]O), 750, 734, 689 (benzene ring). 1H NMR
(DMSO-d6) dH 2.45 (m, 1H, 50-H), 2.70 (dd, 1H, J1Z
13.7 Hz, J2Z8.6 Hz, 40-Haxial), 2.89 (ddd, 2H, J1Z13.7 Hz,
J2Z2.7 Hz, J3Z1.0 Hz, 40-Hequatorial), 3.25 (d, 2H, JZ
6.5 Hz, 20-H), 3.74 (dt, 1H, J1Z13.6 Hz, J2Z1.0 Hz, 20-
H
equatorial), 3.87 (d, 1H, JZ13.6 Hz, 20-Haxial), 7.51–8.00
(m, 5H, aromatic protons).0 13C NMR (DMSO-d6) dC 30.3
(2000-C), 30.400(50-C), 33.5 (4 -C and0060-C), 42.4 (2-C), 127.8
(3 -C and 5 -C), 128.7 (200-C and 6 -C), 133.2 (400-C), 136.7
(100-C), 198.5 (CO). m/z (EI) 238 (MC, 68%). Found C,
60.38; H, 6.01. C12H14OS2 requires: C, 60.46; H, 5.92.
4.5. 2-(1,3-Dithian-5-yl)-1-phenylethanol (12)
Ketone 11 (0.063 g, 0.26 mmol) in THF (3 mL) was added
to NaBH4 (0.058 g, 1.5 mmol) in water (0.4 mL), then the
mixture was vigorously stirred for 3 h and extracted with
Et2O (3!5 mL). The combined organic layers were dried
(Na2SO4) and evaporated at reduced pressure to afford 12
(quantitative yield). Mp 72–74 8C (Et2O/pentane at
K30 8C, white solid). IR (KBr) nmax cmK1: 3548 (OH),
1059 (C–O), 754, 738, 699 (benzene ring). 1H NMR
(CDCl3) dH 1.80–1.95 (m, 2H, 2-H), 2.10 (br s, 1H, OH),
2.15 (m, 1H, 50-H), 2.54–2.65 (m, 2H, 60-H and 40-H), 2.84–
2.93 (m, 2H, 60-H and 40-H), 3.58 (dt, 1H, J1Z13.8 Hz, J2Z
1.5 Hz, 20-Hequatorial), 3.76 (d, 1H, JZ13.8 Hz, 20-Haxial),
4.78 (br m, 1H, 1-H), 7.26–7.36 (m, 5H, aromatic protons).
4.8. Reaction of P3 with mercury(II) perchlorate hydrate
A THF solution of polymer P3 (0.55 mmol of 2-alkylated
1,3-dithiane units at 0.2 M concentration) was treated under
nitrogen and magnetic stirring with a solution of mercury(II)
perchlorate hydrate (1,3-dithiane units:mercury ionsZ
1:2.5, considering a minimum content of 42% metal in the
used reagent) in THF (15 mL). The mixture was stirred 1 h
at room temperature then NaHCO3 (0.75 g, 8.9 mmol) was
added in the minimum amount of water. Stirring was
continued for 5 min, flash-chromatography silica gel (5 g)
was added and most of the solvent removed at in vacuo. The
obtained coarse powder was charged on a flash-chromato-
graphy column packed with pentane/Et2O 100:5 (20 g of
silica gel in a 20 mm diameter column) and 17a was eluted
with this eluent.
13
C NMR (CDCl3) dC 31.6 (20-C), 31.7 (50-C), 34.7 (40-C or
60-C), 35.7 (40-C or 60-C), 44.0 (2-C), 71.9 (1-C), 125.7,
127.8, 128.7 (protonated aromatic carbons), 144.5 (100-C).
Found C, 59.89; H, 6.66. C12H16OS2 requires: C, 59.96; H,
6.71.
4.6. Copolymers P115 and P116
Monomer 15 or 16 and styrene (molar ratio 1:9 and 1:19)
together with the calculated volume of deoxygenated
dioxane to give 8.5 M solutions and AIBN (2% weight of
the monomers) were introduced in a vial with a side arm and
subjected to three freeze-pump-thaw cycles at K78 8C.
After sealing and stirring the vial containing the hom-
ogenous solution was heated at 60 8C in a thermostatic bath
for 72 h. The cooled viscous clear content of the vial was
diluted with dioxane (5 mL per g of monomer charge) and
slowly poured with vigorous stirring into methanol (15
times the volume of the dioxane solution). The powdery
precipitate was filtered, washed with methanol and dried
under vacuum at room temperature up to constant weight.
Yields were always greater then 95% of the mass of the used
monomers.
4.9. Reaction of P3 with periodic acid
A weighted amount of polymer P3 (corresponding to
0.45 mmol of 2-alkylated 1,3-dithiane units) was dissolved
in THF (4.5 mL) under nitrogen and magnetic stirring at
0 8C, and treated with a 0.40 M solution of periodic acid in
THF (3.4 mL, 1.36 mmol). The cooling bath was removed
and stirring continued at room temperature for 2 h. Et2O
(50 mL) was carefully added, the organic solution separ-
ated, washed with 1.6 M sodium sulfite solution, then with
water and dried (Na2SO4). After removal of the solvent the
flash-chromatography of the residue (pentane/acetone

9526
V. Bertini et al. / Tetrahedron 61 (2005) 9519–9526
100:5) afforded a mixture of 17a15 and 18 whose NMR
spectra in CDCl3 allowed to assign the following signals: 1H
NMR dH 4.38 (m, 1H, 2-H); 9.22 (d, 1H, JZ2.9 Hz, 1-H).
13C NMR dC 191.5 (1-C).
4.13. Determination of the chlorine loading in Merrifield
resins R0
A weighted sample of R0 (1 g) was suspended under nitrogen
in dry DMF (12 mL) and added with solid sodium methoxide
(CH2Cl units:methoxide ionZ1:2.5). The mixture was stirred
6 h at 50 8C, then the resin was filtered and accurately washed
with water (150 mL in small portions). The aqueous filtrate
was made strongly acidic with 65% nitric acid (1 mL) and
briefly boiled. After cooling, the chloride ions were
determined according to Volhard procedure, correcting for a
blank titration without resin sample.
4.10. Resins R1
NaH (6.0 mmol, from a corresponding amount of a
commercial 60% dispersion in mineral oil washed with
3!10 mL of dry Et2O) was suspended under nitrogen in dry
DMF (15 mL) and treated under magnetic stirring with 6
(0.820 g, 5.45 mmol). The mixture was further stirred for
3 h at room temperature, then added with the proper amount
(corresponding to 3.60 mmol of chloromethyl groups) of
resin R0 and diluted with 15 mL of anhydrous DMF. After
stirring for additional 6 h in an oil bath at 50 8C, the resin
was filtered, washed with peroxide-free THF and extracted
under magnetical stirring for 1 h with the same solvent
(50 mL). After filtration, the washing with THF was
repeated, then the resin was filtered and washed in turn
with peroxide-free THF, methanol, water and again
methanol. The collected resin was pump-dried at room
temperature to constant weight: more than 97% of the
expected amount of R1 was always recovered.
Acknowledgements
This work was financially supported by MIUR (Programmi
di Ricerca di Rilevante Interesse Nazionale 2004) and
University funds.
References and notes
1. Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A.
Tetrahedron Lett. 1998, 39, 9263–9266.
4.11. Resins R3
2. Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A. J. Org.
Chem. 2000, 65, 4839–4842.
Resin R1 (an amount corresponding to 1.4 mmol of 1,3-
dithiane units) was suspended under nitrogen in the
minimum amount of anhydrous THF necessary to give an
easy to stir slurry (0.13 g resin mLK1), cooled to K60 8C
and added with a 1.6 M solution of n-butyllithium in
hexane. The temperature was raised rapidly to K35 8C and
the suspension of the beads, which turned deep red owing to
their transformation into R2, was magnetically stirred at
K35 to K30 8C for 2 h. The pure alkyl halide (1-bromo-4-
phenylbutane, or 1-bromononane, or 1-bromodecane) was
then added (1,3-dithiane units:n-butyllithium:alkyl halideZ
1:1.25:1.50), the temperature was left to rise to K15 8C in
1 h and the reaction mixture kept at K10 8C overnight. The
pale yellow resin R3 was filtered, washed with peroxide-
free THF and magnetically stirred for 1 h with the same
solvent. After filtration, this treatment was repeated once
again and finally R3 was filtered, washed in turn with
peroxide-free THF, methanol, water, methanol and pump-
dried at room temperature to constant weight.
3. Bertini, V.; Pocci, M.; Lucchesini, F.; Alfei, S.; De Munno, A.
Synlett 2003, 864–866.
4. Bertini, V.; Lucchesini, F.; Pocci, M.; Alfei, S.; De Munno, A.
Synlett 2003, 1201–1203.
5. Lucchesini, F.; Bertini, V.; Pocci, M.; Micali, E.; De Munno,
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158–164. Lu¨ttringhaus, A.; Prinzbach, H. Liebigs Ann. Chem.
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4.12. Aldehydes 17a–c from resins R3
Resin R3 (an amount corresponding to 0.4 mmol of
2-alkylated 1,3-dithiane units) was suspended in peroxide-
free THF (0.27 g mLK1) under nitrogen and added with a
0.5 M THF solution of mercury(II) perchlorate hydrate (1,3-
dithiane units:mercury ionsZ1:3, calculated on the basis of
a 42% metal content in the salt). The mixture was stirred for
1 h at room temperature, then it was treated with a saturated
aqueous solution of NaHCO3 (1 mL). The heterogeneous
mixture was extracted with Et2O (5!5 mL), the organic
layers were combined, the solvent was eliminated at
reduced pressure and aldehydes 17a–c were recovered
from the residue by flash-chromatography (petroleum ether/
Et2O 100:5).
¨
13. Schollkopf, U. Angew. Chem., Int. Ed. Engl. 1970, 9, 763–766.
14. Bertini, V.; Alfei, S.; Pocci, M.; Lucchesini, F.; Picci, N.;
Iemma, F. Tetrahedron 2004, 60, 11407–11414.
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17. Barluenga, J.; Martinez-Gallo, J. M.; Najera, C.; Yus, M.
Synthesis 1986, 678–680.
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