Expanding the scope of methyl xanthate esters - From Barton-McCombie reaction auxiliary to versatile protective group

Article abstract of DOI:10.1016/j.tet.2017.09.022

The methyl xanthate ester is presented as a versatile protective group for alcohols. Hydroxyl groups can easily be transformed into methyl xanthate esters by several methods and are commonly used as an auxiliary in the Barton-McCombie reaction. We show that these methyl xanthate esters can readily and chemoselectively be cleaved under mild conditions by the action of diethylenetriamine using microwave heating. This method is orthogonal to many common hydroxyl protective groups that can be introduced and cleaved in the presence of methyl xanthate ester.

Full text of DOI:10.1016/j.tet.2017.09.022

Accepted Manuscript
Expanding the scope of methyl xanthate esters - From Barton-McCombie reaction
auxiliary to versatile protective group
Karin Thorsheim, Sophie Manner, Ulf Ellervik
PII:
S0040-4020(17)30944-4
10.1016/j.tet.2017.09.022
TET 28973
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 May 2017
Revised Date: 28 August 2017
Accepted Date: 13 September 2017
Please cite this article as: Thorsheim K, Manner S, Ellervik U, Expanding the scope of methyl xanthate
esters - From Barton-McCombie reaction auxiliary to versatile protective group, Tetrahedron (2017), doi:
10.1016/j.tet.2017.09.022.
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Expanding the scope of methyl xanthate
esters - from Barton-McCombie reaction
auxiliary to versatile protective group
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Karin Thorsheim, Sophie Manner, Ulf Ellervik
Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box
124, SE-221 00 Lund, Sweden

1
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Tetrahedron
journal homepage: www.elsevier.com
Expanding the scope of methyl xanthate esters - from Barton-McCombie reaction
auxiliary to versatile protective group
Karin Thorsheim, Sophie Manner, Ulf Ellervik*
Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The methyl xanthate ester is presented as a versatile protective group for alcohols. Hydroxyl
groups can easily be transformed into methyl xanthate esters by several methods and are
commonly used as an auxiliary in the Barton-McCombie reaction. We show that these methyl
xanthate esters can readily and chemoselectively be cleaved under mild conditions by the action
of diethylenetriamine using microwave heating. This method is orthogonal to many common
hydroxyl protective groups that can be introduced and cleaved in the presence of methyl
xanthate ester.
Available online
Keywords:
Methyl xanthate ester
Alcohol protection
Chemoselective
Deprotection
2017 Elsevier Ltd. All rights reserved
.
Diethylenetriamine
1. Introduction
esters could be cleaved from carbohydrates by the action of
Hg(OAc)2.26 Reductive removal using LiAlH4 has also been
presented,25, 27 as well as hydrolysis.28-29 Furthermore, the methyl
xanthate ester has mediated the removal of the Evans auxiliary
using H2O2/LiOH, resulting in cleavage of the xanthate
functionality as well.30 The methyl xanthate ester is an electron-
withdrawing group with low polarity, no stereogenic centers, and
a simple NMR spectroscopic signature (i.e. a singlet at around
2.56 ppm in the 1H-NMR spectrum and signals at around 216 and
19 ppm in the 13C-NMR spectrum), which makes it appealing as
a protective group. Herein, we present the methyl xanthate ester
as a versatile protective group for alcohols that can be cleaved
under mild conditions.
Protective group chemistry is an important field within
synthetic organic chemistry. New protective groups as well as
methods for introduction and removal of well-known protective
groups are frequently published, with reference to special
requirements for reactivity, selectivity, and compatibility.1
Xanthate esters have been used for decades as auxiliary groups in
the Barton-McCombie radical deoxygenation reaction where
hydroxyl groups are transformed into xanthate esters and then
deoxygenated with the aid of a radical initiator and a hydrogen
atom source (Scheme 1).2 Furthermore, methyl xanthate esters
are used in the Chugaev elimination reaction, which forms
olefins by pyrolysis.3 Hence, the xanthate ester is a useful
functional group, commonly employed in total synthesis.4-13
Methyl xanthate esters are generally formed in high yields by
treatment of an alcohol in THF with NaH, CS2, and MeI,
successively. Imidazole may also be present to promote alkoxide
formation.2 Variations such as the use of other strong bases, e.g.
n-BuLi,14 t-BuOK,15 and NaHMDS,16 and other conditions, e.g.
Na,17 NaOH and TBAHS under phase transfer conditions,18
cesium base/TBAI in DMF,19-20 KF-Al2O3,21 Triton-B22 or basic
resin23 in DMSO, and KO2/Et4NBr in DMF,24 have been
employed. Selective monoprotection of a diol can be achieved
using either CsOH H2O/TBAI20 or DBN25 in DMF.
Scheme 1.
2. Results and discussion
In our efforts to find a chemoselective method for cleaving
methyl xanthate esters, we developed a mild and efficient
procedure using diethylenetriamine. Diethylenetriamine was
recently reported to cleave unactivated carbamates and ureas in
the presence of amides, including a few thio derivatives.31
However, reaction temperatures of 130–140 °C for 2–48 h were
To our knowledge, there is no comprehensive study of the use
of the methyl xanthate ester as a protective group, and there are
only a limited number of examples of its removal, usually under
quite harsh conditions. In 1960 it was reported that xanthate

2
Tetrahedron
required. In contrast, we show that methyl xanthate esters can
benzylation with the methyl xanthate ester already present proved
ACCEPTED MANUSCRIPT
be cleaved in 30 min at 160 °C using microwave heating, and
after aqueous work-up, pure alcohols are obtained. The
mechanism of the diethylenetriamine-mediated deprotection is
not known. However, we envision that the methyl xanthate ester
difficult because of the reactivity of the xanthate unit towards
alkoxides.
Removal of the acetate using either catalytic NaOMe or
guanidine/guanidinium nitrate gave only modest yields, due to
partial cleavage of the methyl xanthate ester. However, aqueous
LiOH in THF preserved the xanthate ester moiety (entry 1). The
THP (entry 2) and MOM (entry 3) groups were cleaved under
mild acidic conditions. Debenzylation by hydrogenation using
Pd/C did not regenerate the alcohol, as expected. Most likely, the
sulfur containing xanthate moiety poisons the catalyst. However,
BF3 Et2O and TBAI smoothly cleaved the benzyl protective
group (entry 4). As a precaution, equimolar amounts of acetic
acid were added when the silyl ethers were cleaved with TBAF
(entries 5 and 6).
undergoes
a nucleophilic attack on the thiocarbonyl by
diethylenetriamine. The by-products of the reaction, although the
identities are unknown, are believed to be polar and therefore
water-soluble. Even if the nucleophilic attack would generate
methanethiol, this is a gas and thus causes no purification issues.
Diethylenetriamine is water-soluble and excess reagent is thus
easily removed by aqueous wash. Indeed, aqueous work-up of
the reaction mixtures resulted in pure alcohols characterized by
NMR spectroscopy.
With this new deprotection method in hand, we first examined
the substrate scope (Table 1). Primary (entry 1) and secondary
(entries 2 and 3) methyl xanthate esters, as well as phenolic
xanthate esters (entries 4 and 5), were readily cleaved in excellent
yields. To verify the mildness of the method, three carbohydrate
substrates (entries 6–8), including a disubstituted compound
(entry 8), were subjected to the deprotection protocol, with
excellent yields.
Table 2. Introduction and chemoselective cleavage of alcohol protective
groups in the presence of methyl xanthate ester.
3
4
3
Introduction
Cleavage
Entry PG
Reagents 1
Yield
98%
94%
89%
Reagent(s) 2
Yield
87%
93%
96%
Table 1. Scope of the cleavage of methyl xanthate ester.a
1
2
3
Ac (4a)
Ac2O, Py
1M LiOH
Entry
1
Substance
Product
Yield
92%
THP (4b)
DHP, pTSA
pTSA, THF
1a
1b
2a
2b
MOM (4c)
CH2(OMe)2,
LiBr, pTSA
1M HCl,
MeOH
2
97%
4
Bn (4d)
cf. ref.
32
BF3 Et2O,
TBAI
96%
3
1c
1d
1e
2c
2d
2e
94%
5
6
TBDPS (4e) TBDPSCl,
90%
96%
TBAF, AcOH 96%
TBAF, AcOH 84%
DMAP, Py
TIPS (4f)
TIPSOTf,
2,6-lutidine
4
5
94%
88%
Finally, we investigated the removal of the methyl xanthate
ester in the presence of other hydroxyl protective groups using
our newly developed diethylenetriamine protocol (Table 3). As
anticipated, the acetate group did not tolerate these conditions,
and 1,6-hexanediol was obtained as the major product.
Otherwise, all investigated protective groups were kept intact
under these conditions and the corresponding alcohols were
isolated in excellent yields. As reported by Noshita et al.,31
diethylenetriamine cleaves carbamates. Hence, the methyl
xanthate ester cannot be considered orthogonal to carbamate
protective groups using this deprotection protocol.
6
7
8
1f
2f
99%
99%
96%
Table 3. Chemoselective cleavage of methyl xanthate ester in the
1g
1h
2g
2h
presence of other alcohol protective groups.a
4
5
Entry
PG
Starting material
Product
5a
Yield
14%b
92%
1
2
3
4
5
6
Ac
4a
4b
4c
4d
4e
4f
THP
MOM
Bn
5b
a Diethylenetriamine, 160 °C, 30 min, MW.
5c
96%
5d
quant
99%
To investigate the versatility of the method, 1,6-hexanediol
was monosubstituted as methyl xanthate ester and a range of
representative alcohol protective groups were introduced and
subsequently chemoselectively cleaved (Table 2). The syntheses
of the diprotected compounds were conducted using standard
procedures. The benzylated derivative (entry 4) has been
synthesized before, but by a reversed synthetic procedure, i.e.
benzylation followed by xanthylation.32 Performing the
TBDPS
TIPS
5e
5f
quant
a Diethylenetriamine, 160 °C, 30 min, MW.
b
78% of 1,6-hexanediol was isolated after column chromatography.

3
3. Conclusion
aqueous phase was extracted with CH2Cl2 (3 x). The combined
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organic phases were dried before reduced in vacuo. Column
chromatography (SiO2, EtOAc in petroleum ether) gave the
methyl xanthate protected alcohol.
Hexane-1,6-diol is commercially available. 1a,33 1b,34 1c,35
1d,35 1e,36 and 1g37 are known. Summarized details of known
starting materials are found as Supporting Information (Table
S1).
To conclude, the methyl xanthate ester is a versatile protective
group for alcohols. We have shown that it can be utilized in the
presence of a range of common alcohol protective groups as well
as in a diverse collection of substrates. In addition, short reaction
times, facile purification of products, and no precautions against
atmospheric air or moisture are needed. Methyl xanthate esters
are generally not sensitive towards acids, bases, and Lewis acids
and are moderately reactive towards nucleophiles and reducing
agents (Table 4). However, oxidizing agents are not well
tolerated. This again displays their utility and diversification
versus other functional and protective groups. Literature
references and reaction conditions can be found in the Supporting
Information (Table S3).
4.2.1
Methyl
2-O-benzyl-4,6-O-benzylidene-3-O-
-galactopyranoside (1f).
[(methylthio)thiocarbonyl]-β-
D
Synthesized from methyl 2-O-benzyl-4,6-O-benzylidene-β-D-
galactopyranoside38 2f (141 mg, 0.380 mmol) according to the
general methyl xanthate ester formation procedure. Gave 1f (165
mg, 94%) as an amorphous white solid. Rf (1:1 Hept/EtOAc)
20
0.50. [α]D +149 (c 1.3, CHCl3). vmax (neat): 3062, 3031, 2853,
Table 4. Reactivity chart of methyl xanthate esters.
1496, 1451, 1399, 1365, 1313, 1214, 1178, 1153, 1100, 1052 cm-
1. H NMR (CDCl3): δ 7.52–7.49 (m, 2H, ArH), 7.39–7.24 (m,
Reagents
Acids
Unreactive
Reactive
MeSO3H
RO-
1
pTSA, HCl, AcOH
Py, aq LiOH
BF3 Et2O, TMSI
TBAF
8H, ArH), 5.80 (dd, 1H, J = 10.0, 4.0 Hz, H-3), 5.52 (s, 1H,
CHPh), 4.87 (d, 1H, J = 11.5 Hz, CH2Ph), 4.68 (d, 1H, J = 11.5
Hz, CH2Ph), 4.60 (d, 1H, J = 3.0 Hz, H-4), 4.45 (d, 1H, J = 8.0
Hz, H-1), 4.37 (dd, 1H, J = 12.5, 1.5 Hz, H-6), 4.10 (dd, 1H, J =
12.5, 2.0 Hz, H-6), 4.02 (dd, 1H, J = 10.0, 7.5 Hz, H-2), 3.61 (s,
Bases
Lewis acids
Nucleophiles
NaOMe, RO-,
diethylenetriamine
3H, OMe), 3.54 (d, 1H, J = 1.0 Hz, H-5), 2.51 (s, 3H, SMe); 13
C
NMR (CDCl3): δ 216.0, 138.5, 137.7, 129.0, 128.4, 128.2, 127.9,
127.7, 126.4, 104.7, 100.9, 81.5, 76.3, 75.0, 73.2, 69.1, 66.1,
57.4, 19.1; HRMS (ESI): m/z [M + Na]+ calcd for C23H26O6S2Na
485.1068, found 485.1067.
Reducing
agents
NaBH4, NaBH3CN
LiAlH4, L-selectride, LiBH4,
BH3 SMe2
Oxidative
agents
mCPBA, NaIO4, H2O2/LiOH
4.2.2
[(methylthio)thiocarbonyl]-α-
Synthesized from methyl
Methyl
4,6-O-benzylidene-2,3-di-O-
-galactopyranoside (1h).
4,6-O-benzylidene-α-
Miscellaneous
Ac2O, Pd/C H2
AIBN/nBu3SnH
D
D-
4. Experimental section
4.1 General
galactopyranoside39 2h (242 mg, 0.857 mmol) according to the
general methyl xanthate ester formation procedure. Gave 1h (384
mg, 97%) as a white solid. m.p. 188–189 °C. Rf (1:3
Hept/EtOAc) 0.68. [α]D20 +171 (c 1.3, CHCl3). vmax (neat): 2993,
All solvents were dried using MBRAUN SPS-800 Solvent
purification system prior to use, unless otherwise stated. The
purchased reagents were used without further purification.
Reactions were monitored by TLC using alumina plates coated
with silica gel, and visualized using UV light (254 nm) or by
charring with an ethanolic anisaldehyde or potassium
permanganate solution. A Biotage Initiator Classic microwave
instrument was used for the reactions performed with microwave
heating. Biotage Isolute phase separators were used for drying of
combined organic layers. Preparative chromatography was
performed on A Biotage Isolera One flash purification system
using Biotage SNAP KP-Sil silica cartridges. Optical rotations
were measured on Perkin Elmer instruments, Model 341
polarimeter and are reported as [α]DT (c = g/100 mL), D indicates
the sodium D line (589 nm) and T indicates the temperature.
Melting points were measured on Stuart SMP30 apparatus.
Infrared spectra were recorded on Bruker ALPHA-P fourier
transform spectrometer (FTIR). NMR spectra were recorded on
Bruker Avance II (1H-NMR at 400 MHz and 13C-NMR at 100
MHz) and assigned using 2D methods (COSY, HMQC).
Chemical shifts are reported in ppm downfield from Me4Si, with
reference to residual solvent peaks (δH CDCl3 = 7.26 ppm) and
solvent signals (δC CDCl3 = 77.0 ppm). High-resolution mass
spectra (HRMS) were recorded on Waters QTOF XEVO-G2
(ESI+).
2931, 2916, 2856, 1413, 1201, 1151, 1103, 1062 cm-1. H NMR
1
(CDCl3): δ 7.53–7.51 (m, 2H, ArH), 7.41–7.35 (m, 3H, ArH),
6.33–6.34 (m, 2H, H-2, H-3), 5.56 (s, 1H, CHPh), 5.32 (d, 1H, J
= 1.5 Hz, H-1), 4.75 (d, 1H, J = 1.0 Hz, H-4), 4.33 (dd, 1H, J =
12.5, 1.5 Hz, H-6), 4.12 (dd, 1H, J = 12.5, 1.5 Hz, H-6), 3.86 (d,
1H, J = 1.0 Hz, H-5), 3.46 (s, 3H, OMe), 2.54 (s, 3H, SMe), 2.51
(s, 3H, SMe); 13C NMR (CDCl3): δ 215.6, 215.5, 137.5, 129.1,
128.3, 126.2, 100.8, 97.4, 76.5, 75.9, 73.8, 69.2, 62.3, 56.0, 19.3,
19.0; HRMS (ESI): m/z [M + Na]+ calcd for C18H22O6S4Na
485.0197, found 485.0199.
4.2.3 O-(6-Hydroxyhexyl) S-methyl carbonodithioate (3).
Synthesized from 1,6-hexanediol (1.01 g, 8.56 mmol) according
to the general methyl xanthate ester formation procedure. Gave 3
(963 mg, 54%) as a pale yellow oil. The disubstituted analog was
also isolated in 36% yield as a yellow oil. Rf (1:3 Hept/EtOAc)
0.58. vmax (neat): 3335, 2931, 2858, 1459, 1424, 1383, 1318,
1
1215,1103, 1051 cm-1. H NMR (CDCl3): δ 4.60 (t, 2H, J = 6.5
Hz), 3.66 (t, 2H, J = 6.5 Hz), 2.56 (s, 3H), 1.82 (quint, 2H, J =
7.0 Hz), 1.60 (quint, 2H, J = 7.0 Hz), 1.50–1.38 (m, 4H); 13C
NMR (CDCl3): δ 216.2, 74.2, 63.0, 32.7, 28.4, 25.9, 25.5, 19.1;
HRMS (ESI): m/z [M + Na]+ calcd for C8H16O2S2Na 231.0489,
found 231.0490.
4.3 Preparation of substrates (Table 2)
4.2 General procedure for methyl xanthate ester formation
(Table 1 and 2)
4.3.1 6-(((Methylthio)carbonothioyl)oxy)hexyl acetate (4a).
To 3 (377 mg, 1.81 mmol), were added pyridine (3 mL) and
Ac2O (2.5 mL). After 1.5 h, ice water (20 mL) was added and the
aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The
combined organic layers were washed with aq. HCl (0.5 M, 20
mL), satd. aq. NaHCO3 (20 mL), and brine (20 mL) before being
To a stirred solution of the alcohol in THF (0.07 M), was
added NaH (60% in mineral oil, 2 eq.) and after 20 min CS2 (5
eq.) was added. After an additional 20 min, MeI (5 eq.) was
added and after 20 min satd. aq. NH4Cl was added and the

4
Tetrahedron
ACCEPTED MANUSCRIPT
dried and reduced in vacuo to yield a pale yellow oil. Column
2,6-lutidine (524 µL, 4.50 mmol). After 2 h, water (10 mL) was
chromatography (SiO2, 10 → 30% EtOAc in petroleum ether)
gave 4a (445 mg, 98%) as a pale yellow oil. Rf (1:3 Hept/EtOAc)
0.44. vmax (neat): 2938, 2861, 1735, 1460, 1428, 1387, 1365,
added and the aqueous phase was extracted with CH2Cl2 (3 x 10
mL). The combined organic layers were dried and reduced in
vacuo to yield a pale yellow oil. Column chromatography (SiO2,
0 → 20% EtOAc in petroleum ether) gave 4f (630 mg, 96%) as a
colorless oil. Rf (1:1 Hept/EtOAc) 0.70. vmax (neat): 2938, 2891,
1217, 1109, 1051 cm-1. H NMR (CDCl3): δ 4.60 (t, 2H, J = 6.5
1
Hz), 4.06 (t, 2H, J = 6.5 Hz), 2.56 (s, 3H), 2.05 (s, 3H), 1.82
(quint, 2H, J = 7.0 Hz), 1.65 (quint, 2H, J = 7.0 Hz), 1.49–1.37
(m, 4H); 13C NMR (CDCl3): δ 216.2, 171.4, 74.1, 64.5, 28.6,
28.3, 25.7 (2C), 21.2, 19.1; HRMS (ESI): m/z [M + Na]+ calcd
for C10H18O3S2Na 273.0595, found 273.0590.
2863, 2752, 2725, 1462, 1428, 1385, 1220, 1100, 1058 cm-1. H
1
NMR (CDCl3): δ 4.59 (t, 2H, J = 7.0 Hz), 3.68 (t, 2H, J = 6.5
Hz), 2.56 (s, 3H), 1.81 (quint, 2H, J = 7.0 Hz), 1.56 (quint, 2H, J
= 6.5 Hz), 1.48–1.37 (m, 4H), 1.11–1.02 (m, 21H); 13C NMR
(CDCl3): δ 216.2, 74.4, 63.4, 33.0, 28.4, 25.9, 25.6, 19.1, 18.2,
12.2; HRMS (ESI): m/z [M + Na]+ calcd for C17H36O2S2SiNa
387.1824, found 387.1826.
4.3.2 S-Methyl O-(6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)
carbonodithioate (4b). To a solution of 3 (375 mg, 1.80 mmol) in
CH2Cl2 (5 mL), were added DHP (247 µL, 2.70 mmol) and
pTSA (3.5 mg, 0.018 mmol). After 1.5 h, the reaction mixture
was washed with satd. aq. NaHCO3 (10 mL), dried, and reduced
in vacuo to yield a pale yellow oil. Column chromatography
(SiO2, 0 → 30% EtOAc in petroleum ether) gave 4b (496 mg,
94%) as a colorless oil. Rf (1:1 Hept/EtOAc) 0.59. vmax (neat):
2936, 2861, 1454, 1438, 1382, 1351, 1320, 1218, 1136, 1120,
4.4 Cleavage of alcohol protective groups (Table 2)
4.4.1 Cleavage of acetate. To a solution of 4a (119 mg, 0.475
mmol) in THF (12 mL), was added aq. LiOH (1M, 19 mL). After
3.5 h, the aqueous phase was extracted with CH2Cl2 (3 x 20 mL)
and the combined organic layers were dried before reduced in
vacuo to yield a colorless oil. Column chromatography (SiO2, 20
→ 40% EtOAc in petroleum ether) gave 3 (86 mg, 87%) as a
colorless oil, with data consistent with above stated (4.2.3).
1056, 1024 cm-1. H NMR (CDCl3): δ 4.61–4.56 (m, 3H), 3.89–
1
3.84 (m, 1H), 3.74 (dt, 1H, J = 9.5, 6.5 Hz), 3.53–3.50 (m, 1H),
3.39 (dt, 1H, J = 9.5, 6.5 Hz), 2.56 (s, 3H), 1.87–1.78 (m, 3H),
1.75–1.68 (m, 1H), 1.65–1.49 (m, 6H), 1.47–1.39 (m, 4H); 13C
NMR (CDCl3): δ 216.2, 99.0, 74.3, 67.6, 62.5, 30.9, 29.8, 28.4,
26.1, 25.9, 25.6, 19.9, 19.1; HRMS (ESI): m/z [M + Na]+ calcd
for C13H24O3S2Na 315.1064, found 315.1058.
4.4.2 Cleavage of THP acetal. To a solution of 4b (147 mg,
0.504 mmol) in THF (4 mL), were added pTSA (5.9 mg, 0.032
mmol) and H2O (1 mL) and the reaction mixture was heated to
50 °C. After 3 d, satd. aq. NaHCO3 (15 mL) was added and the
aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The
combined organic layers were dried and reduced in vacuo to
yield a colorless oil. Column chromatography (SiO2, 20 → 40%
EtOAc in petroleum ether) gave 3 (97 mg, 93%) as a colorless
oil, with data consistent with above stated (4.2.3).
4.3.3
O-(6-(Methoxymethoxy)hexyl)
S-methyl
carbonodithioate (4c). To a solution of 3 (376 mg, 1.80 mmol) in
dimethoxymethane (3.6 mL), were added LiBr (31 mg, 0.36
mmol) and pTSA (36 mg, 0.19 mmol). After 24 h, additional
LiBr (16 mg, 0.19 mmol) and pTSA (13 mg, 0.069 mmol) were
added and after another 24 h, satd. aq. NaHCO3 (15 mL) was
added. The aqueous phase was extracted with Et2O (3 x 25 mL)
and the combined organic layers were dried and reduced in vacuo
to yield a pale yellow oil. Column chromatography (SiO2, 0 →
30% EtOAc in petroleum ether) gave 4c (403 mg, 89%) as a
colorless oil. Rf (1:1 Hept/EtOAc) 0.58. vmax (neat): 2932, 2862,
4.4.3 Cleavage of MOM ether. To a solution of 4c (132 mg,
0.524 mmol) in MeOH (5 mL), was added conc HCl (37%, 0.3
mL) dropwise. After 2 d, satd. aq. NaHCO3 (15 mL) was added
and the aqueous phase was extracted with CH2Cl2 (3 x 15 mL).
The combined organic layers were dried and reduced in vacuo to
yield a colorless oil. Column chromatography (SiO2, 20 → 40%
EtOAc in petroleum ether) gave 3 (105 mg, 96%) as a colorless
oil, with data consistent with above stated (4.2.3).
2821, 2769, 1462, 1386, 1215, 1149, 1107, 1043 cm-1. H NMR
1
(CDCl3): δ 4.62 (s, 2H), 4.60 (t, 2H, J = 6.5 Hz), 3.53 (t, 2H, J =
6.5 Hz), 3.36 (s, 3H), 2.56 (s, 3H), 1.82 (quint, 2H, J = 7.0 Hz),
1.62 (quint, 2H, J = 6.5 Hz), 1.49–1.39 (m, 4H); 13C NMR
(CDCl3): δ 216.2, 96.6, 74.2, 67.7, 55.3, 29.7, 28.4, 26.0, 25.9,
19.1; HRMS (ESI): m/z [M + Na]+ calcd for C10H20O3S2Na
275.0752, found 275.0752.
4.4.4 Cleavage of benzyl ether. To a solution of 4d (52 mg,
0.17 mmol) in CH2Cl2 (2 mL), were added TBAI (190 mg, 0.513
mmol) and BF3 Et2O (0.06 mL, 0.47 mmol). After 16 h, satd. aq.
NaHCO3 (10 mL) was added and the aqueous phase was
extracted with CH2Cl2 (3 x 10 mL). The combined organic layers
were washed with 50% aq Na2S2O3 (50 mL) and H2O (50 mL),
dried, and reduced in vacuo to yield a pale yellow oil. Column
chromatography (SiO2, 20 → 40% EtOAc in petroleum ether)
gave 3 (35 mg, 96%) as a colorless oil, with data consistent with
above stated (4.2.3).
4.3.4
O-(6-((tert-Butyldiphenylsilyl)oxy)hexyl)
S-methyl
carbonodithioate (4e). To a solution of 3 (374 mg, 1.80 mmol) in
pyridine (4 mL), were added TBDPSCl (700 µL, 2.70 mmol) and
DMAP (22 mg, 0.18 mmol). After 6 h, aq. HCl (1 M, 10 mL)
was added and the aqueous phase was extracted with CH2Cl2 (3 x
10 mL). The combined organic layers were washed with aq.
CuSO4 (4 x 25 mL), dried, and reduced in vacuo to yield a pale
yellow oil. Column chromatography (SiO2, 0 → 20% EtOAc in
petroleum ether) gave 4e (723 mg, 90%) as a pale yellow oil. Rf
(1:1 Hept/EtOAc) 0.60. vmax (neat): 3070, 3048, 2997, 2930,
4.4.5 Cleavage of TBDPS ether. To a solution of 4e (225 mg,
0.503 mmol) in THF (5 mL), were added TBAF (1 M in THF, 1
mL, 1 mmol) and AcOH (57 µL, 1.0 mmol) and the reaction
mixture was heated to 50 °C. After 2 h, satd. aq. NaHCO3 (10
mL) was added and the aqueous phase was extracted with CH2Cl2
(3 x 10 mL). The combined organic layers were dried and
2856, 1469, 1427, 1388, 1360, 1220, 1107, 1056 cm-1. H NMR
1
(CDCl3): δ 7.68–7.65 (m, 4H), 7.45–7.36 (m, 6H), 4.57 (t, 2H, J
= 6.5 Hz), 3.66 (t, 2H, J = 6.5 Hz), 2.55 (s, 3H), 1.78 (quint, 2H,
J = 7.0 Hz), 1.61–1.54 (m, 2H), 1.45–1.36 (m, 4H), 1.05 (s, 9H);
13C NMR (CDCl3): δ 216.2, 135.7, 134.2, 129.7, 127.7, 74.3,
63.9, 32.5, 28.4, 27.0, 25.8, 25.6, 19.4, 19.1; HRMS (ESI): m/z
[M + Na]+ calcd for C24H34O2S2SiNa 469.1667, found 469.1671.
reduced in vacuo to yield
a pale yellow oil. Column
chromatography (SiO2, 20 → 40% EtOAc in petroleum ether)
gave 3 (101 mg, 96%) as a colorless oil, with data consistent with
above stated (4.2.3).
4.4.6 Cleavage of TIPS ether. To a solution of 4f (182 mg,
0.499 mmol) in THF (5 mL), were added TBAF (1 M in THF, 1
mL, 1 mmol) and AcOH (57 µL, 1.0 mmol) and the reaction
mixture was heated to 50 °C. After 9 h, satd. aq. NaHCO3 (10
4.3.5
S-Methyl
O-(6-((triisopropylsilyl)oxy)hexyl)
carbonodithioate (4f). To a solution of 3 (373 mg, 1.79 mmol) in
CH2Cl2 (4 mL), were added TIPSOTf (726 µL, 2.70 mmol) and

5
13. Cons BD, Bunt AJ, Bailey CD, Willis CL. Org. Lett.
2013;15:2046.
14. Jin J, Newcomb M. J. Org. Chem. 2007;72:5098.
mL) was added and the aqueous phase was extracted with CH2Cl2
ACCEPTE
D
MANUSCRIPT
(3 x 10 mL). The combined organic layers were dried and
reduced in vacuo to yield pale yellow oil. Column
a
15. Hagiwara H, Kobayashi K, Miya S, Hoshi T, Suzuki T, Ando M.
Org. Lett. 2001;3:251.
16. Tanaka R, Ohishi K, Takanashi N, Nagano T, Suizu H, Suzuki T,
Kobayashi S. Org. Lett. 2012;14:4886.
chromatography (SiO2, 20 → 40% EtOAc in petroleum ether)
gave 3 (88 mg, 84%) as a colorless oil, with data consistent with
above stated (4.2.3).
4.5 General procedure for methyl xanthate cleavage (Table 1
and 3)
17. Majetich G, Irvin TC, Thompson SB. Tetrahedron Lett.
2015;56:3326.
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1989;19:547.
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20. Nagle AS, Salvatore RN, Cross RM, Kapxhiu EA, Sahab S,
Yoon CH, Jung KW. Tetrahedron Lett. 2003;44:5695.
21. Villemin D, Hachemi M. Synth. Commun. 1996;26:2449.
22. Chaturvedi D, Ray S. Monatsh. Chem. 2006;137:1219.
23. Chaturvedi D, Ray S. J. Sulfur Chem. 2006;27:265.
24. Singh SK, Singh KN. Phosphorus, Sulfur Silicon Relat. Elem.
2011;186:94.
25. Schlessinger RH, Schultz JA. J. Org. Chem. 1983;48:407.
26. Willard JJ, Pacsu E. J. Am. Chem. Soc. 1960;82:4347.
27. Kapeller DC, Hammerschmidt F. J. Org. Chem. 2009;74:2380.
28. Humeres E, Soldi V, Klug M, Nunes M, Oliveira CMS, Barrie
PJ. Can. J. Chem. 1999;77:1050.
To a 0.5–2.0 mL microwave vial with a magnetic stirring bar,
were added methyl xanthate ester (0.3–0.6 mmol) and
diethylenetriamine (0.5 mL, 4.6 mmol) under air and the vial was
sealed with a microwave vial cap with septum. The reaction
mixture was heated to 160 °C for 30 min by microwave heating.
Aq. HCl (1 M, 15 ml) was added and the aqueous phase was
extracted with CH2Cl2 (3 x 15 mL). The combined organic
phases were washed with satd. aq. NaHCO3 (20 mL) and brine
(20 mL) before being dried and reduced in vacuo to yield the
alcohols, which all are either commercially available (hexane-
1,6-diol, 2a, 2b, 2c, 2d, and 2e) or known (2f,38 2g,38 2h,39 5a,40
5b,41 5c,41 5d,42 5e,41 5f41). Summarized details of individual
cleavage reactions are found as supporting information (Table
S3).
29. Barboni L, Datta A, Dutta D, Georg GI, Vander Velde DG,
Himes RH, Wang M, Snyder JP. J. Org. Chem. 2001;66:3321.
30. Hager A, Kuttruff CA, Herrero-Gomez E, Trauner D.
Tetrahedron Lett. 2014;55:59.
31. Noshita M, Shimizu Y, Morimoto H, Ohshima T. Org. Lett.
2016;18:6062.
Acknowledgments
This work was supported by grants from Lars Hiertas Memorial
Foundation, the Magnus Bergwall Foundation, Lund University,
and the Royal Physiographic Society in Lund.
32. Ueng S-H, Solovyev A, Yuan X, Geib SJ, Fensterbank L, Lacote
E, Malacria M, Newcomb M, Walton JC, Curran DP. J. Am. Chem.
Soc. 2009;131:11256.
Supplementary Material
33. Majetich G, Irvin TC, Thompson SB. Tetrahedron Lett.
2015;56:3326.
34. Chaturvedi D, Ray S. J. Sulfur Chem. 2006;27:265.
35. Kiyoshi K, Yoichiro T, Kazundo S, Manabu K, Tamejiro H. Bull.
Chem. Soc. Jpn 2000;73:471.
These data include summarized details of individual reactions
and NMR spectra of new compounds.
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