Unusual Reactions of the 1,3-Dithiane Derivative of the Garner Aldehyde and Related Compounds

Article abstract of DOI:10.1055/s-0033-1338874

Treatment of the 1,3-dithiane derivative of the Garner aldehyde with alkyl halides in the presence of n-butyllithium resulted in a ring-opening reaction to give differentially substituted propane-1,3-dithioethers, instead of the expected 2,2-dialkylated 1,3-dithiane products. The corresponding 1,3-dithiolane derivative also reacted in a similar manner. Such ring-opening reactions of dithiane or dithiolane derivatives are rare. A detailed study of this unusual reaction was carried out and a possible mechanism is proposed. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338874

PAPER
▌1997
paper
Unusual Reactions of the 1,3-Dithiane Derivative of the Garner Aldehyde and
Related Compounds
Unusual Reactions of 1,3-Dithiane Derivatives
Anijamol T. Philip, Shibin Chacko, Ramesh Ramapanicker*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
Fax +91(512)2597436; E-mail: rameshr@iitk.ac.in
Received: 19.03.2013; Accepted after revision: 30.04.2013
HS(CH2)3SH
BF3·OEt2
O
HO
Abstract: Treatment of the 1,3-dithiane derivative of the Garner al-
dehyde with alkyl halides in the presence of n-butyllithium resulted
in a ring-opening reaction to give differentially substituted propane-
1,3-dithioethers, instead of the expected 2,2-dialkylated 1,3-dithi-
ane products. The corresponding 1,3-dithiolane derivative also re-
acted in a similar manner. Such ring-opening reactions of dithiane
or dithiolane derivatives are rare. A detailed study of this unusual
reaction was carried out and a possible mechanism is proposed.
S
N
BocHN
CHO
CH2Cl2, –20 °C
Boc
S
1
3 70%
Me2C(OMe)2 benzene
reflux
p-TsOH
Key words: dithianes, dithiolanes, butyllithium, ring opening,
umpolung
O
S
N
Boc
S
Garner’s aldehyde (1) and a number of related derivatives
have been widely used in the synthesis of various natural
and unnatural products. Aldehyde 1 has quite often been
used as an efficient chiral starting material for the synthe-
sis of a number of amino acids and carbohydrate deriva-
tives.1 In connection with our efforts to develop new
methods for the synthesis of unnatural amino acids,2 we
postulated that the use of the 1,3-dithiane derivative of 1,
as an umpolung equivalent of the aldehyde function,
could be a suitable starting material. Although the chem-
istry of the Garner aldehyde (1) has been widely studied
and applied, its 1,3-dithiane derivative has not been re-
ported. We believed that the use of such a derivative could
add a new dimension to the chemistry of this versatile syn-
thetic precursor. To our surprise, the 1,3-dithiane deriva-
tive 2 synthesized from 1 reacted quite differently to other
dithianes and in a completely unpredictable manner. Our
observations and the results of related studies toward un-
derstanding this rather unusual reactivity are reported
here.
2 96%
Scheme 1 Synthesis of the 1,3-dithiane derivative 2 of the Garner al-
dehyde (1)
only a single product could be isolated; however, the
NMR spectra of the product did not match what was ex-
pected for 4 and looked very simple, unlike those of many
dithiane derivatives. A careful spectroscopic analysis of
the product indicated that the dithiane ring had been
cleaved under the reaction conditions. The product
formed was an unsymmetrical propane-1,3-dithioether,
namely 5a (Figure 1). The 1H and 13C NMR spectra con-
firmed the presence of a double bond in the compound.
The individual peaks in 1H NMR spectrum were correlat-
ed with the 13C peaks using heteronuclear correlation
spectroscopy and the configuration of the double bond
was determined from NOE experiments.
O
O
Ph
S
n-BuLi, PhCH2Br
S
The 1,3-dithiane derivative of the Garner aldehyde was
synthesized by treatment of 1 with propane-1,3-dithiol
(BF3·OEt2, CH2Cl2, –20 °C). The reaction conditions re-
sulted in the opening of the oxazolidine ring, yielding an
amino alcohol derivative 3, which was recyclized with
2,2-dimethoxypropane (p-TsOH, benzene, 80 °C) to pro-
vide 2 (Scheme 1).
N
N
THF, –20 °C
Boc
Boc
S
S
2
4 (not formed)
Scheme 2 Expected reaction of 2 with benzyl bromide in the pres-
ence of n-butyllithium
O
As an initial reaction, we attempted to couple 1,3-dithiane
2 with benzyl bromide, after generating the corresponding
anion using n-butyllithium (1.5 equiv, THF, –20 °C), and
expected to obtain the 2,2-disubstituted 1,3-dithiane de-
rivative 4 (Scheme 2). The reaction proceeded cleanly and
S
S
N
Boc
H
5a
δ
H = 6.18 ppm (s), no NOE with the CH2 in the oxazolidine ringg
Figure 1 Structure of 5a formed from the reaction between 2 and
benzyl bromide
SYNTHESIS 2013, 45, 1997–2002
Advanced online publication: 11.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338874; Art ID: SS-2013-T0226-OP
© Georg Thieme Verlag Stuttgart · New York

1998
A. T. Philip et al.
PAPER
In order to further confirm the structure of the product
formed in this reaction, the oxazolidine ring of 5a was
opened and the Boc group was removed by treatment with
trifluoroacetic acid (50% in MeOH). As expected, the ke-
tone derivative 6 was isolated, in 91% yield (Scheme 3),
confirming the structure of 5a as that shown in Figure 1.
Table 1 Reaction of 1,3-Dithiane 2 with Alkyl Halides
O
O
n-BuLi, RX
S
N
S
S
R
Boc
N
THF
S
Boc
H
2
5
Yielda (%)
O
Entry
RX
Temp (°C)
5
S
S
N
1
2
3
4
5
PhCH2Br
–20
–20
–20
–20
–78
5a
5b
5c
5d
5d
52
47
50
54
51
Boc
5a
H2C=CHCH2Br
i-PrBr
TFA (50%)
MeOH
HO
MeI
S
S
MeI
O
6 91%
a Isolated yield.
Scheme 3 Acidolysis of 5a
0.5 equivalents of n-butyllithium and the reaction mixture
was quenched with D2O, almost half of compound 2 could
be recovered; however, an NMR analysis of 2 isolated
from the reaction mixture did not indicate the presence of
deuterium. The experiment suggests that deprotonation of
1,3-dithiane 2 leads to its decomposition, unless a very re-
active electrophile such as an alkyl halide is present.
The formation of 5a as the only isolable product was sur-
prising, and we could not isolate even traces of the expect-
ed product 4. Products similar to 5a, formed via opening
of the dithiane ring, have very rarely been observed. The
only other report of such a reaction was in the case of a di-
thian-2-yl derivative of diethyl malonate, which under-
went a ring-opening reaction on treatment with sodium
hydride and iodomethane.3 It has also been shown that S-
alkylation of dithianes can be exploited to achieve ring
opening of dithianes.4 However, since then, cleavage of
the dithiane ring as a side reaction during umpolung reac-
tions has not been reported. This prompted us to study this
reaction further to comprehend our observation of this un-
usual reactivity. We performed the reaction of 1,3-dithi-
ane 2 with three other alkyl halides, and the results are
listed in Table 1. All of the alkyl halides studied reacted
with 2 in the same way as benzyl bromide, and the yields
were generally good. Alkyl iodides and bromides reacted
in the same manner, and varying the temperature of the re-
action did not have any effect on the nature of the product
formed (see entries 4 and 5).
It is known that protons in the α-position to a N-Boc group
are reasonably acidic.5 Hence, it is justified to assume that
in compound 2 the C–H adjacent to the N-Boc group is
more acidic than the 2-H in the 1,3-dithiane, and thus de-
protonated upon treatment with n-butyllithium. We pro-
pose the following mechanism for the unusual reaction of
2 with alkyl halides in the light of these assumptions
(Scheme 4). It is most likely that the cleavage of the 1,3-
dithiane ring happens only as a result of the formation of
the sulfonium ion A. If a sulfide anion was formed prior
to the reaction of the sulfur atom with benzyl bromide, the
same anion could have reacted with ethyl acrylate, but it
does not. Any stable anionic species formed as an inter-
mediate in the above reaction could have given an isolable
product on treatment with D2O. The absence of any isol-
able deuterated product even after repeated attempts indi-
cates the possible formation of A which, when not
We attempted the reaction of 1,3-dithiane 2 with other
electrophiles, such as 4-nitrobenzaldehyde and ethyl acry-
late. These compounds did not react with 2 to give any
isolable products; however, unreacted 2 could not be iso-
lated from the reaction mixture. After the addition of n-
butyllithium, the 1,3-dithiane 2 disappeared completely
by TLC, indicating that it decomposes in the absence of an
alkyl halide to react with. In order to confirm this obser-
vation and also to understand the exact nature of the de-
protonation of 2 with n-butyllithium, we tried to quench
the anion with D2O and CD3OD. When one or more
equivalents of n-butyllithium were used and the reaction
was quenched with deuterated solvents, we could not iso-
late any amount of deuterated 2. TLC showed complete
disappearance of the starting material and formation of a
mixture of polar products, none of which could be isolated
and characterized. When the reaction was carried out with
n-Bu–
Ph
O
N
O
Br
H
S
••
S
••
–
S
N
Boc
Boc
S
2
Ph
O
N
O
N
S+
–
S
S
Boc
Boc
Ph
S
5a
A
Scheme 4 Proposed mechanism for the formation of 5a from 2
Synthesis 2013, 45, 1997–2002
© Georg Thieme Verlag Stuttgart · New York

PAPER
Unusual Reactions of 1,3-Dithiane Derivatives
1999
O
possible in the absence of an alkyl halide, results in com-
plete decomposition of the anion formed.
S
N
Boc
S
If the C–H adjacent to the N-Boc group was rendered less
acidic, the reaction of 2 could have proceeded as expect-
ed. To substantiate this argument, we prepared the O-ben-
zyl derivative 7 of the amino alcohol 3, and treated it with
allyl bromide in the presence of excess n-butyllithium.
The reaction yielded the 2-allyl-1,3-dithiane derivative 8,
albeit in moderate yield (Scheme 5). The reaction may
have proceeded with deprotonation of the NHBoc group,
thereby reducing the acidity of the adjacent C–H.6 Excess
n-butyllithium deprotonates the 1,3-dithiane at the 2-posi-
tion, generating the dithianyl anion B, which reacts with
allyl bromide to give derivative 8, as expected.
9
n-BuLi, PhCH2Br THF, –20 °C
O
S
10 52%
N
Boc
S
Ph
Scheme 6 Reaction of the 1,3-dithiolane 9 with benzyl bromide
able product was the dithio derivative 13, in low yield. On
performing the reaction with 2.5 equivalents of n-butyl-
lithium and 2 equivalents of benzyl bromide, product 13
could be isolated in 62% yield (Scheme 7). The formation
of 13 gives a new insight into these reactions. The 2-H in
the 1,3-dithiolane is the first proton to be removed in this
reaction, which results in the elimination of ethylene and
formation of the benzyl dithiocarboxylate derivative C;
however, the proton adjacent to the N-Boc group becomes
more acidic after the formation of derivative C, and is de-
protonated. The formation of thioenolate D from C results
in a subsequent reaction with one more equivalent of ben-
zyl bromide, giving the product 13 (Scheme 7). This is a
clear indication that the acidity of the 2-alkyl-2-dithiola-
nyl proton, and possibly that of 2-alkyl-2-dithianyl pro-
tons, lies between the acidity of the C–H adjacent to the
N-Boc group in 9 and that of the adjacent C–H in 11. Un-
fortunately, the reaction of the corresponding 1,3-dithiane
12 with n-butyllithium and benzyl bromide was quite
complex and we could not isolate any products from the
reaction, even after repeated efforts at different tempera-
tures (Scheme 8).
BnO
BnO
n-BuLi
–
S
S
–
BocN
BocHN
THF
S
S
7
B
Br
THF
BnO
BocHN
S
S
8 38%
Scheme 5 Reaction of the 1,3-dithiane derivative 7 with allyl bro-
mide
The reaction of dithianes with a base is quite different to
that of the corresponding dithiolanes. Dithiolanyl anions
are known to dissociate into dithiocarboxylates and ethyl-
ene.7 We assumed that if a dithiolane equivalent of 2 could
be prepared, its reaction with n-butyllithium would con-
firm the position of initial deprotonation. If the deproton-
ation occurs at the 2-position of the dithiolane the product
would be a dithiocarboxylate derivative, whereas deprot-
onation of the C–H adjacent to the N-Boc group would re-
sult in a product similar to 5. The 1,3-dithiolane derivative
9 was prepared from the Garner aldehyde (1) using a pro-
cedure similar to that used for the preparation of 1,3-dithi-
ane 2. When 9 was treated with benzyl bromide and n-
butyllithium, the dithioether 10 was obtained (Scheme 6),
confirming the proposed mechanism for the reaction of 2.
n-BuLi (2.5 equiv)
PhCH2Br (2 equiv)
S
Ph
S
N
N
Boc
Boc
THF, –20 °C
S
11
S
Ph
13 62%
n-BuLi
– Br–
Ph
S
–
N
Boc
–
S
Br
Ph
N
S
Br
Boc
S
Based on the above observations, a similar reactivity pro-
file could be anticipated for the 1,3-dithiane and 1,3-dithi-
olane derivatives of N-protected prolinals. We
synthesized the 1,3-dithiolane 11 and 1,3-dithiane 12 de-
rivatives of Boc-prolinal following the procedure used for
the synthesis of derivatives 9 and 2. When the 1,3-dithio-
lane derivative 11 was treated with n-butyllithium
(1.5 equiv) and benzyl bromide (1 equiv), the only isol-
Ph
D
– C2H4
– Br–
n-BuLi
S
N
Boc
S
Ph
C
Scheme 7 Reaction of 1,3-dithiolane 11 with benzyl bromide
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1997–2002

2000
A. T. Philip et al.
PAPER
mixture was refluxed for 2.5 h, quenched with sat. Na2CO3 soln
(10 mL) and extracted with Et2O (2 × 30 mL). The crude solution
was dried over anhyd Na2SO4 and concentrated, and the 1,3-dithi-
ane 2 was purified by column chromatography.
n-BuLi, PhCH2Br
THF, –20 °C
complex
reaction mixture
S
N
Boc
S
12
N-Boc-Protected 2-Amino-2-(1,3-dithian-2-yl)ethanol (3)
Yield: 976 mg (70%); oily liquid; Rf = 0.45 (PE–EtOAc, 7:3).
IR (thin film): 3418, 1694 cm–1.
Scheme 8 Reaction of 1,3-dithiane 12 with benzyl bromide
1H NMR (500 MHz, CDCl3): δ = 5.18–5.22 (m, 1 H), 4.29 (d,
J = 5.0 Hz, 1 H), 3.99 (br s, 1 H), 3.91 (dd, J = 11.2, 3.7 Hz, 1 H),
3.74 (dd, J = 11.5, 4.6 Hz, 1 H), 2.79–2.93 (m, 4 H), 1.86–2.07 (m,
2 H), 1.43 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 156.0, 80.0, 63.0, 54.9, 48.6,
29.6, 28.3, 25.7.
In conclusion, our studies clearly suggest that dithianes
and dithiolanes react in an unusual manner if an acidic β-
hydrogen is present in the molecule. Ideally, a base-
induced reaction, such as those with dithianes, should not
have any other acidic protons in the substrate. However, a
clear definition of how much acidity could be accommo-
dated in such a reaction is not trivial. Our studies shed
more light on defining such a limit for reactions involving
dithianes and dithiolanes, and also provide a very curious
reactivity profile for compounds with an acidic β-hydro-
gen. The ring-opening reaction is facilitated if the β-car-
bon is sterically hindered, as in the case of the Garner
aldehyde or prolinal derivatives. From our studies, it is
safe to say that the acidity of the 2-CH of 2-alkyl-1,3-di-
thianes and -dithiolanes is between that of the 2-CH of a
N-Boc-protected pyrrolidine and the 4-CH of a N-Boc-
protected oxazolidine.
HRMS (ESI): m/z [M + Na+] calcd for C11H21NO3S2: 302.0861;
found: 302.0754.
N-Boc-Protected 4-(1,3-Dithian-2-yl)-2,2-dimethyloxazolidine
(2)
Yield: 918 mg (96%); white crystalline solid; mp 71–73 °C;
Rf = 0.50 (PE–EtOAc, 15:1).
IR (KBr): 1698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.45–4.49 (m, 1 H), 4.12–4.19 (m,
2 H), 3.88–3.91 (m, 1 H), 2.72–2.85 (m, 4 H), 1.79–2.05 (m, 2 H),
1.41–1.57 (m, 15 H).
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 152.7,
151.8, 94.7, 94.1, 80.6, 80.4, 65.2, 65.0, 60.3, 60.1, 51.3, 49.1, 30.4,
30.1, 28.6, 28.5, 26.1, 25.9, 24.3.
HRMS (ESI): m/z [M + Na+] calcd for C14H25NO3S2: 342.1174;
found: 342.1171.
All the chemicals were purchased from commercial sources and
1
were used without further purification. H and 13C NMR spectra
were recorded either on a 400 MHz (100 MHz for 13C) or on a 500
MHz (125 MHz for 13C) JEOL-Lambda NMR spectrometer at
25 °C. The 1H NMR signals are referenced to TMS (δ = 0.00 ppm)
and the 13C NMR peaks are referenced to the residual CHCl3 signal
(δ = 77.0 ppm). The chemical shifts are reported in parts per million
and coupling constants in Hz. The multiplicities are assigned as s
(singlet), d (doublet), t (triplet), qu (quintet), br s (broad singlet), dd
(double doublet) and m (multiplet). High-resolution mass spectra
were obtained using a Waters Q/Tof Premier micromass HAB 213
spectrometer with an ESI source. IR spectra were recorded on a
Bruker Vector 22 FTIR instrument and melting points were record-
ed on a DBK Automatic Programmable digital instrument. Column
chromatography was performed using 100–200 mesh silica gel, and
appropriate mixtures of petroleum ether (PE) and EtOAc were used
as eluent.
N-Boc-Protected 2-(1,3-Dithian-2-yl)pyrrolidine (12)
Yield: 1.29 g (89%); solid; mp 66–68 °C; Rf = 0.50 (PE–EtOAc,
97:3).
IR (KBr): 1684 cm–1.
1H NMR (500 MHz, CDCl3): δ (mixture of rotamers) = 4.79 (br s),
4.60 (br s), 4.07 (br s), 3.98 (br s), 3.70 (br s), 3.49 (br s), 3.22–3.27
(m), 2.74–2.89 (m), 2.57–2.61 (m), 2.06–2.08 (br s), 1.92–1.93 (br
s), 1.42–1.45 (m).
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 154.7,
154.2, 79.9, 79.6, 61.3, 60.2, 53.8, 52.1, 47.6, 47.1, 33.5, 33.4, 31.4,
30.7, 30.1, 28.6, 27.7, 27.4, 26.4, 24.5, 24.4, 23.8, 23.5, 23.3.
HRMS (ESI): m/z [M + H+] calcd for C13H23NO2S2: 290.1248;
found: 290.1248.
1,3-Dithiane Derivatives of the Garner Aldehyde and Boc-Pro-
linal
1,3-Dithiolane Derivatives of the Garner Aldehyde and Boc-
Prolinal
A soln of the Garner aldehyde (1; 1.145 g, 5 mmol) or Boc-prolinal
(0.995 g, 5 mmol) in CH2Cl2 was cooled to –20 °C, and propane-
1,3-dithiol (0.500 mL, 0.540 g, 5 mmol) was added under nitrogen.
The solution was stirred at –20 °C and BF3·OEt2 (0.001 mL) was
added. The reaction mixture was allowed to attain r.t. (30 °C) and
the stirring was continued until complete disappearance of the start-
ing material (by TLC). The reaction was quenched by adding H2O
(10 mL) and the mixture was diluted with CH2Cl2 (50 mL) and then
transferred into a separating funnel. The organic layer was separat-
ed and washed with a 10% soln of KOH (15 mL) and with brine (15
mL), dried over anhyd Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy. Although the expected 1,3-dithiane derivative 12 was obtained
from Boc-prolinal, the product obtained from the Garner aldehyde
was the amino alcohol derivative 3, which was cyclized to provide
the 1,3-dithiane derivative 2 in a subsequent step.
The 1,3-dithiolane derivatives 9 and 11 of the Garner aldehyde and
Boc-prolinal, respectively, were prepared using a similar procedure
to that used for the 1,3-dithiane derivatives.
N-Boc-Protected 4-(1,3-Dithiolan-2-yl)-2,2-dimethyloxazoli-
dine (9)
Yield: 960 mg (63%); white crystalline solid; mp 70–72 °C;
Rf = 0.50 (PE–EtOAc, 15:1).
IR (KBr): 1703 cm–1.
1H NMR (500 MHz, CDCl3): δ (mixture of rotamers) = 5.07, 4.92
(1 H), 4.20, 4.06 (1 H), 3.96–4.00 (m, 2 H), 3.19–3.25 (m, 4 H),
1.45–1.61 (m, 15 H).
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 152.9,
152.0, 95.3, 94.7, 80.6, 80.4, 65.7, 65.3, 61.1, 60.9, 55.7, 55.2, 38.9,
38.9, 38.7, 38.5, 28.5, 28.4.
HRMS (ESI): m/z [M + H+] calcd for C13H23NO3S2: 306.1198;
found: 306.1194.
The amino alcohol derivative 3 (0.837 g, 3 mmol) was suspended in
benzene (10 mL), and 2,2-dimethoxypropane (0.734 mL, 0.624 g, 6
mmol) and p-TsOH (0.010 g, 0.06 mmol) were added. The reaction
Synthesis 2013, 45, 1997–2002
© Georg Thieme Verlag Stuttgart · New York

PAPER
Unusual Reactions of 1,3-Dithiane Derivatives
2001
N-Boc-Protected 2-(1,3-Dithiolan-2-yl)pyrrolidine (11)
Yield: 963 mg (70%); gummy solid; Rf = 0.50 (PE–EtOAc, 97:3).
HRMS (ESI): m/z [M + Na+] calcd for C17H31NO3S2: 384.1643;
found: 384.1647.
IR (KBr): 1686 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.08 (s, 1 H), 3.51 (s, 1 H), 3.29–
N-Boc-Protected (E)-2,2-Dimethyl-4-((3-(methylthio)propyl-
thio)methylene)oxazolidine (5d)
Yield: 170 mg (51%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
3.34 (m, 2 H), 3.16–3.23 (m, 4 H), 1.72–2.03 (m, 4 H), 1.46 (s, 9 H).
IR (thin film): 1706 cm–1.
13C NMR (125 MHz, CDCl3): δ = 154.6, 79.8, 61.7, 56.3, 47.6,
1H NMR (500 MHz, CDCl3): δ = 6.14 (s, 1 H), 4.55 (d, J = 2.2 Hz,
2 H), 2.67 (t, J = 7.1 Hz, 2 H), 2.57 (t, J = 7.1 Hz, 2 H), 2.03 (s, 3
H), 1.85–1.89 (m, 2 H), 1.55 (s, 6 H), 1.51 (s, 9 H).
38.9, 38.8, 29.8, 28.6.
HRMS (ESI): m/z [M + H+] calcd for C12H21NO2S2: 276.1092;
found: 276.1095.
13C NMR (125 MHz, CDCl3): δ = 150.7, 138.1, 128.7, 98.1, 96.4,
81.9, 66.9, 33.8, 32.8, 28.2, 25.5, 15.5.
HRMS (ESI): m/z [M + Na+] calcd for C15H27NO3S2: 356.1330;
found: 356.1331.
Reaction of 1,3-Dithianes and 1,3-Dithiolanes with Alkyl
Halides; General Procedure
The 1,3-dithiane or 1,3-dithiolane (1 mmol) was dissolved in THF
(10 mL) under nitrogen atmosphere; the solution was cooled to
–20 °C and 1.6 M n-BuLi in hexane (0.950 mL, 1.5 mmol) was add-
ed dropwise. The mixture was stirred for 30 min, then a soln of the
alkyl halide (1 mmol) in THF (3 mL) was added dropwise over a pe-
riod of 10 min. The stirring was continued for 30 min, then the re-
action mixture was brought to r.t. and quenched with sat. NH4Cl
soln (3 mL). The solution was partitioned between H2O (30 mL) and
EtOAc (30 mL), the organic layer was separated and the aqueous
layer was extracted with EtOAc (30 mL). The organic layers were
combined, dried over anhyd Na2SO4 and concentrated under re-
duced pressure. The crude product was purified by silica gel column
chromatography.
O-Benzyl-N-Boc-Protected 2-(2-Allyl-1,3-dithian-2-yl)-2-ami-
noethanol (8)
n-BuLi (3 equiv) was used for this reaction.
Yield: 155 mg (38%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
IR (thin film): 3065, 1714 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.18–7.27 (m, 5 H), 5.91–6.01 (m,
1 H), 4.99–5.08 (m, 2 H), 4.41–4.52 (m, 2 H), 3.81 (m, 2 H), 3.07
(m, 1 H), 2.84 (m, 1 H), 2.57–2.66 (m, 4 H), 1.78–1.92 (m, 2 H),
1.38 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 138.1, 133.4, 128.4, 127.7,
127.7, 118.5, 79.6, 73.1, 69.5, 56.4, 53.5, 41.3, 28.5, 26.5, 26.2,
24.7.
HRMS (ESI): m/z [M + H+] calcd for C21H31NO3S2: 410.1824;
found: 410.1811.
N-Boc-Protected (E)-4-((3-(Benzylthio)propylthio)methylene)-
2,2-dimethyloxazolidine (5a)
Yield: 213 mg (52%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
IR (thin film): 1705 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.23–7.30 (m, 5 H), 6.18 (s, 1 H),
4.58 (d, J = 2.0 Hz, 2 H), 3.69 (s, 2 H), 2.63 (t, J = 7.2 Hz, 2 H), 2.50
(t, J = 7.2 Hz, 2 H), 1.84 (qu, J = 7.2 Hz, 2 H), 1.56 (s, 6 H), 1.52 (s,
9 H).
N-Boc-Protected (E)-4-((2-(Benzylthio)ethylthio)methylene)-
2,2-dimethyloxazolidine (10)
Yield: 205 mg (52%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
IR (thin film): 1714 cm–1.
13C NMR (125 MHz, CDCl3): δ = 150.7, 138.5, 138.1, 128.9, 128.6,
127.1, 98.1, 96.4, 81.9, 77.5, 77.1, 76.9, 66.9, 36.3, 33.9, 30.0, 29.2,
28.4, 25.6.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.30 (m, 5 H), 6.18 (s, 1 H),
4.59 (s, 2 H), 3.71–3.74 (m, 2 H), 2.68–2.71 (m, 2 H), 2.60–2.63 (m,
2 H), 1.56 (s, 6 H), 1.53 (s, 9 H).
HRMS (ESI): m/z [M + Na+] calcd for C21H31NO3S2: 432.1643;
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 150.7,
139.6, 138.3, 128.9, 128.3, 127.0, 126.8, 98.3, 95.4, 82.1, 67.0,
66.5, 36.4, 36.3, 34.8, 31.4, 31.1, 28.3, 25.6.
found: 432.1645.
N-Boc-Protected (E)-4-((3-(Allylthio)propylthio)methylene)-
2,2-dimethyloxazolidine (5b)
Yield: 169 mg (47%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
HRMS (ESI): m/z [M + Na+] calcd for C20H29NO3S2: 418.1487;
IR (thin film): 1706 cm–1.
found: 418.1486.
1H NMR (500 MHz, CDCl3): δ = 6.17 (s, 1 H), 5.71–5.79 (m, 1 H),
5.05–5.09 (m, 2 H), 4.57–4.58 (m, 2 H), 3.09 (d, J = 7.1 Hz, 2 H),
2.64 (t, J = 7.1 Hz, 2 H), 2.51 (t, J = 7.0 Hz, 2 H), 1.83 (qu, J = 7.3
Hz, 2 H), 1.56 (s, 6 H), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 150.7, 138.1, 134.4, 117.1, 98.1,
96.4, 81.9, 66.9, 34.8, 33.9, 29.3, 29.2, 28.4, 25.5.
N-Boc-Protected 2-(Bis(benzylthio)methylene)pyrrolidine (13)
n-BuLi (2.5 equiv) and BnBr (2 equiv) were used for this reaction.
Yield: 252 mg (62%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
IR (thin film): 1701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.17–7.33 (m, 10 H), 3.99 (s, 2 H),
3.90 (s, 2 H), 3.39 (t, J = 7.0 Hz, 2 H), 2.13 (t, J = 7.6 Hz, 2 H), 1.56
(s, 9 H), 1.39–1.45 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 152.6, 151.5, 138.9, 138.8, 129.2,
128.3, 128.1, 126.6, 110.7, 81.2, 49.7, 39.1, 37.9, 32.3, 29.8, 28.5,
20.6, 14.3.
HRMS (ESI): m/z [M + Na+] calcd for C17H29NO3S2: 382.1487;
found: 382.1489.
N-Boc-Protected (E)-4-((3-(Isopropylthio)propylthio)methy-
lene)-2,2-dimethyloxazolidine (5c)
Yield: 181 mg (50%); oily liquid; Rf = 0.70 (PE–EtOAc, 97:3).
IR (thin film): 1701 cm–1.
HRMS (ESI): m/z [M + H+] calcd for C24H29NO2S2: 428.1718;
found: 428.1809.
1H NMR (500 MHz, CDCl3): δ = 6.16 (s, 1 H), 4.57 (d, J = 2.0 Hz,
2 H), 2.86–2.87 (m, 1 H), 2.65 (t, J = 6.9 Hz, 2 H), 2.58 (t, J = 6.9
Hz, 2 H), 1.83–1.86 (m, 2 H), 1.53 (s, 6 H), 1.46 (s, 9 H), 1.23 (s, 3
H), 1.21 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.7, 138.0, 128.7, 98.1, 96.5,
81.9, 66.9, 34.9, 34.1, 29.8, 29.2, 28.3, 25.7, 23.5.
1-(3-(Benzylthio)propylthio)-3-hydroxypropan-2-one (6)
The disulfide derivative 5a (0.410 g, 1 mmol) was dissolved in
MeOH (3 mL), and TFA (3 mL) was added to this solution at 0 °C.
After 30 min, the volatiles were removed under reduced pressure
and the crude product was filtered through a silica gel column.
Yield: 245 mg (91%); oily liquid; Rf = 0.40 (PE–EtOAc, 4:1).
IR (thin film): 3428, 1715 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1997–2002

2002
A. T. Philip et al.
PAPER
1H NMR (500 MHz, CDCl3): δ = 7.21–7.32 (m, 5 H), 4.44 (s, 2 H),
3.69 (s, 2 H), 3.46 (s, 1 H), 3.21 (s, 2 H), 2.57 (t, J = 7.1 Hz, 2 H),
2.47 (t, J = 7.1 Hz, 2 H), 1.78 (qu, J = 7.1 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 205.2, 138.3, 128.9, 128.6, 127.1,
66.5, 36.6, 36.3, 31.1, 29.9, 28.2.
Acknowledgment
This work was supported by the Department of Science and Tech-
nology. A.T.P. thanks the University Grants Commission and S.C.
thanks the Council of Scientific and Industrial Research for senior
research fellowships.
HRMS (ESI): m/z [M + Na+] calcd for C13H18O2S2: 293.0646;
found: 293.0647.
Supporting Information for this article is available online at
O-Benzyl-N-Boc-Protected 2-Amino-2-(1,3-dithian-2-yl)etha-
nol (7)
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
The amino alcohol derivative 3 (0.280 g, 1 mmol) dissolved in THF
(2 mL) was added to a suspension of NaH (0.026 mg, 1 mmol) in
THF (5 mL) at 0 °C. After 15 min, a soln of BnBr (0.171 mg, 0.118
mL, 1 mmol) in THF (1 mL) was added dropwise to the above so-
lution with constant stirring, and the stirring was continued at r.t. for
16 h. The reaction was quenched with MeOH (1 mL), the volatiles
were removed under reduced pressure and the residue was dissolved
in Et2O (50 mL), which was then washed with sat. NH4Cl soln (20
mL). The ether solution was dried over anhyd Na2SO4 and concen-
trated under reduced pressure, and the benzyl derivative 7 was iso-
lated by column chromatography.
References
(1) (a) Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin
Trans. 1 2001, 2136. (b) Zhang, X.; Ni, W.; Van der Donk,
W. A. J. Org. Chem. 2005, 70, 6685. (c) Passiniemi, M.;
Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9, 1774.
(d) Chandrasekhar, B.; Rao, J. P.; Rao, B. V.; Naresh, P.
Tetrahedron Lett. 2011, 52, 5921. (e) Dubey, A.; Harbindu,
A.; Kumar, P. Synthesis 2011, 901.
(2) Chacko, S.; Ramapanicker, R. Eur. J. Org. Chem. 2012,
7120.
(3) Kruse, C. G.; Janse, A. C. V.; Dert, V.; van der Gen, A.
J. Org. Chem. 1979, 44, 2916.
Yield: 100 mg (27%); oily liquid; Rf = 0.50 (PE–EtOAc, 97:3).
IR (thin film): 1711 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.31–7.34 (m, 5 H), 5.04 (d,
J = 8.9 Hz, 1 H), 4.52 (s, 2 H), 4.17–4.24 (m, 1 H), 3.59–3.86 (m, 2
H), 2.72–3.01 (m, 4 H), 1.88–2.06 (m, 2 H), 1.44 (s, 9 H).
(4) Marshall, J. A.; Seitz, D. E. J. Org. Chem. 1975, 40, 534.
(5) Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Li, B. J. Am.
Chem. Soc. 1999, 121, 7509.
(6) Examples of similar reactions can be found, see: Chen, Y.
L.; Leguijt, R.; Redlich, H.; Fröhlich, R. Synthesis 2006,
4212.
(7) Wilson, S. R.; Georgiadis, G. M.; Khatri, H. N.; Bartmess,
E. J. Am. Chem. Soc. 1980, 102, 3577.
13C NMR (125 MHz, CDCl3): δ = 155.6, 138.0, 128.4, 127.8, 127.7,
79.7, 73.3, 69.3, 52.8, 47.9, 28.7, 25.8.
HRMS (ESI): m/z [M + H+] calcd for C18H27NO3S2: 370.1511;
found: 370.1531.
Synthesis 2013, 45, 1997–2002
© Georg Thieme Verlag Stuttgart · New York