Pot-economy autooxidative condensation of 2-Aryl-2-lithio-1,3-dithianes

Article abstract of DOI:10.1021/acs.joc.7b02896

The autoxidative condensation of 2-aryl-2-lithio-1,3-dithianes is here reported. Treatment of 2-aryl-1,3-dithianes with n-BuLi in the absence of any electrophile leads to condensation of three molecules of 1,3-dithianes and formation of highly functionalized α-thioether ketones orthothioesters in 51-89% yields upon air exposure. The method was further expanded to benzaldehyde dithioacetals, affording corresponding orthothioesters and α-thioether ketones in 48-97% yields. The experimental results combined with density functional theory studies support a mechanism triggered by the autoxidation of 2-aryl-2-lithio-1,3-dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2-aryl-2-lithio-1,3-dithiane.

Full text of DOI:10.1021/acs.joc.7b02896

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Article
Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-dithianes
João R. Vale, Tatu Rimpiläinen, Elina Sievanen, Kari Rissanen, Carlos A. M. Afonso, and Nuno R. Candeias
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02896 • Publication Date (Web): 15 Jan 2018
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The Journal of Organic Chemistry
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Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-
dithianes
João R. Vale†§, Tatu Rimpiläinen†, Elina Sievänen‡, Kari Rissanen‡, Carlos A. M. Afonso*§, Nuno R.
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Candeias*†
† Lab. of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland
‡ University of Jyvaskyla, Department of Chemistry, Nanoscience Center, P.O. Box 35, 40014 Jyväskylä, Finland
§ Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof.
Gama Pinto, 1649ꢀ003 Lisboa, Portugal
ABSTRACT: The autooxidative condensation of 2ꢀarylꢀ2ꢀlithioꢀ1,3ꢀdithianes is here reported. Treatment of 2ꢀarylꢀ1,3ꢀdithianes
with nꢀBuLi in the absence of any electrophile leads to condensation of three molecules of 1,3ꢀdithianes and formation of highly
functionalized αꢀthioether ketones orthothioesters in 51ꢀ89% yields upon air exposure. The method was further expanded to
benzaldehyde dithioacetals, affording corresponding orthothioesters and αꢀthioether ketones in 48ꢀ97% yields. The experimental
results combined with density functional theory studies support a mechanism triggered by the autooxidation of 2ꢀarylꢀ2ꢀlithioꢀ1,3ꢀ
dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2ꢀarylꢀ2ꢀlithioꢀ1,3ꢀdithiane.
in THF, proposed by the authors to arise from the unlikely
reaction of the desired intermediate with solvent.20 Presence of
dimers derived from single electron transfer processes have
been observed in several other works,12a,14c,21 especially in
presence of nitro substituted compounds.22 The nucleophilic
addition of 2ꢀlithioꢀ1,3ꢀdithianes to acyl chlorides and esters
reported by Kutateladze and coꢀworkers23 is one example from
the vast array of dithiane umpolung reactivity of carbonyl
compounds (Scheme 1). Interestingly, when an aldehyde other
than acetaldehyde is used, the reaction proceeds through
addition of a second dithiane molecule through ringꢀopening
of the firstly installed dithiane unit.24
INTRODUCTION
Organolithium compounds can undergo autoxidation
towards formation of highly unstable organolithium peroxides,
which upon fast interaction with another organolithium leads
to the ultimate formation of lithium alkoxides.1 Oxidation of
RLi with ROOLi was proven by Müller and Töpel2 in 1939
and used in several oxidative processes,3 and the autoxidation
of organolithiums further explored in preparation of alcohols.4
The first reports of Corey and Seebach5 on the use of
lithiated 1,3ꢀdithianes as synthetic equivalents to acyl anions
have rapidly gathered the attention of the synthetic
community. The umpolung strategy rendered by
transformation of aldehydes to 2ꢀsubstituted 1,3ꢀdithianes and
subsequent formation of the lithiated acyl anion equivalent
have been explored for preparation of a wide array of
products,6,7 namely in natural product synthesis.8 Other
thioacetals can lead to the formation of similar acyclic
lithiated anions,9 but it was soon realized that cyclic 2ꢀlithioꢀ
1,3ꢀdithianes were advantageous due to their ease of
preparation and general suitability.6b Despite the undisputable
importance of 2ꢀlithioꢀ1,3ꢀdithianes in synthetic chemistry,
inconsistent yields and formation of side products have been
reported.10 Problems derived from its high reactivity and
strong basicity have been overcome either by
transmetalation,11,12,13 or using less reactive silyl,14,15,16 or
tin10a,17 analogues. The autoxidation of 2ꢀlithioꢀ1,3ꢀdithiane
(Scheme 1) upon air exposure has been reported by Wade and
coꢀworkers,18 after observing formation of 1 and 2 in absence
of an electrophile. The formation of 1 was also later reported
by Argade and coꢀworkers when preparing 2ꢀlithioꢀ1,3ꢀ
dithiane.19 The presence of an oxidizing impurity in older
bottles of nꢀBuLi was advanced as the cause for the formation
of the oxidized products. The same compound was reported to
be formed in 25% yield when preparing 2ꢀlithioꢀ1,3ꢀdithiane
Considering the previous reports on the autoxidation of 2ꢀ
lithioꢀ1,3ꢀdithianes, we envisioned that 2ꢀarylꢀ2ꢀlithioꢀ1,3ꢀ
dithianes could be oxidized in situ to yield a thioester capable
of undergoing a similar attack by the excess organolithium
eventually forming compounds similar to those described by
Kutateladze in
a
pot economy.25 Previously reported
transformations of the envisioned products include
desulfurizing difluorination of the αꢀthioether ketone and
dithioketal moieties26 or trifluoromethylation of benzylic
27
orthothioesters.26b,
Orthothioesters can be converted to
esters, thioesters or orthoesters28 and αꢀthioether ketones have
also been used in the oxidative coupling of benzyl ketones.29
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min, and opened to air 1 minute before addition of NH4Cl
saturated aqueous solution. b Isolated Yield
1
Scheme 1.
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Finally, the optimized protocol retrieved formation of
orthothioester 5a in 76% and the scope of the method was
evaluated (Scheme 2). Formation of ortholithiation derived
products was not observed even in presence of directing
metalating groups. The correspondent orthothioesters derived
from electron rich or electron poor aryl dithianes could be
obtained in reasonable yields. Phenylꢀ1,3ꢀdithianes decorated
with halogens at the paraꢀposition were successfully
transformed into the corresponding orthothioesters 5d and 5e,
although LDA had to be used for the bromide derivative to
avoid transmetalation with nꢀBuLi. TBDMS and TBDPS silyl
protective groups were stable to the reaction conditions, and
silyl ethers 5j and 5k could be obtained in up to 89% yield. A
dithiane derived from 2ꢀformylpyridine resulted in formation
of 5i in 57% yield. Despite several attempts on the
autooxidative addition of nitrophenylꢀ1,3ꢀdithianes, only
alkylated derivatives or starting materials were obtained. Other
electron deficient dithianes such as pentafluorophenyl or paraꢀ
trifluoromethylphenyl derivatives were unstable towards the
lithiation conditions tested.
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RESULTS AND DISCUSSION
Gratifyingly, when reacting 2ꢀphenylꢀ2ꢀlithiumꢀ1,3ꢀdithiane
with Sꢀbenzyl benzothioate, product 5a was obtained in 89%
yield (Table 1, entry 1). The ability of the thioester group to
undergo the same transformation as benzoylchloride (entry 2)
prompted us to assess the possibility for in situ formation of
the thioester by oxidation of the lithium dithiane. Hence, the
argon atmosphere of a solution of 2ꢀphenylꢀ2ꢀlithiumꢀ1,3ꢀ
dithiane from 4a was replaced by oxygen and kept for 5
minutes to afford the thioorthoester in 69% yield (entry 3).
The simple exposure of the reaction mixture to air for 30 min
allowed formation of thioorthoester 5a in 41% yield (entry 4),
which was increased to 68% by decreasing exposure to air to
less than a minute (entry 5), and to 71% by forming the
lithiated dithiane at 0 °C (entry 6). Modification of the
stoichiometric amounts of nꢀBuLi or other solvents (entries 7ꢀ
10) did not improve the reaction success. Although a fast
process at 0 °C, air exposure of the organolithium at ꢀ78 °C
led to only traces of product and unreacted dithiane (entry 11).
Scheme 2.a
Table 1. Optimization of reaction conditions
Entry
Deviation from reaction conditionsa
PhC(O)SBn (0.65 eq.), no air
PhC(O)Cl (0.65 eq.), no air
O2 balloon for 5 min
Yield (%)b
1
89
2
71
a for reaction conditions see footnote a, table 1 bLDA as base
3
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Acyclic benzaldehyde dithioacetals derived from primary
and secondary thiols undergo the same process to yield αꢀ
4
30 min air exposure
41
thioether ketones
7 and orthothioesters 8 (Table 2).
5
r.t., 20 min
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Dithioacetal 6e derived from tertꢀbutyl mercaptan failed to
provide the corresponding ketone or orthothioesters likely due
to steric hindrance as only thioester 9 could be obtained. The
use of O2 instead of air was observed to be detrimental for the
reaction yield, as complex mixtures of products were obtained
in such cases.
In order to evaluate the scope of the transformation
concerning the nature of the 2ꢀsubstituent of 1,3ꢀdithianes,
several 2ꢀalkylꢀ1,3ꢀdithianes were submitted to our
autooxidative conditions (Scheme 3). The autooxidation of 2ꢀ
lithioꢀ1,3ꢀdithiane under our reaction conditions resulted in the
6
0°C to r.t., 20 min
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7
1.0 eq. nꢀBuLi, 0°C to r.t., 20 min
1.6 eq. nꢀBuLi, 0°C to r.t., 20 min
Et2O, 0°C to r.t., 20 min
Toluene
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air exposure at ꢀ78 °C
traces
a
nꢀBuLi (2.5 M in hexanes, 1.3 mmol) was added dropwise to a
solution of dithiane 4a (1 mmol) in THF (5 ml) under argon
atmosphere at ꢀ78 °C. The mixture was left to reach rt after 20
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The role of atmospheric oxygen as the oxidant species in
unsurprised formation of alcohol 1a as previously reported by
Wade and coꢀworkers (Scheme 3, eq 1).18 2ꢀAlkyl substituted
1,3ꢀdithianes undergo autooxidation to some extent, however
the reaction is halted before orthothioester formation and 10
are obtained in up to 27% yields (Scheme 3, eq 2) probably
due to the competitive formation of the lithium enolate of
product. Similar yields of the products were observed when
increasing the amount of nꢀBuLi. The presence of a bulky tꢀ
butyl substituent alters the outcome of the reaction. Dithioester
11, resulting from condensation of two oxidized species was
the only product identified (Scheme 3, eq 3). The
autooxidative addition of 1,3ꢀdithiane derived from silyl
protected glycoaldehyde yields 10p together with hexyl
substituted 1,3ꢀdithiane. The formation of the later is likely to
occur by trapping of the ketene dithiane with nꢀbutyl lithium.30
Several attempts to apply this procedure to 2ꢀsilyl substituted
1,3ꢀdithianes, such as 2ꢀTMSꢀ1,3ꢀdithiane 2ꢀTBDPSꢀ1,3ꢀ
dithiane, resulted in the formation of complex mixtures of
unidentified products.
the process was confirmed by running the autooxidative
condensation reaction under 18O2, affording the 18O
isotopically labeled 5a in 72% yield (Scheme 4, eq 1).
Impelled by the previous suggestions that a SET mechanism
could be involved, the exposure to air in presence of TEMPO
was performed (Scheme 4, eq 2). Trapped intermediates were
1
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4
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8
not identified and only compound 2 was isolated, already
14c, 21
known to derive from SET.12a,
Notably, formation of
compound 5a was not observed, which might indicate the SET
process to be a pitfall prior to the organolithium autooxidation.
The presence of 12 as intermediate in the reaction was
supported by its reaction with lithium dithiane derived from 4a
(Scheme 4, eq 3).
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Scheme 4.
Table 2. Autooxidative condensation of benzaldehyde-
derived dithioacetals
Entrya
R
7 Yield (%)b 8 Yield (%)b
1
2
3
4
5
Ph
7a, 48
7b, 97
8a, ꢀc
8b, 72
8c, 56
8d, ꢀc
nꢀBu
(CH2)11Me 7c, 73
In order to get some insight on the reaction mechanism, the
several putative processes involved in the transformation were
studied by DFT calculations.31 The spontaneous autooxidation
of the organolithium compound was verified through
optimization of relevant intervenient species (Scheme 5). The
process seems highly favorable, as the lithium alkoxide
formation is balanced by the release of 25.4 kcal/mol upon
reaction of lithium dithiane with triplet oxygen3a followed by
release of 88.9 kcal/mol upon reaction of the lithium peroxide
with lithium dithiane to form the corresponding lithium
alkoxide.
secꢀBu
tꢀBu
7d, 67
9, 62
a For reaction conditions see footnote a, table 1. b Isolated Yield. c
Observed in 1H NMR of the crude mixture but not isolated.
Scheme 3.a
Scheme 5.
According to our calculations, formation of thioester B from
lithium alkoxide A requires only 2.7 kcal/mol (Figure 1). The
thiolate charge in thioester B is highly stabilized by lithium
and becomes more stabilized upon interaction with a lithium
dithiane molecule (C). The presence of lithium increases the
C=O polarization of the thioester assisting the nucleophilic
a
b
For reaction conditions see footnote a, table 1. Isolated Yields
c
unreacted dithiane 4 was isolated as the major species. 2ꢀ(nꢀ
hexyl)ꢀ1,3ꢀdithiane was also isolated in 23%.
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attack of a lithium dithiane molecule, and requires 11.2 suggested by the rather long forming CꢀC bond and small
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1
kcal/mol. The transition state TSCD resembles an early one, as
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S
Li
Li
S
S
Li
Li
O
S
Li
S
O
Li
O
S
S
Ph
O
S
S
Ph
S
Ph
Ph
Li
S
S
Ph
Ph
A
B
S
D
Ph
E
S
Figure 1. Free energy profile (PBE0) for deterioration of lithium alkoxide and reaction with 2ꢀphenylꢀ2ꢀlithioꢀ1,3ꢀdithiane, and
mechanistic representation. Optimized structures of minima and transition states are presented with bond distances and Wiberg indexes (in
italics) for the more relevant bonds. Free energies values are presented in kcal/mol, referring to the initial intermediate A.
Wiberg index32 (d = 2.84 Å and WI = 0.13), which becomes
considerably shorter in the tetrahedral intermediate D (d =
1.61 Å and WI = 0.90). The collapse of intermediate D to the
more stable pair of ketone and lithium thiolate (E) requires
only 5.0 kcal/mol to overcome the transition state TSDE energy
barrier. Interaction of the lithium cations with sulfur atoms is
visible in calculated TSDE, although such stabilization is likely
to take place by the solvent molecules. The pair of products
represented in E is highly stabilized by interaction of lithium
cations with both sulfur atoms of the thiolate and the carbonyl
oxygen.
nucleophilic attack might indicate this as the main route for
formation of the orthothioester product.
Condensation of the ketone 12 in E with another lithium
dithiane molecule was considered, as observed experimentally
(Scheme 4, eq 3), by taking the nucleophilic attack of the
organolithium to a sulfur atom of the αꢀdisubstituted ketone
(Figure 2).24 The calculated transition state for this reaction
TSFG is characterized by distension of the CꢀS bond of the
ketone (2.11 Å in TSFG and 1.85 Å in F) and formation of a
new CꢀS bond (2.49 Å and WI = 0.29) with the lithium
dithiane molecule, demanding for 11.2 kcal/mol. Weakening
of the carbonꢀoxygen bond from F to G is visible by its length
(1.23 Å in F and 1.29 Å in G) and weaker Wiberg index in the
lithium enolate product G (WI = 1.65 in F and 1.31 in G),
accompanied by strengthening of the CꢀC bond (1.55 Å; WI =
0.95 in F and 1.40 Å; WI = 1.47 in G). Although we cannot
rule out a radical mechanism based on our calculations (as
suggested by Kutateladze23 and considered in supporting
information), the low energy barrier determined for the ionic
Figure 2. Free energy profile (PBE0) for nucleophilic
condensation of αꢀdisubstituted ketone with 2ꢀphenylꢀ2ꢀlithioꢀ1,3ꢀ
dithiane and mechanistic representation. Optimized structures of
minima and transition states are presented with bond distances
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and Wiberg indexes (in italics) for the more relevant bonds. Free
energies values are presented in kcal/mol, referring to the initial
intermediate A from Figure 1.
brine (10 mL). The organic solvent was dried over MgSO4 and
filtered. After evaporating the solvent, the product was
recrystallized in isopropanol. Note: Reactions were conducted
in different scales depending on availability of aldehyde
starting material.
1
2
3
CONCLUSION
4
5
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8
9
4a: Prepared according to method A. 77% yield (3.425 g,
17.45 mmol), white crystals. Obtained with same spectral
characterization as previously described.34 1H NMR (300
MHz, CDCl3): δ ppm 7.49ꢀ7.45 (m, 2H), 7.37ꢀ7.29 (m, 3H),
5.17 (s, 1H), 3.12ꢀ3.02 (m, 2H), 2.95ꢀ2.88 (m, 2H), 2.22ꢀ2.14
(m, 1H), 2.01ꢀ1.86 (m, 1H).
In summary, we have shown that 2ꢀarylꢀ2ꢀlithiumꢀ1,3ꢀ
dithianes undergo autooxidative condensation forming αꢀ
thioether ketones orthothioesters in reasonable to good yields
upon aerobic oxidation. The procedure can be expanded to
other benzaldehyde derived dithioacetals, affording
orthothioesters and αꢀthioether ketones in good to excellent
yields. 2ꢀAlkyl substituted 1,3ꢀdithianes also undergo a similar
autooxidative process upon treatment with nꢀBuLi and air
exposure, however condensation of a third dithiane unit is
hampered by presence of enolizable positions on the
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4b: Prepared according to a modified previously reported
method.35 4ꢀ(Dimethylamino)benzaldehyde (1 g, 6.7 mmol, 1
equiv.) and 1,3ꢀpropanedithiol (0.74 mL, 7.4 mmol, 1.1
equiv.) were dissolved in 10 mL of dry DCM in an argon
purged roundꢀbottom flask. The solution was cooled to 0ᵒC
and BF3•OEt2 (1.16 mL, 9.4 mmol, 1.4 equiv.) was added
dropwise. The solution was then left warming to room
temperature for 1 hour. The reaction was quenched with a 10%
aqueous NaOH solution (10 mL). The layers were separated
and the organic phase collected and washed with water (10
mL) and Brine (10 mL). The organic solvent was dried over
MgSO4 and filtered. After evaporation of the solvent, the
product was recrystallized from isopropanol to give 4b as
yellow crystals in 93% yield (1.498 g, 6.26 mmol). Obtained
with same spectral characterization as previously described.36
1H NMR (300 MHz, CDCl3): δ ppm 7.33 (d, J=8.8 Hz, 2H),
6.67 (d, J=8.8 Hz, 2H), 5.12 (s, 1H), 3.17ꢀ2.86 (m, 4H), 2.94
(s, 6H), 2.20ꢀ2.10 (m, 1H), 1.97ꢀ1.82 (m, 1H).
condensation intermediate. DFT calculations support
a
reaction mechanism that starts with the highly thermodynamic
favorable autoxidation of the organolithium dithiane, leading
to formation of the thioester that is further trapped by another
2ꢀlithiumꢀ1,3ꢀdithiane. The herein described process might be
on the basis of the known limitations on the use of 2ꢀlithioꢀ
1,3ꢀdithianes in synthetic chemistry, and it is also a way to
achieve highly functionalized and stable orthothioesters.
EXPERIMENTAL SECTION
General remarks: Reactions were monitored through thinꢀ
layer chromatography (TLC) with commercial silica gel plates
(Merck silica gel, 60 F254). Visualization of the developed
plates was performed under UV lights at 254 nm and by
staining with cerium ammonium molybdate, 2,4ꢀ
dinitrophenylhydrazine and vanillin stains. Flash column
chromatography was performed on silica gel 60 (40ꢀ63 µm) as
stationary phase. Preparative TLCs were conducted on PLC
silica gel 60 F254, 1 mm.1H NMR spectra were recorded at
300 MHz, 13C NMR spectra were recorded at 75 MHz and 19F
spectrum was recorded at 282 MHz in a 300 MHz Varian
Mercury spectrometer, using CDCl3 as solvent. Chemical
shifts (δ) are reported in ppm referenced to the CDCl3 residual
peak (δ 7.26) or TMS peak (δ 0.00) for 1H NMR and to CDCl3
(δ 77.16) for 13C NMR. The following abbreviations were used
to describe peak splitting patterns: s = singlet, d = doublet, t =
triplet, m = multiplet. Coupling constants, J, were reported in
Hertz (Hz). Highꢀresolution mass spectra were recorded on a
Waters ESIꢀTOF MS spectrometer. Tetrahydrofuran (THF)
was dried by distillation under argon with sodium metal and
benzophenone as indicator. Dichloromethane (DCM) was
dried by distillation under argon with calcium hydride. Isotope
labelled oxygenꢀ18 (99% isotopic purity) was purchased from
SigmaꢀAldrich (CAS Number 32767ꢀ18ꢀ3). A small balloon
was filled with oxygenꢀ18 and used directly in the oxidation
reaction.
4c: Prepared according to method A. 89% yield (2.997 g,
13.54 mmol), white crystals. Obtained with same spectral
34
characterization as previously described.
1H NMR (300
MHz, CDCl3): δ ppm 7.65ꢀ7.57 (m, 4H), 5.17 (s, 1H), 3.11ꢀ
3.01 (m, 2H), 2.96ꢀ2.90 (m, 2H), 2.23ꢀ2.15 (m, 1H), 2.01ꢀ1.86
(m, 1H).
4d: Prepared according to method A. 81% yield (3.628 g,
13.18 mmol), white crystals. Obtained with same spectral
34
characterization as previously described.
1H NMR (300
MHz, CDCl3): δ ppm 7.49ꢀ7.44 (m, 2H), 7.37ꢀ7.32 (m, 2H),
5.11 (s, 1H), 3.10ꢀ3.00 (m, 2H), 2.94ꢀ2.86 (m, 2H), 2.22ꢀ2.12
(m, 1H), 1.99ꢀ1.84 ppm (m, 1H).
4e: Prepared according to method A. 76% yield (1.515 g,
7.07 mmol), white crystals. Obtained with same spectral
characterization as previously described.37 1H NMR (300
MHz, CDCl3): δ ppm 7.47ꢀ7.42 (m, 2H), 7.05ꢀ6.99 (m, 2H),
5.14 (s, 1H), 3.10ꢀ3.01 (m, 2H), 2.94ꢀ2.87 (m, 2H), 2.22ꢀ2.13
(m, 1H), 1.99ꢀ1.84 (m, 1H).
4f: Prepared according to method A. 69% yield (1.253 g,
5.96 mmol), white crystals. Obtained with same spectral
34
characterization as previously described.
1H NMR (300
MHz, CDCl3): δ ppm 7.61ꢀ7.57 (m, 1H), 7.24ꢀ7.13 (m, 3H),
5.33 (s, 1H), 3.14ꢀ3.04 (m, 2H), 2.95ꢀ2.88 (m, 2H), 2.45 (s,
3H), 2.23ꢀ2.14 (m, 1H), 2.02ꢀ1.87 (m, 1H).
General procedure for preparation of 2-substituted 1,3-
dithianes (Method A), based on modified previously reported
method.33 Aldehyde (15 mmol,
1
equiv.) and 1,3ꢀ
4g: Prepared according to method A. 88% yield (1.681 g,
5.56 mmol), pale yellow solid. Product was isolated by flash
chromatography (Hex:AcOEt, 95:5). 1H NMR (300 MHz,
CDCl3): δ ppm 7.60 (dd, J=7.6, 1.8 Hz, 1H), 7.47ꢀ7.30 (m,
5H), 7.21 (td, J=7.8, 1.5 Hz, 1H), 7.00 ꢀ6.95 (m, 1H), 6.89 (d,
J=8.2 Hz, 1H), 5.76 (s, 1H), 5.13 (s, 2H), 3.13ꢀ2.85 (m, 2H),
2.92ꢀ2.85 (m, 2H), 2.20ꢀ2.11 (m, 1H), 2.00ꢀ1.85 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ ppm 154.8, 137.2, 129.4, 129.3,
128.7, 128.1, 128.0, 127.3, 121.5, 112.7, 70.6, 44.2, 44.1,
propanedithiol (3mL, 16.5 mmol, 1.1 equiv.) were dissolved in
dichloromethane (50 mL) in a roundꢀbottom flask. Iodine (381
mg, 1.5 mmol, 0.1 equiv.) was slowly added do the stirring
solution as to prevent vigorous boiling of the solvent. The
reaction was quenched with a 2% Na2S2O3 aqueous solution
(10 mL) 30 minutes after complete iodine addition. Upon
separation, the organic layer was washed successively with a
10% aqueous NaOH solution (10 mL), water (10 mL) and
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+
32.5, 25.5. HRꢀMS (ESI) m/z calculated for C17H19OS2
temperature for 24 h. The reaction was quenched with H2O (10
[M+H]+ 303.0872, found 303.0884.
mL) and the layers were separated. The organic layer was
collected and washed with water (10 mL) and Brine (10 mL),
dried over MgSO4, filtered and evaporated. The product was
purified by flash chromatography (Hex:EtOAc, 95:5) to yield
4k in 90% yield (1.056 mg, 2.86 mmol) as a colorless thick oil
with same spectral characterization as previously described.40
1H NMR (300 MHz, CDCl3): δ ppm 6.97 (d, J=1.8 Hz, 1H),
6.92ꢀ6.89 (m, 1H), 6.79ꢀ6.76 (m, 1H), 5.11 (s, 1H), 3.81 (s,
3H), 3.10ꢀ3.01 (m, 2H), 2.93ꢀ2.86 (m, 2H), 2.21ꢀ2.11 (m, 1H),
1.99ꢀ1.84 (m, 1H), 0.98 (s, 9H), 0.14 (s, 6H).
1
2
3
4
5
6
7
8
4h: Prepared according to method A. 76% yield (1.172 g,
4.57 mmol), white crystals. Obtained with same spectral
34
characterization as previously described.
1H NMR (300
MHz, CDCl3): δ ppm 7.15 (dd, J=2.3, 1.2 Hz, 1H), 6.83ꢀ6.76
(m, 2H), 5.67 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.16ꢀ3.06 (m,
2H), 2.93ꢀ2.86 (m, 2H), 2.20ꢀ2.12 (m, 1H), 2.01ꢀ1.86 (m, 1H).
4i: Prepared according to a modified previously reported
method.38 Freshly distilled picolinaldehyde (1 mL, 10.51
mmol, 1 equiv.) and 1,3ꢀpropanedithiol (1.16 mL, 11.56
mmol, 1.1 equiv.) were dissolved in DCE (20 mL). pꢀ
Toluenosulfonic acid (200 mg, 1.05 mmol, 0.1 equiv.) was
added to the mixture and the solution refluxed for 24 hours.
The reaction was cooled to room temperature and quenched
with a 10% aqueous NaOH solution (10 mL). The layers were
separated and the organic phase collected and washed with
water (10 mL) and brine (10 mL). The organic solvent was
dried over MgSO4 and filtered. The solvent was evaporated
and the product isolated by flash chromatography
(Hex:AcOEt, 70:30) to give 4i as a yellow solid in 54% yield
(1.111 g, 5.63 mmol), with same spectral characterization as
previously described.38 1H NMR (300 MHz, CDCl3): δ ppm
8.57 (dd, J=4.4, 1.5 Hz, 1H), 7.67 (td, J=7.6, 1.8 Hz, 1H), 7.46
(d, J=7.6 Hz, 1H), 7.22ꢀ7.18 (m, 1H), 5.35 (s, 1H), 3.11ꢀ2.92
(m, 4H), 2.23ꢀ2.13 (m, 1H), 2.05ꢀ1.90 (m, 1H).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4l: Prepared according to a modified previously reported
method.41 In an argon purged roundꢀbottom flask were added
10 mL of dry DCM, 5 mL of glacial acetic acid, and BF3•OEt2
(2.47 mL, 20 mmol, 1 equiv.). Then, a solution of 1,3ꢀ
propanedithiol (2 mL, 20 mmol, 1 equiv.) and chloromethyl
methyl ether (1.67 mL, 22 mmol, 1.1 equiv.) in 30 mL of dry
DCM was added dropwise for 10 min at room temperature.
The solution was left stirring for 3 hours at room temperature,
and then quenched with 40 mL of water. The layers were
separated and the organic phase collected and washed with
water (40 mL), a 10% aqueous NaOH solution (2 × 40 mL)
and brine (40 mL). The organic solvent was dried over
MgSO4, filtered and evaporated. Sublimation under reduced
pressure gave pure 4l as a white solid in 32% yield (778 mg,
6.47 mmol), with same spectral characterization as previously
described.42 1H NMR (300 MHz, CDCl3): δ ppm 3.78 (s, 2H),
2.84ꢀ2.80 (m, 4H), 2.11ꢀ2.03 (m, 2H).
4-(1,3-Dithian-2-yl)-2-methoxyphenol:
Prepared
according to method A and used in preparation of 4j and 4k.
84% yield (6.723 g, 27.73 mmol), white crystals. Obtained
with same spectral characterization as previously described.39
1H NMR (300 MHz, CDCl3): δ ppm 7.00ꢀ6.84 (m, 2H), 6.87ꢀ
6.84 (m, 1H), 5.64 (s, 1H), 5.11 (s, 1H), 3.90 (s, 3H), 3.10ꢀ
2.87 (m, 2H), 2.93ꢀ2.86 (m, 2H), 2.21ꢀ2.12 (m, 1H), 1.99ꢀ1.84
(m, 1H).
4m: Prepared according to method A. 53% yield (560 mg,
2.66 mmol), pale green solid. 1.2 equiv. of 1,3ꢀpropanedithiol
were used. Obtained with same spectral characterization as
previously described,43 after purification by flash
chromatography (Hex:EtOAc, 85:15). 1H NMR (300 MHz,
CDCl3): δ ppm 7.34ꢀ7.22 (m, 5H), 4.24 (t, J = 7.3 Hz, 1H),
3.02 (d, J = 7.3 Hz, 2H), 2.85ꢀ2.80 (m, 4H), 2.15ꢀ2.05 (m,
1H), 1.92ꢀ1.79 (m, 1H).
4j: 4ꢀ(1,3ꢀDithianꢀ2ꢀyl)ꢀ2ꢀmethoxyphenol (0.5 g, 2.06
mmol, 1 equiv.), imidazole (155 mg, 2.27 mmol, 1.1 equiv.)
and 4ꢀdimethylaminopyridine (25 mg, 0.2 mmol, 0.1 equiv.)
were dissolved in dry DCM (10 mL), in an argon purged
roundꢀbottom flask. Then, tertꢀbutyl(chloro)diphenylsilane
was added dropwise to the stirring solution. The mixture was
left stirring at room temperature for 24 h. The reaction was
quenched with H2O (10 mL) and the layers were separated.
The organic layer was collected and washed with water (10
mL) and Brine (10 mL), dried over MgSO4, filtered and
evaporated. The product was purified by flash chromatography
(Hex:DCM, 1:1) to yield 4j in 93% yield (918 mg, 1.91 mmol)
4n: Prepared according to a modified previously reported
method.35 Butyraldehyde (0.45 mL, 5 mmol, 1 equiv.) and
1,3ꢀpropanedithiol (0.6 mL, 6 mmol, 1.2 equiv.) were
dissolved in 20 mL of dry DCM under argon. The solution
was stirred at room temperature and BF3•OEt2 (0.43 mL, 0.7
mmol, 0.7 equiv.) was added dropwise. After 90 minutes, the
reaction was quenched by washing the reaction mixture twice
with 20 mL of 10% aqueous NaOH. The combined aqueous
layers were then extracted twice with 20 mL of DCM. The
organic layers were combined, washed with 25 mL of brine
and dried over MgSO4. The organic solvent was evaporated
under reduced pressure and the resulting oil was purified by
flash chromatography (hexane/EtOAc 97:3), which afforded
4n as a colorless oil in 99% yield (808 mg, 4.98 mmol).
Obtained with same spectral characterization as previously
described.34 1H NMR (300 MHz, CDCl3): δ ppm 4.05 (t, J=6.7
Hz, 1H), 2.92ꢀ2.76 (m, 4H), 2.14ꢀ2.06 (m, 1H), 1.90ꢀ1.77 (m,
1H), 1.75ꢀ1.67 (m, 2H), 1.59ꢀ1.45 (m, 2H), 0.85ꢀ0.97 (m, 3H).
1
as a colorless thick oil. H NMR (300 MHz, CDCl3): δ ppm
7.69 (dd, J=7.6, 1.8 Hz, 4H), 7.42ꢀ7.31 (m, 6H), 6.89 (d, J=1.8
Hz, 1H), 6.76ꢀ6.73 (m, 1H), 6.55ꢀ6.63 (m, 1H), 5.05 (s, 1H),
3.57 (s, 3H), 3.07ꢀ2.98 (m, 2H), 2.91ꢀ2.83 (m, 2H), 2.18ꢀ
2.09(m, 1H), 1.96ꢀ1.81 (m, 1H), 1.10 ppm (s, 9H). 13C NMR
(75 MHz, CDCl3): δ ppm 150.6, 145.2, 135.5, 133.6, 132.3,
129.7, 127.6, 120.2, 120.0, 111.8, 55.5, 51.5, 32.3, 26.8, 25.2,
19.9. HRꢀMS (ESI) m/z calculated for C27H33O2S2Si+ [M+H]+
481.1686, found 481.1687.
4o: Prepared according to a modified previously reported
method.44 Pivalaldehyde (5 mmol,
1 equiv.) and Nꢀ
4k: 4ꢀ(1,3ꢀDithianꢀ2ꢀyl)ꢀ2ꢀmethoxyphenol (0.8 g, 3.30
mmol, 1 equiv.), imidazole (270 mg, 3.96 mmol, 1.2 equiv.)
and 4ꢀdimethylaminopyridine (42 mg, 0.34 mmol, 0.1 equiv.)
were dissolved in dry DCM (10 mL), in an argon purged
roundꢀbottom flask. Then, tertꢀbutyldimethylsilyl chloride
(597 mg, 3.96 mmol, 1.2 equiv.) was added dropwise to the
stirring solution. The mixture was left stirring at room
bromosuccinimide (178 mg, 1 mmol, 0.2 equiv.) were
dissolved in CH2Cl2 (25 ml). The solution was then stirred
under argon at r.t. and 1,3ꢀpropanedithiol (1.2 equiv.) was
added dropwise. The reaction was monitored by TLC and
quenched with 10% aqueous NaOH (25 ml) when the
aldehyde was consumed (30ꢀ80 min). Aqueous and organic
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The Journal of Organic Chemistry
separated and the organic layer collected and washed
layers were separated and the aqueous layer was washed with
1
2
3
4
5
6
7
8
CH2Cl2 (2 x 25 ml). The combined organic layers were
washed with 25 ml brine, dried over MgSO4, filtered and
concentrated under reduced pressure. 62% yield (544 mg, 3.08
mmol), white solid was obtained with same spectral
characterization as previously described.34 1H NMR (300
MHz, CDCl3): δ ppm 3.99 (s, 1H), 2.90ꢀ2.86 (m, 4H), 2.11ꢀ
2.02 (m, 1H), 1.86ꢀ1.74 (m, 1H), 1.10 (s, 9H).
successively with a 10% aqueous NaOH solution (10 mL),
water (10 mL) and brine (10 mL). The organic solvent was
dried over MgSO4 and filtered. After evaporating the solvent,
the product was purified by flash chromatography (hexane) to
give 6c as a white amorphous solid in 57% yield (5.563 g,
11.29 mmol). 1H NMR (300 MHz, CDCl3): δ ppm 7.45ꢀ7.42
(m, 2H), 7.35ꢀ7.22 (m, 3H), 4.86 (s, 1H), 2.62ꢀ2.45 (m, 4H),
1.59ꢀ1.49 (m, 4H), 1.35ꢀ1.24 (m, 36H), 0.90ꢀ0.86 (m, 6H). 13
C
4p: Prepared according to method A. Flash chromatography
NMR (CDCl3, 75MHz) δ ppm 140.8, 128.6, 127.9, 127.8,
53.3, 32.4, 32.1, 29.8, 29.7, 29.6, 29.5, 29.3, 29.3, 29.0, 22.8,
gradient eluent: Hex:AcOEt (85:15 to 60:40). 33% yield (433
9
1
mg, 1.64 mmol), colorless oil. H NMR (300 MHz, CDCl3): δ
14.3. HRꢀMS (ESI) m/z calculated for C31H55S2 [MꢀH]+
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ppm 4.17ꢀ4.17 (m, 1H), 3.85 (d, J=6.4 Hz, 2H), 2.90ꢀ2.75 (m,
4H), 2.15ꢀ2.06 (m, 1H), 1.96ꢀ1.85 (m, 1H), 0.90 (s, 9H), 0.09
(s, 6H). 13C NMR (75 MHz, CDCl3): δ ppm 66.1, 48.6, 29.1,
26.2, 26.0, 18.6, ꢀ5.2. HRꢀMS (ESI) m/z calculated for
C11H24OS2SiNa+ [M+Na]+ 287.0930, found 287.0953.
491.3740, found 491.3757.
6d: Prepared according to method B. 86% yield (1.150 g,
4.29 mmol), colorless oil. Flash chromatography eluent:
Hex:AcOEt (97.5:2.5). 1H NMR (300 MHz, CDCl3): δ ppm
7.47 (d, J = 7.6 Hz, 2H), 7.34ꢀ7.22 (m, 3H), 4.94 (s, 1H), 2.88ꢀ
2.63 (m, 2H), 1.66ꢀ1.42 (m, 4H), 1.24ꢀ1.20 (m, 6H), 0.97ꢀ0.88
(m, 6H). 13C NMR (75 MHz, CDCl3): δ ppm 141.1, 128.5,
127.8, 127.7, 50.8, 50.6, 42.5, 42.4, 29.5, 29.5, 20.7, 20.6,
General procedure for preparation of dithioacetals 6
(Method B), based on modified previously reported method. 44
Aldehyde (5 mmol, 1 equiv.) and Nꢀbromosuccinimide (178
mg, 1 mmol, 0.2 equiv.) were dissolved in CH2Cl2 (25 ml).
The solution was then stirred under argon at r.t. and thiol (2.5
equiv.) was added dropwise. The reaction was monitored by
TLC and quenched with 10% aqueous NaOH (25 ml) when
the aldehyde was consumed (30ꢀ80 min). Aqueous and
organic layers were separated and the aqueous layer was
washed with CH2Cl2 (2 x 25 ml). The combined organic layers
were washed with 25 ml brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was
then purified by recrystallization or by flash chromatography.
+
20.6, 11.2, 11.1. HRꢀMS (ESI) m/z calculated for C15H23S2
[MꢀH]+ 267.1236, found 267.1243.
6e: Prepared according to method B. 87% yield (1.171 g,
4.37 mmol), white solid. Flash chromatography eluent:
Hex:AcOEt (97.5:2.5). 1H NMR (300 MHz, CDCl3): δ ppm
7.48ꢀ7.44 (m, 2H), 7.32ꢀ7.26 (m, 2H), 7.23ꢀ7.18 (m, J = 1.3
Hz, 1H), 5.02 (s, 1H), 1.29 (s, 18H). 13C NMR (75 MHz,
CDCl3): δ ppm 144.1, 128.7, 127.7, 127.4, 48.8, 45.8, 31.3.
+
HRꢀMS (ESI) m/z calculated for C15H23S2 [MꢀH]+ 267.1236,
found 267.1243.
6a: Prepared according to a modified previously reported
method.33 Benzaldehyde (0.51 ml, 5 mmol, 1 equiv.) and
benzenethiol (1.08 ml, 10.5 mmol, 2.1 equiv.) were dissolved
in CHCl3 (25 ml). The solution was then stirred at r.t. and I2
(0.13 g, 0.5 mmol, 0.1 equiv.) was added. The reaction was
monitored by TLC. When the aldehyde was consumed (30
min) the reaction was quenched with aqueous Na2S2O3 (0.1 M,
25 ml) and then washed twice with 10% aqueous NaOH (25
ml). Aqueous and organic layers were separated and the
aqueous layer was washed with CHCl3 (25 ml). The combined
organic layers were washed with 20 ml of H2O, dried over
MgSO4, filtered and concentrated under reduced pressure to
yield the crude product. The crude product was then purified
by recrystallization from hexane to afford 6a as white crystals
in 66% yield (1.01 g, 3.28 mmol) with the same spectral
characterization as previously described.45 1H NMR (300
MHz, CDCl3): δ ppm 7.39ꢀ7.20 (m, 15H), 5.42 (s, 1H).
12: Prepared according to a modified previously reported
method.46 Benzil (1g, 4.76 mmol, 1.2 equiv.) was dissolved in
dry DCM (5 mL) in an argon purged roundꢀbottom flask. The
solution was cooled to 0ᵒC in an ice bath bath. A solution of
1,3ꢀpropanedithiol (398 µL, 3.96 mmol, 1 equiv.) and
BF3•Et2O (489 µL, 3.96 mmol, 1 equiv.) in dry DCM (1.5 mL)
was added dropwise at 0 ᵒC. The solution was warmed to room
temperature for 3 hours and quenched with 10 mL of a
saturated aqueous NaHCO3 solution. The layers were
separated and the organic phase collected. The aqueous phase
was extracted with DCM (3 × 10 mL) and the organic phases
combined, dried over MgSO4, filtered and the solvent
evaporated. The dry crude was dissolved in hot isopropanol
and left cooling at room temperature. After 3 hours, the
product precipitated as a white solid and was filtered and
washed with cold isopropanol to yield 12 as a white solid in
54% yield (641 mg, 2.13 mmol). 1H NMR (300 MHz, CDCl3):
δ ppm 7.69ꢀ7.66 (m, 2H), 7.57 (dd, J=7.9, 1.5 Hz, 2H), 7.38ꢀ
7.28 (m, 4H), 7.22ꢀ7.17 (m, 2H), 3.26 (ddd, J=14.4, 12.0, 2.9
Hz, 2H), 2.80ꢀ2.73 (m, 2H), 2.17ꢀ2.08 (m, 1H), 2.01ꢀ1.86 (m,
1H). 13C NMR (300 MHz, CDCl3): δ ppm 192.8, 139.0, 134.5,
132.2, 130.8, 129.2, 128.8, 127.7, 127.5, 63.5, 29.3, 24.1. HRꢀ
6b: Prepared according to method B. Flash chromatography
eluent: Hex:AcOEt (97.5:2.5). 91% yield (1.218 g, 4.54
mmol), colorless oil. 1H NMR (300 MHz, CDCl3): δ ppm
7.45ꢀ7.42 (m, 2H), 7.34ꢀ7.22 (m, 3H), 4.87 (s, 1H), 2.63ꢀ2.46
(m, 4H), 1.58ꢀ1.48 (m, 4H), 1.42ꢀ1.30 (m, 4H), 0.87 (t, J = 7.3
Hz, 6H). 13C NMR (75 MHz, CDCl3): δ ppm 140.7, 128.5,
127.8, 127.8, 53.3, 32.0, 31.3, 22.1, 13.7. HRꢀMS (ESI) m/z
calculated for C15H23S2+ [MꢀH]+ 267.1236, found 267.1246.
MS (ESI) m/z calculated for C17H17OS2 [M+H]+ 301.0715,
+
found 301.0734.
General procedure for autooxidative addition of
dithianes 4a-c and 4e-k: Dithiane (1.02 mmol, 1 equiv.) was
dissolved in dry THF (5 mL) in an argon purged roundꢀbottom
flask. The solution was cooled to ꢀ78 ᵒC in an acetone/liquid
nitrogen bath. n-BuLi (1.3 equiv.) solution in hexanes was
added dropwise to the reaction mixture at ꢀ78 ᵒC. The solution
was left stirring at ꢀ78 ᵒC for 20 minutes and then left to warm
up to room temperature for 40 minutes. The argon balloon was
6c: Prepared according to a modified previously reported
method.33 Benzaldehyde (2 mL, 19.7 mmol, 1 equiv.) and
dodecanethiol (10.4mL, 43.3 mmol, 2.2 equiv.) were dissolved
in dichloromethane (30 mL) in a roundꢀbottom flask. Then,
iodine (508, 2 mmol, 0.1 equiv.) was slowly added do the
stirring solution as to prevent vigorous boiling of the solvent.
After 2 hours of complete addition, the reaction was quenched
with a 2% Na2S2O3 aqueous solution (10 mL). The layers were
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4H), 2.37 (s, 3H), 2.33 (s, 3H), 2.15ꢀ2.04 (m, 1H), 1.98ꢀ1.84
(m, 1H), 1.74ꢀ1.64 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
ppm 199.0, 138.7, 138.4, 138.0, 137.7, 136.1, 134.2, 133.8,
131.9, 131.2, 130.9, 129.2, 129.0, 128.4, 128.1, 127.6, 126.7,
125.6, 125.5, 64.9, 54.7, 32.8, 31.1, 29.2, 28.6, 24.3, 23.6,
20.8, 19.8. HRꢀMS (ESI) m/z calculated for C30H34OS4Na+
[M+Na]+ 561.1385, found 561.1389.
1
2
3
4
5
6
7
8
needle was inserted in the septum as to allow air flow through
the surface of the solution. As oxidation took place the
solution warmed up and color change was usually observed.
After 1 minute the solution was quenched with 10 mL of a
saturated aqueous NH4Cl solution. 10 mL of Et2O were added
and the layers were separated. The organic phase was
collected and the aqueous phase was extracted two times with
Et2O (2 × 10 mL). The organic phases were combined and
dried over MgSO4. The solvent was filtered and evaporated.
The product was purified by flash chromatography.
5g: 58% yield (324 mg, 0.40 mmol), pale yellow oil. Flash
chromatography eluent: Hex:AcOEt (80:20). 1H NMR (300
MHz, CDCl3): δ ppm 7.87ꢀ7.85 (m, 1H), 7.59 (d, J=7.6 Hz,
2H), 7.43 (dt, J=7.6, 2.1 Hz, 2H), 7.36ꢀ7.13 (m, 16H), 6.94ꢀ
6.76 (m, 6H), 6.12 (s, 1H), 5.17 (s, 2H), 4.95ꢀ4.79 (m, 4H),
3.32ꢀ3.24 (m, 2H), 2.71ꢀ2.64 (m, 2H), 2.40ꢀ2.30 (m, 4H),
2.07ꢀ1.96 (m, 1H), 1.94ꢀ1.80 (m, 1H), 1.56ꢀ1.46 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ ppm 198.0, 157.1, 156.8, 156.0,
137.5, 136.9, 136.4, 132.8, 130.8, 130.3, 129.8, 129.6, 129.4,
128.8, 128.7, 128.6, 128.6, 128.4, 128.1, 127.9, 127.5, 127.5,
127.3, 127.2, 125.7, 121.0, 120.8, 120.5, 114.8, 112.7, 111.8,
71.0, 70.4, 70.2, 63.1, 52.5, 32.9, 31.0, 28.9, 28.5, 24.3. HRꢀ
MS (ESI) m/z calculated for C48H46O4S4Na+ [M+Na]+
837.2171, found 837.2196.
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5a: 76% yield (128 mg, 0.26 mmol), pale yellow oil. Flash
1
chromatography eluent: Hex:AcOEt (90:10). H NMR (300
MHz, CDCl3): δ ppm 7.96 ꢀ 7.90 (m, 4 H) 7.54 ꢀ 7.23 (m, 11
H) 5.51 (s, 1 H) 3.30 (ddt, J=13.8, 10.8, 2.9, 2.9 Hz, 2 H) 2.75
ꢀ 2.68 (m, 2 H) 2.57 ꢀ 2.44 (m, 4 H) 2.15 ꢀ 2.04 (m, 1 H) 1.96 ꢀ
1.83 (m, 1 H) 1.76ꢀ1.66 (m, 2 H). 13C NMR (75 MHz, CDCl3):
δ ppm 195.1, 141.6, 136.7, 135.8, 133.4, 129.1, 129.0, 128.9,
128.8, 128.6, 128.5, 128.1, 128.0, 64.3, 55.6, 32.7, 30.6, 29.2,
28.4, 24.4. HRꢀMS (ESI) m/z calculated for C27H28OS4Na+
[M+Na]+ 519.0915, found 519.0894.
5b: 64% yield (135 mg, 0.22 mmol), amorphous yellow
solid. Flash chromatography eluent: Hex:AcOEt (60:40). H
5h: 68% yield (157 mg, 0.23 mmol), colorless oil. Flash
chromatography eluent: Hex:AcOEt (80:20). H NMR (300
1
1
NMR (300 MHz, CDCl3): δ ppm 7.90ꢀ7.87 (m, 2H), 7.79ꢀ7.76
(m, 2H), 7.30ꢀ7.26 (m, 2H), 6.67ꢀ6.56 (m, 6H), 5.47 (s, 1H),
3.36ꢀ3.26 (m, 2H), 3.01 (s, 6H), 2.95 (s, 6H), 2.90 (s, 6H),
2.72ꢀ2.67 (m, 2H), 2.59ꢀ2.45 (m, 4H), 2.12ꢀ2.03 (m, 1H),
1.94ꢀ1.84 (m, 1H), 1.81ꢀ1.71 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ ppm 193.5, 153.4, 150.2, 150.0, 131.3, 129.5,
129.0, 128.4, 124.9, 123.6, 112.7, 111.9, 110.7, 64.4, 54.9,
40.6, 40.5, 40.1, 32.9, 30.6, 29.4, 28.7, 24.5. HRꢀMS (ESI)
m/z calculated for C33H43N3OS4Na+ [M+Na]+ 648.2181, found
648.2187.
MHz, CDCl3): δ ppm 7.45 (d, J=2.9 Hz, 1H), 7.13 (d, J=3.5
Hz, 1H), 6.99 (t, J=1.5 Hz, 1H), 6.95ꢀ6.78 (m, 4H), 6.71 (d,
J=1.8 Hz, 2H), 6.03 (s, 1H), 3.82 (s, 3H), 3.76 (s, 6H), 3.73 (s,
3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.36ꢀ3.26 (m, 2H), 2.74ꢀ2.68
(m, 2H), 2.54ꢀ2.49 (m, 4H), 2.10ꢀ2.01 (m, 1H), 1.96ꢀ1.83 (m,
1H), 1.75ꢀ1.65 ppm (m, 2H). 13C NMR (75 MHz, CDCl3): δ
ppm 197.4, 153.7, 153.4, 153.2, 152.6, 152.4, 151.1, 130.7,
128.2, 126.7, 119.5, 116.0, 115.6, 115.6, 114.8, 114.2, 113.8,
113.0, 111.8, 62.5, 57.6, 56.2, 55.9, 55.8, 55.8, 52.1, 32.9,
30.9, 29.0, 28.6, 24.4. HRꢀMS (ESI) m/z calculated for
C33H40O7S4Na+ [M+Na]+ 699.1549, found 699.1572.
5c: 60% yield (232 mg, 0.41 mmol), amorphous white solid.
1
Flash chromatography eluent: Hex:AcOEt (70:30). H NMR
5i: 62% yield (63 mg, 0.13 mmol), yellow oil. Flash
chromatography was run with eluent Hex:AcOEt:Et3N
(50:50:2) because the compound was unstable on silica
without treatment with triethylamine. 1H NMR (300 MHz,
CDCl3): δ ppm 8.65ꢀ8.61 (m, 1H), 8.52ꢀ8.45 (m, 2H), 8.10ꢀ
8.07 (m, 1H), 7.85ꢀ7.78 (m, 2H), 7.70ꢀ7.66 (m, 3H), 7.49ꢀ7.41
(m, 1H), 7.19ꢀ7.11 (m, 2H), 6.39 (s, 1H), 3.46ꢀ3.34 (m, 2H),
2.75ꢀ2.68 (m, 2H), 2.64ꢀ2.49 (m, 2H), 2.42 (t, J=7.3 Hz, 2H),
2.18ꢀ2.10 (m, 1H), 1.95ꢀ1.81 (m, 1H), 1.61ꢀ1.51 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ ppm 195.4, 161.0, 157.8, 152.3,
149.2, 149.1, 148.0, 137.1, 137.1, 136.8, 127.4, 124.0, 123.2,
123.2, 122.3, 122.2, 65.9, 53.2, 32.7, 31.2, 28.3, 28.2, 24.9.
HRꢀMS (ESI) m/z calculated for C24H25N3OS4Na+ [M+Na]+
522.0773, found 522.0806.
(300 MHz, CDCl3): δ ppm 8.05 – 8.02 (m, 4H), 7.75 (d, J=8.8
Hz, 2H), 7.67 ꢀ 7.56 (m, 6H), 5.43 (s, 1H), 3.20 (tdd, J=2.3,
9.9, 14.1 Hz, 2H), 2.73 (ddd, J=2.9, 6.9, 14.2 Hz, 2H), 2.60ꢀ
2.44 (m, 4H), 2.12 ꢀ 2.02 (m, 1H), 1.97 ꢀ 1.84 (m, 1H), 1.73ꢀ
1.64 (m, 2H). 13C NMR (75 MHz, CDCl3): δ ppm 192.3,
146.8, 141.1, 138.4, 132.7, 132.4, 129.8, 129.4, 129.0, 118.5,
118.3, 117.7, 117.1, 112.4, 112.3, 63.5, 54.2, 32.4, 30.8, 29.3,
28.1, 23.9. HRꢀMS (ESI) m/z calculated for C30H25N3OS4Na+
[M+Na]+ 594.0773, found 594.0773.
5e: 60% yield (112 mg, 20 mmol), colorless oil. Flash
chromatography eluent: Hex:AcOEt (94:6). 1H NMR (300
MHz, CDCl3): δ ppm 8.00ꢀ7.88 (m, 4H), 7.42ꢀ7.38 (m, 2H),
7.12ꢀ7.00 (m, 6H), 5.44 (s, 1H), 3.26 (ddt, J=13.8, 10.9, 2.6
Hz, 2H), 2.76ꢀ2.68 (m, 2H), 2.57ꢀ2.46 (m, 4H), 2.13ꢀ2.04 (m,
1H), 1.96ꢀ1.82 (m, 1H), 1.76ꢀ1.66 (m, 2H). 19F NMR
(282MHz, CDCl3): δ ppm ꢀ104.01ꢀꢀ104.09 (m, 1F), ꢀ113.35ꢀꢀ
113.45 (m, 1F), ꢀ113.56ꢀꢀ113.66 ppm (m, 1F). 13C NMR (75
MHz, CDCl3): δ ppm 193.3, 167.6, 164.2, 164.2, 160.9, 137.4,
137.4, 132.3, 132.2, 131.9, 131.9, 131.8, 131.7, 130.6, 130.5,
130.1, 130.0, 116.2, 115.9, 115.5, 115.2, 63.6, 54.4, 32.7,
30.7, 29.3, 28.3, 24.2. HRꢀMS (ESI) m/z calculated for
C27H25F3OS4Na+ [M+Na]+ 573.0633, found 573.0640.
5j: 89% yield (239 mg, 0.19 mmol), amorphous white solid.
1
Flash chromatography eluent: Hex:AcOEt (80:20). H NMR
(300 MHz, CDCl3): δ ppm 7.69ꢀ7.61 (m, 12H), 7.41ꢀ7.15 (m,
22H), 6.79 (s, 1H), 6.66ꢀ6.59 (m, 4H), 5.28 (s, 1H), 3.53 (s,
3H), 3.52 (s, 3H), 3.47 (s, 3H), 3.24ꢀ3.15 (m, 2H), 2.63 (dt,
J=14.1, 2.9 Hz, 2H), 2.45ꢀ2.32 (m, 4H), 2.06ꢀ1.96 (m, 1H),
1.87ꢀ1.75 (m, 1H), 1.63ꢀ1.54 (m, 2H), 1.10ꢀ1.08 ppm (m,
27H). 13C NMR (75 MHz, CDCl3): δ ppm 194.2, 151.1, 150.7,
150.4, 150.0, 145.2, 144.9, 135.5, 135.3, 134.5, 133.5, 133.5,
133.0, 130.2, 130.0, 129.7, 129.7, 129.6, 127.8, 127.6, 127.5,
123.0, 121.1, 120.2, 120.2, 119.7, 119.5, 112.4, 112.3, 112.2,
64.1, 55.5, 55.5, 55.4, 32.7, 30.5, 29.3, 28.4, 26.8, 26.7, 26.6,
24.4, 19.9, 19.9, 19.9. HRꢀMS (ESI) m/z calculated for
C78H88O7S4Si3Na+ [M+Na]+ 1371.4613, found 1371.4641.
5f: 66% yield (120 mg, 0.22 mmol), colorless oil. Flash
chromatography eluent: Hex:AcOEt (95:5). 1H NMR (300
MHz, CDCl3): δ ppm 7.97ꢀ7.94 (m, 1H), 7.42 (d, J=5.9 Hz,
2H), 7.32ꢀ7.27 (m, 1H), 7.19ꢀ7.12 (m, 8H), 5.52 (s, 1H), 3.40ꢀ
3.30 (m, 2H), 2.83 (s, 3H), 2.75ꢀ2.68 (m, 2H), 2.55ꢀ2.48 (m,
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The Journal of Organic Chemistry
5k: 61% yield (148 mg, 0.15 mmol), amorphous white
7.38ꢀ7.17 (m, 12H), 5.85 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ ppm 194.8, 136.6, 135.6, 134.1, 133.4, 133.1, 129.0, 128.9,
128.8, 128.7, 128.1, 128.0, 60.4. HRꢀMS (ESI) m/z calculated
for C20H17OS+ [M+H]+ 305.0995, found 305.1013. The
corresponding orthothioester product, 8a could not be isolated
due to low polarity and structural similarity to 6a. However,
the following characteristic peaks for the 8a can be observed
from the NMR spectrum of a mixture with the dithioacetal. 8a:
1H NMR (300 MHz, CDCl3): 7.69ꢀ7.64 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ ppm 139.4, 132.9, 128.8, 128.4, 128.3,
128.0, 127.9, 77.0.
solid. Flash chromatography eluent: Hex:DCM (1:1). 1H NMR
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2
3
4
5
6
7
8
1
(300 MHz, CDCl3): δ ppm H NMR (CDCl3, 300MHz): d =
7.49ꢀ7.45 (m, 3H), 7.37ꢀ7.34 (m, 1H), 6.96 (d, J=2.3 Hz, 1H),
6.85ꢀ6.74 (m, 4H), 5.43 (s, 1H), 3.80 (s, 6H), 3.77 (s, 3H),
3.33ꢀ3.24 (m, 2H), 2.74ꢀ2.67 (m, 2H), 2.58ꢀ2.44 (m, 4H),
2.12ꢀ2.05 (m, 1H), 1.94ꢀ1.82 (m, 1H), 1.74ꢀ1.65 (m, 2H), 0.98
(s, 9H), 0.97 (s, 9H), 0.96 (s, 9H), 0.15ꢀ0.11 (m, 18H) 13C
NMR (75 MHz, CDCl3): δ ppm 194.2, 151.4, 151.1, 150.8,
150.3, 145.2, 144.9, 134.7, 130.3, 129.8, 123.3, 121.5, 120.8,
120.5, 120.4, 120.3, 112.3, 112.2, 112.1, 64.2, 55.7, 55.6,
55.5, 55.3, 32.8, 30.7, 29.4, 28.5, 25.8, 25.7, 24.5, 18.6, 18.5, ꢀ
4.4, ꢀ4.5. HRꢀMS (ESI) m/z calculated for C48H76O7S4Si3Na+
[M+Na]+ 999.3679, found 999.3645.
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7b: 97% yield (92 mg, 0.32 mmol), white solid. Flash
1
chromatography eluent: Hex:AcOEt (95:5). H NMR (300
MHz, CDCl3): δ ppm 7.99ꢀ7.96 (m, 2H), 7.53ꢀ7.23 (m, 8H),
5.55 (s, 1H), 2.56ꢀ2.42 (m, 2H), 1.58ꢀ1.48 (m, 2H), 1.41ꢀ1.29
(m, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ ppm 195.3, 136.9, 135.9, 133.3, 129.0, 128.9, 128.9, 128.7,
128.0, 55.5, 31.3, 31.2, 22.1, 13.7. HRꢀMS (ESI) m/z
calculated for C18H21OS+ [M+H]+ 285.1308, found 285.1328.
5d: Dithiane 4d (281 mg, 1.02 mmol, 1 equiv.) was
dissolved in dry THF (5 mL) in an argon purged roundꢀbottom
flask. The solution was cooled to ꢀ78ᵒC in an acetone/liquid
nitrogen bath. LDA (0.85mL of a 1.5 M solution, 1.3 equiv.)
solution in hexanes was added dropwise to the reaction
mixture at ꢀ78 ᵒC. The solution was left stirring at ꢀ78 ᵒC for
20 minutes and then left to warm up to room temperature for
40 minutes. The argon balloon was replaced with an
atmospheric air balloon and an additional needle was inserted
in the septum as to allow air flow through the surface of the
solution. As oxidation took place the solution warmed up and
color change was observed. After 1 minute the solution was
quenched with 10 mL of a saturated aqueous NH4Cl solution.
The aqueous layer was extracted three times with Et2O (3 × 10
mL). The organic phases were combined and dried over
MgSO4. The solvent was evaporated and the product purified
by flash chromatography (eluent Hex:AcOEt, 90:10) to afford
the desired compound 5d in 51% yield (127 mg, 0.17 mmol)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ ppm 7.83ꢀ
7.77 (m, 4H), 7.59ꢀ7.54 (m, 2H), 7.50ꢀ7.44 (m, 4H), 7.32ꢀ7.26
(m, 2H), 5.37 (s, 1H), 3.29ꢀ3.19 (m, 2H), 2.75ꢀ2.69 (m, 2H),
2.59ꢀ2.45 (m, 4H), 2.13ꢀ2.03 (m, 1H), 1.96ꢀ1.82 (m, 1H),
1.76ꢀ1.66 (m, 2H). 13C NMR (75 MHz, CDCl3): δ ppm 193.5,
140.7, 135.4, 134.2, 132.2, 132.2, 131.7, 130.6, 130.5, 129.9,
128.9, 122.7, 122.4, 63.7, 54.5, 32.6, 30.7, 29.3, 28.3, 24.2.
8b: 72% yield (86 mg, 0.24 mmol), colorless oil. Flash
chromatography eluent: Hex:AcOEt (95:5). 1H NMR (300
MHz, CDCl3): δ ppm 7.87ꢀ7.84 (m, 2H), 7.35ꢀ7.21 (m, 3H),
2.58 (t, J = 7.3 Hz, 6H), 1.51ꢀ1.29 (m, 12H), 0.88ꢀ0.83 (m,
9H). 13C NMR (75 MHz, CDCl3): δ ppm 141.8, 131.3, 127.9,
127.6, 73.5, 31.5, 30.5, 22.3, 13.7. HRꢀMS (ESI) m/z
calculated for C15H23S2 [MꢀS(CH2)3CH3]+ 267.1236, found
+
267.1255.
7c: 73% yield (99 mg, 0.25 mmol), pale yellow solid. Flash
chromatography gradient eluent: Hex:Toluene (80:20 to
1
50:50). H NMR (300 MHz, CDCl3): δ ppm 7.99ꢀ7.96 (m,
2H), 7.54ꢀ7.23 (m, 8H), 5.55 (s, 1H), 2.55ꢀ2.41 (m, 2H), 1.59ꢀ
1.49 (m, 2H), 1.30ꢀ1.22 (m, 18H), 0.90ꢀ0.86 (m, 3H). 13C
NMR (75 MHz, CDCl3): δ ppm 195.3, 136.9, 136.0, 133.3,
129.1, 129.0, 128.9, 128.7, 128.0, 55.6, 32.1, 31.6, 29.8, 29.7,
29.6, 29.5, 29.3, 29.2, 29.0, 22.8, 14.3. HRꢀMS (ESI) m/z
calculated for C26H37OS+ [M+H]+ 397.2560, found 397.2591.
8c: 56% yield (131 mg, 0.19 mmol), white solid. Flash
chromatography eluent: Hexane (100%). 1H NMR (300 MHz,
CDCl3): δ ppm 7.87 ꢀ7.84 (m, 2H), 7.35ꢀ7.21 (m, 3H), 2.57 (t,
J=7.3 Hz, 6H), 1.54ꢀ1.44 (m, 6H), 1.31ꢀ1.24 (m, 54H), 0.90ꢀ
0.86 (m, 9H). 13C NMR (75 MHz, CDCl3): δ ppm 142.1,
128.1, 127.8, 73.7, 32.1, 32.0, 29.8, 29.8, 29.6, 29.5, 29.4,
29.3, 28.6, 22.9, 14.3. HRꢀMS (ESI) m/z calculated for
C31H55S2+ [MꢀS(CH2)11CH3]+ 491.3740, found 491.3737.
ꢀ
HRꢀMS (ESI) m/z calculated for C27H24Br3OS4 [MꢀH]ꢀ
728.8266, found 728.8265.
General procedure for autooxidative addition of
dithioacetals 6a-6d: Dithioacetal 6 (1.02 mmol, 1 equiv.) was
dissolved in dry THF (5 mL) in an argon purged roundꢀbottom
flask. The solution was cooled to ꢀ78 ᵒC in an acetone/liquid
nitrogen bath. nꢀBuLi (1.3 equiv.) solution in hexanes was
added dropwise to the reaction mixture at ꢀ78 ᵒC. The solution
was left stirring at ꢀ78 ᵒC for 20 minutes and then left to warm
up to room temperature for 40 minutes. The argon balloon was
replaced with an atmospheric air balloon and an additional
needle was inserted in the septum as to allow air flow through
the surface of the solution. After 1 minute the solution was
quenched with 10 mL of a saturated aqueous NH4Cl solution.
10 mL of Et2O were added and the layers were separated. The
organic phase was collected and the aqueous phase was
extracted two times with Et2O (2 × 10 mL). The organic
phases were combined and dried over MgSO4. The solvent
was filtered and evaporated. Products 7 and 8 were obtained
after purification by flash chromatography.
7d: 67% yield (63 mg, 0.22 mmol), pale yellow solid. 1:1
mixture of diastereomers. Flash chromatography eluent:
Hex:AcOEt (95:5). 1H NMR (300 MHz, CDCl3): δ ppm 8.01ꢀ
7.97 (m, 4H), 7.54ꢀ7.23 (m, 16H), 5.61 (s, 2H), 2.75ꢀ2.61 (m,
2H), 1.72ꢀ1.42 (m, 4H), 1.30 (d, J = 6.4 Hz, 3H), 1.19 (d, J =
7.0 Hz, 3H), 0.98ꢀ0.86 (m, 6H). 13C NMR (75 MHz, CDCl3): δ
ppm 195.5, 195.4, 137.2, 135.9, 133.3, 129.0, 128.9, 128.9,
128.7, 127.9, 54.7, 54.6, 42.1, 41.9, 29.7, 29.7, 21.0, 20.6,
11.3, 11.2. HRꢀMS (ESI) m/z calculated for C18H21OS+
[M+H]+ 285.1308, found 285.1303. The corresponding
orthothioester product 8d could not be isolated due to low
polarity and structural similarity to 6d. However, the
following characteristic peaks for 8d can be observed in NMR
spectrum of the crude reaction mixture: 8d:13C NMR (75
MHz, CDCl3): δ ppm 69.3, 29.0 20.1, 11.5.
7a: 48% yield (97 mg, 0.32 mmol), white solid. Flash
1
9: Dithioacetal 6e (0.5 mmol, 1 equiv.) was dissolved in dry
THF (2.5 mL) in an argon purged roundꢀbottom flask. The
solution was cooled to ꢀ78 ᵒC in an acetone/liquid nitrogen
chromatography eluent: Hex:AcOEt (97.5:2.5). H NMR (300
MHz, CDCl3): δ ppm 7.94ꢀ7.90 (m, 2H), 7.49ꢀ7.44 (m, 1H),
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The Journal of Organic Chemistry
Page 10 of 13
bath. n-BuLi (1.3 equiv.) solution in hexanes was added
Hz, 2H), 1.20 (s, 18H). 13C NMR (75 MHz, CDCl3): δ ppm
206.6, 46.5, 29.7, 27.5, 27.5. HRꢀMS (ESI) m/z calculated for
C13H25O2S2+ [M+H]+ 277.1290, found 277.1323.
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5
6
7
8
dropwise to the reaction mixture at ꢀ78 ᵒC. The solution was
left stirring at ꢀ78 ᵒC for 20 minutes and then left to warm up
to room temperature for 40 minutes. The argon balloon was
replaced with an atmospheric air balloon and an additional
needle was inserted in the septum as to allow air flow through
the surface of the solution. After 1 minute the solution was
quenched with 5 mL of a saturated aqueous NH4Cl solution. 5
mL of Et2O were added and the layers were separated. The
organic phase was collected and the aqueous phase was
extracted two times with Et2O (2 × 5 mL). The organic phases
were combined and dried over MgSO4. The solvent was
evaporated and the product was purified by preparative TLC
(eluent: pentane) to yield 9 as a colorless oil (62%, 60 mg,
0.31 mmol) with the same spectral characterization as
previously described.47 1H NMR (300 MHz, CDCl3): δ ppm
7.93ꢀ7.90 (m, 2H), 7.56ꢀ7.51 (m, J = 7.3 Hz, 1H), 7.44ꢀ7.39
(m, 2H), 1.58 (s, 9H).
10p: 31% yield (44 mg, 0.13 mmol), colorless oil. Flash
chromatography gradient eluent: Hex:DCM (85:15 to 60:40).
1H NMR (300 MHz, CDCl3): δ ppm 3.02ꢀ2.92 (m, 2H), 2.67ꢀ
2.57 (m, 4H), 2.07ꢀ2.01 (m, 1H), 1.97ꢀ1.92 (m, 2H), 1.87ꢀ1.71
(m, 1H), 1.66ꢀ1.57 (m, 2H), 1.42ꢀ1.28 (m, 10H), 0.90ꢀ0.83 (m,
6H). 13C NMR (75 MHz, CDCl3): δ ppm 204.5, 61.5, 38.5,
35.8, 32.1, 31.6, 27.9, 25.0, 24.7, 24.1, 22.6, 22.3, 14.1, 14.0.
2ꢀ(nꢀhexyl)ꢀ1,3ꢀdithiane was isolated in 23% yield (44 mg, 23
mmol), colorless oil with same spectral characterization as
previously described:48 1H NMR (300 MHz, CDCl3): δ ppm
4.03 (t, J=7.0 Hz, 1H), 2.91ꢀ2.76 (m, 4H), 2.14ꢀ2.06 (m, 1H),
1.91ꢀ1.79 (m, 1H), 1.76ꢀ1.68 (m, 2H), 1.54ꢀ1.44 (m, 2H),
1.32ꢀ1.24 (m, 4H), 0.89ꢀ0.85 (m, 3H). HRꢀMS (ESI) m/z
calculated for C15H29OS2+ [M+H]+ 289.1654, found 289.1676.
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Reaction of 4a with benzoyl chloride: Dithiane 4a (200
mg, 1.02 mmol, 1 equiv.) was dissolved in dry THF (5 mL) in
an argon purged roundꢀbottom flask. The solution was cooled
to ꢀ78 ᵒC in an acetone/liquid nitrogen bath. n-BuLi (0.53 mL
of a 2.5 M solution, 1.32 mmol, 1.3 equiv.) solution in
hexanes was added dropwise to the reaction mixture at ꢀ78 ᵒC.
The solution was left stirring at ꢀ78 ᵒC for 20 minutes and then
left to warm up to room temperature for 40 minutes. Benzoyl
chloride (77 µL, 0.66 mmol, 0.65 equiv.) was added dropwise
to the solution and after 2 minutes, while under argon, the
reaction was quenched with 10 mL of a saturated aqueous
NH4Cl solution. 10 mL of Et2O were added and the layers
were separated. The organic phase was collected and the
aqueous phase was extracted two times with Et2O (2 × 10
mL). The organic phases were combined and dried over
MgSO4. The solvent was filtered and evaporated. The product
was purified by flash chromatography (eluent Hex:AcOEt,
90:10) to afford 5a in 71% yield (180 mg, 0.36 mmol) as a
pale yellow oil.
General Procedure for autoxidative addition of 2-alkyl-
1,3-dithianes 4l-p: Dithiane (1.02 mmol, 1 equiv.) was
dissolved in dry THF (5 mL) in an argon purged roundꢀbottom
flask. The solution was cooled to ꢀ78 ᵒC in an acetone/liquid
nitrogen bath. n-BuLi (1.3 equiv.) solution in hexanes was
added dropwise to the reaction mixture at ꢀ78 ᵒC. The solution
was left stirring at ꢀ78ᵒC for 20 minutes and then left to warm
up to room temperature for 40 minutes. The argon balloon was
replaced with an atmospheric air balloon and an additional
needle was inserted in the septum as to allow air flow through
the surface of the solution. After 5 minutes the solution was
quenched with 10 mL of a saturated aqueous NH4Cl solution.
10 mL of Et2O were added and the layers were separated. The
organic phase was collected and the aqueous phase was
extracted two times with Et2O (2 × 10 mL). The organic
phases were combined and dried over MgSO4. The solvent
was filtered and evaporated. The product was purified and
separated from unreacted starting material by flash
chromatography.
Reaction of 4a with S-benzyl benzothioate: Dithiane 4a
(200 mg, 1.02 mmol, 1 equiv.) was dissolved in dry THF (5
mL) in an argon purged roundꢀbottom flask. The solution was
cooled to ꢀ78 ᵒC in an acetone/liquid nitrogen bath. n-BuLi
(0.53 mL of a 2.5 M solution,1.32 mmol, 1.3 equiv.) solution
in hexanes was added dropwise to the reaction mixture at ꢀ78
ᵒC. The solution was left stirring at ꢀ78 ᵒC for 20 minutes and
then left to warm up to room temperature for 40 minutes.
Then, Sꢀbenzyl benzothioate (151 mg, 0.66 mmol, 0.65 equiv.)
in dry THF (1 mL) was added dropwise to the solution. After
2 minutes, while under argon, the reaction was quenched with
10 mL of a saturated aqueous NH4Cl solution. 10 mL of Et2O
were added and the layers were separated. The organic phase
was collected and the aqueous phase was extracted two times
with Et2O (2 × 10 mL). The organic phases were combined
and dried over MgSO4. The solvent was filtered and
1a: 63% yield (47 mg, 0.18 mmol), white solid. Flash
chromatography eluent: DCM (100%). Obtained with same
spectral characterization as previously described.19 1H NMR
(300 MHz, CDCl3): δ ppm 4.28 (s, 3H), 3.15 (s, 1H), 3.07ꢀ
2.95 (m, 4H), 2.78ꢀ2.62 (m, 4H), 2.07ꢀ2.00 (m, 4H). 13C NMR
(75 MHz, CDCl3): δ ppm 74.7, 47.4, 27.9, 27.2, 25.5.
10m: 27% yield, (45 mg, 0.14 mmol), white solid. Flash
chromatography eluent: Hex:AcOEt (95:5). 1H NMR (300
MHz, CDCl3): δ ppm 7.33ꢀ7.21 (m, 10H), 4.00 (s, 2H), 3.41
(s, 2 H), 2.86ꢀ2.76 (m, 2H), 2.60ꢀ2.53 (m, 2H), 1.99ꢀ1.90 (m,
1H), 1.84ꢀ1.73 (m, 1H). 13C NMR (75 MHz, CDCl3): δ ppm
200.6, 134.9, 134.3, 130.2, 129.9, 128.5, 128.5, 127.7, 127.0,
62.5, 44.3, 43.4, 28.0, 24.2. HRꢀMS (ESI) m/z calculated for
C19H21OS2+ [M+H]+ 329.1028, found 329.1052.
10n: 24% yield (29 mg, 0.12 mmol), colorless oil. Flash
chromatography eluent: Hex:DCM (55:45). 1H NMR (300
MHz, CDCl3): δ ppm 3.02ꢀ2.92 (m, 2H), 2.66ꢀ2.56 (m, 4H),
2.09ꢀ2.00 (m, 1H), 1.96ꢀ1.91 (m, 2H), 1.97ꢀ1.76 (m, 1H),
1.71ꢀ1.59 (m, 2H), 1.47ꢀ1.34 (m, 2H), 0.95ꢀ0.89 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ ppm 204.3, 61.4, 40.6, 37.8, 27.9,
25.0, 18.4, 18.0, 14.4, 13.9. HRꢀMS (ESI) m/z calculated for
C11H21OS2+ [M+H]+ 233.1028, found 233.1050.
evaporated.
The product was purified by flash
chromatography (eluent Hex:AcOEt, 90:10) to afford 5a in
89% yield (226 mg, 0.45 mmol) as a pale yellow oil.
Reaction of 4a in presence of 18O2: General procedure for
autooxidative addition of dithianes was used, although a small
ballon filled with 18O2 was used directly in the oxidation
reaction. HRꢀMS (ESI) m/z calculated for C27H2818OS4Na+
[M+Na]+ 521.0958, found 521.0930.
11: 22% yield (61 mg, 0.22 mmol), colorless oil. Flash
1
chromatography eluent: Hex:AcOEt (97:3). H NMR (300
Reaction of 4a in presence of TEMPO: Dithiane 4a (200
mg, 1.02 mmol, 1 equiv.) was dissolved in dry THF (5 mL) in
MHz, CDCl3): δ ppm 2.86 (t, J=7.0 Hz, 4H), 1.79 (quin, J=7.2
ACS Paragon Plus Environment

Page 11 of 13
The Journal of Organic Chemistry
JRV
and
CAMA
(SFRH/BD/120119/2016,
an argon purged roundꢀbottom flask. The solution was cooled
UID/DTP/04138/2013). CSC–IT Center for Science Ltd, Finland
is acknowledged for the allocation of computational resources.
1
2
3
4
5
6
7
8
to ꢀ78ᵒC in an acetone/liquid nitrogen bath. n-BuLi (0.53 mL
of a 2.5 M solution, 1.3 equiv.) solution in hexanes was added
dropwise to the reaction mixture at ꢀ78 ᵒC. The solution was
left stirring at ꢀ78 ᵒC for 20 minutes and then left to warm up
to room temperature for 40 minutes. Then, TEMPO (206 mg
in 1.5 mL of dry THF, 1.12 mmol, 1.3 equiv.) was added
dropwise to the solution. After 2 minutes, the argon balloon
was replaced with an atmospheric air balloon and an additional
needle was inserted in the septum as to allow air flow through
the surface of the solution. After 1 minute the solution was
quenched with 10 mL of a saturated aqueous NH4Cl solution.
10 mL of Et2O were added and the layers were separated. The
organic phase was collected and the aqueous phase was
extracted two times with Et2O (2 × 10 mL). The organic
phases were combined and dried over MgSO4. The solvent
was filtered and evaporated. Flash chromatography
(Hex:AcOEt, 95:5) yielded starting material 4a (20%, 39 mg,
0.20 mmol) and dimer 2 (27%, 53 mg, 0.14 mmol) as a white
solid, with same spectral characterization as previously
described.49 2:1H NMR (300 MHz, CDCl3): δ ppm 7.54ꢀ7.15
(m, 10H), 2.70ꢀ2.49 (m, 8H), 2.01ꢀ1.75 (m, 4H). 13C NMR (75
MHz, CDCl3): δ ppm 135.0, 133.0, 127.6, 127.3, 70.9, 29.0,
24.7.
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Reaction of 4a with 12: Dithiane 4a (200 mg, 1.02 mmol, 1
equiv.) was dissolved in dry THF (5 mL, 0.2 M) in an argon
purged roundꢀbottom flask. The solution was cooled to ꢀ78 ᵒC
in an acetone/liquid nitrogen bath. n-BuLi (0.45 mL of a 2.5 M
solution, 1.12 mmol, 1.1 equiv.) solution in hexanes was
added dropwise to the reaction mixture at ꢀ78 ᵒC. The solution
was left stirring at ꢀ78 ᵒC for 20 minutes and then left to warm
up to room temperature for 40 minutes. Phenyl(2ꢀphenylꢀ1,3ꢀ
dithianꢀ2ꢀyl)methanone 12 (337 mg, 1.12 mmol, 1.1 equiv.) in
THF (5 mL) was added dropwise to the solution. After 2
minutes, while under argon, the reaction was quenched with
10 mL of a saturated aqueous NH4Cl solution. 10 mL of Et2O
were added and the layers were separated. The organic phase
was collected and the aqueous phase was extracted two times
with Et2O (2 × 10 mL). The organic phases were combined
and dried over MgSO4. The solvent was filtered, evaporated
and the product purified by flash chromatography (eluent
Hex:AcOEt, 90:10) to afford 5a in 75% yield (381 mg, 0.77
mmol) as a pale yellow oil.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website and includes full accounts on
computational calculations and copies of spectra for all reported
compounds.
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: nuno.rafaelcandeias@tut.fi; carlosafonso@ff.ulisboa.pt
Author Contributions
All authors have given approval to the final version of the manuscript.
ACKNOWLEDGMENT
AKA is acknowledged for the financial support to NRC
(Decisions No. 287954 and 294067); FCT for financial support to
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The Journal of Organic Chemistry
Page 12 of 13
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