Microwave-assisted cross-metathesis of unsaturated thiocyanates: Application to the synthesis of thiocyanatins A and B and analogues

Article abstract of DOI:10.1055/s-0029-1217089

The syntheses of thiocyanatin B and related dithiocyanates have been carried out by cross metathesis of unsaturated thiocyanates promoted by a ruthenium catalyst. The efficiency of the reaction depends strongly on the nature of the catalyst, the length of

Full text of DOI:10.1055/s-0029-1217089

PAPER
233
Microwave-Assisted Cross-Metathesis of Unsaturated Thiocyanates:
Application to the Synthesis of Thiocyanatins A and B and Analogues
M
icrowave-As
a
siste
d
Cros
n
s-Metathesis
n
of Unsatura
y
tedThiocyanates Cros, Béatrice Pelotier, Olivier Piva*
Université de Lyon, Université Lyon 1, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
43, Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(4)72448136; E-mail: piva@univ-lyon1.fr
Received 27 May 2009; revised 14 September 2009
Thiocyanatins possess potential nematocidal properties
Abstract: The syntheses of thiocyanatin B and related dithiocyan-
against the livestock parasite Haemonchus contortus.6
Their structures have been elucidated by total synthesis
ates have been carried out by cross metathesis of unsaturated thio-
cyanates promoted by a ruthenium catalyst. The efficiency of the
reaction depends strongly on the nature of the catalyst, the length of
using Wittig reaction as coupling process and introduction
the alkenyl chain, and the mode of activation (conventional heating of the thiocyanato groups at the final stage.4 In connection
or microwave activation). In the later case, isomerization of double
with our interest in metathesis reactions and related tan-
dem procedures,7,8 we have investigated a more straight-
bonds took place and altered the course of the reaction. Alternative-
ly, thiocyanatins A and B were synthesized by only a three-step and
forward approach to thiocyanatins 3 and 4 and related
a two-step procedure, respectively, from readily available tosylates.
analogues (Scheme 1).
Key words: metathesis, thiocyanates, Hoveyda–Grubbs catalyst,
marine natural products, thiocyanatins
OH
X
OH
CM
6
+
( )4
CM
( )4
X
Marine natural products possessing a thiocyanate group
are rare.1 Some of them depicted in Figure 1 exhibit, how-
ever, significant biological activities. Psammaplin B (1)
has been reported as a histone decarboxylase inhibitor2
while fascicularin (2) – structurally close to cylindricines
– exhibits DNA damage properties.3 More intriguing
structures bearing at both extremities a thiocyanato group,
namely thiocyanatins A–C (3–5), have been also isolated
from a marine sponge of the genus Oceanapia collected
off the northern Rottnest Shelf in Australia (Figure 1).4
Compounds with similar structures were previously ex-
tracted from Pseudaxinyssa sp., a Fijian sponge.5
X
( )4
3 (X = SCN)
CM
NCS
( )6
( )6
( )6
SCN
SCN
4
Scheme 1 Disconnection approach for thiocyanatins A and B
Target compound 3 could result from a double cross-
metathesis between commercially available alcohol 6 and
two identical unsaturated functionalized alkenes. Sym-
metric dithiocyanate 4 could be built by the self-metathe-
sis of an unsaturated compound – ideally the isocyanate
7d. Despite the absence of precedence in the literature, we
investigated at first a possible synthesis of 4 and ana-
logues by self coupling of unsaturated thiocyanates per-
formed in the presence of the well established Grubbs
catalyst II (GBII). As already pointed out in the literature,
metathesis of thio derivatives9 and also nitriles10 are usu-
ally problematic. To overcome the lack of reactivity of
these substrates, various strategies have been considered.
The use of co-catalysts such as copper salts renders the re-
action with unsaturated nitriles much more efficient.11
OH
Br
NCS
N
O
SCN
N
H
N
HO
1
2
OH
NCS
NCS
3
SCN
SCN
( )4
( )4
4 (n = 4, m = 4)
5 (n = 3, m = 5)
( )m
Alternatively, activation of the medium by microwaves
was advertized for a large number of processes12 and re-
cently reviewed.13 First attempts were performed on thio-
cyanate 7a readily prepared by nucleophilic substitution
of commercially available 4-bromobut-1-ene with potas-
sium thiocyanate in ethanol. When conducted in refluxing
dichloromethane in the presence of second generation
Grubbs catalyst, only traces of the expected adduct 8a
were detected in the NMR spectra of the crude product,
( )n
Figure 1 Some natural marine isocyanates
SYNTHESIS 2010, No. 2, pp 0233–0238
x
x
.
x
x
.2
0
0
9
Advanced online publication: 26.10.2009
DOI: 10.1055/s-0029-1217089; Art ID: T10809SS
© Georg Thieme Verlag Stuttgart · New York

234
F. Cros et al.
PAPER
even after a long period of reaction (Table 1). By contrast, instead of a direct thermal microwave effect.16 We envi-
the same reaction performed in the presence of Hoveyda– sioned that these competitive reactions could be affected
Grubbs catalyst14 (HG) (5 mol%) under conventional by the mode of activation whatever the catalyst used and
heating delivered dithiocyanate 8a in an encouraging 40% the functionalities present on the starting material. There-
yield as a single stereoisomer for which the E-configura- fore, we investigated the dimerization of commercially
tion was attributed. The yield was considerably enhanced available 6-bromohex-1-ene into 9 under different condi-
by microwave (MW) activation within a shorter time of tions and results are collected in Table 2.
reaction and represents the first successful example of
Table 2 Cross-Metathesis of 6-Bromohex-1-ene
metathesis with thiocyanate derivatives.
Br
( )3
( )3
Br
Br
catalyst
heating
Table 1 Cross-Metathesis of Thiocyanates 7a–d
9
( )3
Br
catalyst
CH2Cl2
heating
Br
NCS
( )m
( )n
( )n
( )n
( )n
SCN
SCN
CH2Cl2
10–13
7a–c (n = 1–3)
7d (n = 6)
8a–c (n = 1–3)
4 (n = 4)
Compound C (n + m + 4)
9a
10a
11a
C8
12a
C9
13a
C11
7
a
a
a
a
b
n
1
1
1
1
2
Conditionsa
GBII (2 × 2.5 mol%), reflux, 16 h
Yield (%)b
5
C10 C7
GBII (5 mol%), MW, 100 °C,
(20 + 10 min)
45.9 2.1
11.2 32.6 8.2
GBII (4 + 1 mol%), MW, (20 + 10 min) 22
GBII (2.5 mol%), 40 °C, 4 h
71.3
–
–
3.7 24.1 0.2
HG (2 × 2.5 mol%), reflux, 16 h
40
81
99
GBII (5 mol%), r.t., 5 h 30 min 88.4
–
11.6
–
HG (4 + 1 mol%), MW, (20 + 10 min)
HG (4 + 1 mol%), MW, (20 + 10 min)
a Ratio determined by GC/MS measurements.
a See experimental conditions.
According to Table 2, it appears as if the self-metathesis
is strongly affected by the mode of activation and the tem-
perature of the reaction.17 Therefore, MW activation,
which has been favorably used for the metathesis of deac-
tivated compounds, should be more carefully considered
with more reactive long chain structures. These results
prompted us also to modify our initial strategy toward the
synthesis of the two target molecules 3 and 4. We decided
to introduce at a later stage the thiocyanato group by nu-
cleophilic substitution on a ditosylate (Scheme 2).
b Isolated yield of dithiocyanates 8a or 8b.
These conditions were next applied to other unsaturated
thiocyanates 7b–d. The reaction proceeded equally well
with pentenyl thiocyanate 7b (n = 2) and delivered the
dimeric structure in quantitative yield. Unfortunately, for
substrates with a longer chain 7c (n = 3) and 7d (n = 6),
the process was more sluggish and afforded in each case,
a complex mixture of inseparable compounds by flash
chromatography. GC analysis coupled with mass spec-
troscopy revealed the presence of the expected compound
8c and 4 contaminated with structures missing one or two
methylene subunits, respectively. Their formation could
effectively result from a preliminary internal migration of
the terminal double bond into the aliphatic chain before
coupling with another unsaturated thiocyanate fragment.
Such isomerizations are well known and have been no-
ticed in numerous metathesis processes and have been in
some cases advantageously exploited in synthesis.15 More
intriguing, the formation of compounds possessing an ad-
ditional methylene group was also observed. This later
process is rarely reported with the Hoveyda–Grubbs cata-
lyst under conventional heating. It could be rationalized
by isomerization of the C=C bond of the initially formed
adduct 8, followed by a cross metathesis with the starting
material 7 still present in the medium. At this stage, it
should be pointed out that microwave-assisted metatheses
were performed in sealed vessels preventing the escape of
ethylene formed during the reaction. In contrast, this by-
product was released in the atmosphere, under classical
heating. Therefore, the difference in the product distribu-
tion observed could result from the presence of ethylene
( )7
( )7
TsO
NCS
a
b
OTs
OTs
SCN
OTs
( )7
( )7
( )7
15
4
14
OH
OH
( )5
c
( )
5 OTs
+
( )5
17
6
16
OTs
OH
OH
d
e
OTs
NCS
SCN
( )6
18
( )6
TsO
( )7
( )8
3
Scheme 2 Reagents and conditions: (a) 7.5 mol% Grubbs II cata-
lyst, CH2Cl2, 20 °C, 16 h, 79%; (b) KSCN (3 equiv), EtOH, reflux, 12
h, 94%; (c) 7.5 mol% Grubbs II catalyst, CH2Cl2, 20 °C, 5 h, 99%; (d)
H2 (1 atm), 5 mol% PtO2, EtOAc, 20 °C, 1 h, 91%; (e) KSCN (3
equiv), EtOH, reflux, 12 h, 62%.
The synthesis of thiocyanatin B (4) required at first the
preparation of the tosylate of non-8-en-1-ol, which was
obtained in 61% yield by a four step sequence from 8-bro-
mooct-1-ene (see experimental part). The self-metathesis
Synthesis 2010, No. 2, 233–238 © Thieme Stuttgart · New York

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Microwave-Assisted Cross-Metathesis of Unsaturated Thiocyanates
235
4-Thiocyanatobut-1-ene (7a)18
Yield: 194 mg, 1.71 mmol (86%); colorless liquid.
of 14 was performed at room temperature in the presence
of catalytic amount of Grubbs II reagent and delivered af-
ter 18 hours of reaction the ditosylate 15 in 79% yield 1H NMR (300 MHz, CDCl3): d = 2.50 (2 H, br q, J = 6.8 Hz, H-3),
2.96 (2 H, t, J = 7.1 Hz, H-4), 5.08–5.16 (2 H, m, H-1), 5.73 (1 H,
(Scheme 2). The reaction proceeded with high stereocon-
trol; the E-configuration attributed to the sole stereoiso-
ddt, J = 17.1, 10.3, 6.6 Hz, H-2).
mer detected, was confirmed in the next step, after
comparison with literature data. Substitution of the tosy-
late group with KSCN delivered directly 4 in 94% yield.
The synthesis of thiocyanatin A (3) was next investigated.
In that case, introduction of thiocyanato group was neces-
sary planned at the final stage to avoid competitive reduc-
5-Thiocyanatopent-1-ene (7b)19
Yield: 255 mg, 2.00 mmol (99%); colorless liquid.
1H NMR (300 MHz, CDCl3): d = 1.93 (2 H, quint, J = 7.1 Hz, H-4),
2.23 (2 H, q, J = 7.1 Hz, H-3), 2.95 (2 H, t, J = 7.1 Hz, H-5), 5.04–
5.11 (2 H, m, H-1), 5.75 (1 H, ddt, J = 17.1, 10.3, 6.6 Hz, H-2).
tion of this labile group during the hydrogenation of the
two double bonds. The synthesis summarized in
Scheme 2 starts with a double cross-metathesis of alcohol
6 with tosylate 16. Hydrogenation of the double bonds of
the ditosylate 17 followed by treatment with KSCN af-
forded thiocyanatin A 3 in an overall yield of nearly 50%.
6-Thiocyanatohex-1-ene (7c)
Yield: 284 mg, 2.00 mmol (99%); colorless liquid.
IR (neat): 914, 993, 1265, 1439, 1640, 2154, 2936, 2977, 3078
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 (2 H, quint, J = 7.2 Hz, H-5),
1.84 (2 H, quint, J = 7.2 Hz, H-4), 2.11 (2 H, q, J = 7.2 Hz, H-3),
2.95 (2 H, t, J = 7.2 Hz, H-6), 4.97–5.06 (2 H, m, H-1), 5.78 (1 H,
ddt, J = 16.9, 10.1, 6.6 Hz, H-2).
13C NMR (75 MHz, CDCl3): d = 26.7 (CH2), 28.9 (CH2), 32.5
(CH2), 33.5 (CH2), 111.9 (C, C-7), 114.9 (CH2, C-1), 137.3 (CH, C-
2).
In conclusion, we have demonstrated for the first time that
unsaturated thiocyanates with medium chains can be fa-
vorably implicated in metathesis reactions under MW ac-
tivation in the presence of the Hoveyda–Grubbs catalyst.
Substrates bearing longer chains could undergo rear-
rangement in noticeable yields under the same conditions.
Furthermore, the straightforward syntheses of thiocyana-
tin A and B (3 and 4) have been achieved by metathesis of
unsaturated tosylates followed by substitution with potas-
sium thiocyanate. These sequences could be favorably
compared to the previous synthesis in term of yields and
number of steps.
HRMS: m/z calcd for [C7H11NS + H]+: 142.0690; found: 142.0691.
9-Thiocyanatonon-1-ene (7d)
Prepared starting from 9-bromonon-1-ene (0.40 mmol); yield: 71
mg, 0.39 mmol (97%); colorless liquid.
IR (neat): 910, 995, 1261, 1463, 1640, 2154, 2855, 2928, 3076
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33–1.42 (8 H, m, H-5, H-6, H-
7, H-8), 1.82 (2 H, br quint, J = 7.4 Hz, H-4), 2.04 (2 H, br q, J = 6.6
Hz, H-3), 2.94 (2 H, t, J = 7.3 Hz, H-9), 4.91–5.03 (2 H, m, H-1),
5.80 (1 H, ddt, J = 16.9, 10.1, 6.6 Hz, H-2).
13C NMR (75 MHz, CDCl3): d = 28.0 (CH2), 28.8 (2 CH2), 28.9
(CH2), 29.9 (CH2), 33.8 (CH2), 34.1 (CH2), 111.7 (C, C-10), 114.4
(CH2, C-1), 139.0 (CH, C-2).
Microwave assisted synthesis was carried out in an InitiatorTM 2.0
single mode MW at 2.45 GHz (Biotage AB, Uppsala). The reactions
were performed in sealed vessels (0.5 to 20 mL) equipped with a
Teflon-coated stirring bar and under an argon atmosphere. A vari-
able power was employed to reach the temperature desired and then
to maintain it in the vessel during the period of time programmed.
1H and 13C NMR spectra were recorded with a Bruker AM 300 MHz
NMR spectrometer, which provided all the necessary data for the
full assignment of each compound. Chemicals shifts are reported in
ppm. High-resolution mass spectrometry (HRMS) analyses were
conducted by using a ThermoFinigan-MAT 95 XL instrument. IR
spectra were measured with a Perkin-Elmer Spectrum One FT-IR
spectrometer. Melting points were measured with a B-540 Büchi
apparatus. TLC analyses were performed on plates (layer thickness
0.25mm) and were visualized with UV light, phosphomolybdic acid
or p-anisaldehyde solution. Column chromatography was per-
formed on silica gel (40–63 mm) using EtOAc and hexanes as elu-
ents. Solvents and reagents were dried by distillation over the
appropriate drying agents prior to use. Et2O and THF were distilled
from Na/benzophenone and used fresh. CH2Cl2 was distilled from
CaH2.
HRMS: m/z calcd for [C10H17NS + H]+: 184.1160; found: 184.1157.
Self-Metathesis of Thiocyanates 7a–d; General Procedure
Thiocyanate 7 (0.2 mmol) was dissolved in freshly distilled CH2Cl2
(1 mL). After bubbling with an argon stream for 5 min, Hoveyda–
Grubbs catalyst (0.03 equiv) was added to the solution. The mixture
was irradiated in a sealed vessel by microwaves at 100 °C for 20
min. After cooling, the same catalyst (0.01 equiv) was added again
to the mixture, which was irradiated for an additional 10 min at the
same temperature. After cooling and concentration under vacuum,
the crude mixture was purified on silica gel (eluent: EtOAc–hex-
anes, 5:95).
(E)-1,6-Dithiocyanatohex-3-ene (8a)
Yield: 32 mg, 0.16 mmol (81%); colorless liquid.
IR (neat): 872, 1067, 1227, 1283, 1423, 2152, 2936 cm–1.
Thiocyanatoalkenes 7a–d; General Procedure
1H NMR (300 MHz, CDCl3): d = 2.57 (4 H, br q, J = 6.3 Hz, H-2),
3.00 (4 H, t, J = 6.9 Hz, H-3), 5.59–5.61 (2 H, m, H-1).
13C NMR (75 MHz, CDCl3): d = 32.8 (2 CH2), 33.5 (2 CH2), 112.4
(2 C, C-4), 129.7 (2 CH, C-1).
HRMS: m/z calcd for [C8H10N2S2 + H]+: 199.0364; found:
199.0363.
To a stirred solution of the desired alkenyl bromide (2 mmol) in
EtOH (5 mL) was added KSCN (6 mmol). The resulting mixture
was heated under reflux overnight. After concentration, the crude
product was partitioned between 1:1 H2O/Et2O (25 mL). The aque-
ous phase was extracted with Et2O (3 × 10 mL) and the combined
organic layers were successively washed with H2O (10 mL) and
brine (10 mL), and dried (MgSO4). After filtration, the crude mix-
ture was concentrated under vacuum to deliver the thiocyanato de-
rivative, which was used without further purification.
1,8-Dithiocyanatooct-4-ene (8b)
Yield: 45 mg, 0.20 mmol (99%); colorless liquid.
Synthesis 2010, No. 2, 233–238 © Thieme Stuttgart · New York

236
F. Cros et al.
PAPER
IR (neat): 971, 1277, 1438, 2153, 2850, 2935 cm–1.
mixture was stirred at r.t. for 5 h 30 min. After cooling and concen-
tration, the mixture was submitted to chromatography on silica gel
(eluent: EtOAc–hexanes, 5:95). GC/MS analysis revealed the fol-
lowing composition: ratio: C9 = 11.6% and C10 = 88.4%.
1H NMR (300 MHz, CDCl3): d = 1.90 (4 H, br quint, J = 7.2 Hz, H-
3), 2.18 (4 H, br q, J = 6.0 Hz, H-2), 2.94 (4 H, t, J = 7.1 Hz, H-4),
5.43–5.44 (2 H, m, H-1).
13C NMR (75 MHz, CDCl3): d = 29.4 (2 CH2), 30.6 (2 CH2), 33.3
Thiocyanatin B (4) via Tosylate 14
8-Nonenonitrile:20 8-Bromo-1-octene (0.22 mL, 1.31 mmol) was
dissolved in DMSO (7 mL). NaI (6 mg, 0.04 mmol) and KCN (119
mg, 1.83 mmol) were carefully added to the solution and the mix-
ture was stirred at r.t. for 2 h. After hydrolysis with aq NaHCO3 (25
mL), followed by extraction of the aqueous phase with CH2Cl2
(3 × 10 mL), the combined organic layers were washed successive-
ly with H2O (2 × 10 mL) and brine (10 mL), and dried (MgSO4). Af-
ter filtration and concentration, the pale yellow oil obtained was
directly used in the next step.
(2 CH2), 112.3 (2 C, C-5), 129.9 (2 CH, C-1).
HRMS: m/z calcd for [C10H14N2S2 + H]+: 227.0677; found:
227.0677.
1,10-Dithiocyanatodec-5-ene (8c)
GC/MS analysis of the crude product: C9 = 1.7%, C10 = 11.1%,
C11 = 28.1%, C12 = 54.6%, and C13 = 4.5%.
Data for the major compound (C12) obtained, C12H18N2S2: colorless
oil.
1H NMR (300 MHz, CDCl3): d = 1.31–1.50 (6 H, m, H-4, H-5, H-
6), 1.65 (2 H, br quint, J = 7.2 Hz, H-7), 2.05 (2 H, br q, J = 6.8 Hz,
H-3), 2.33 (2 H, t, J = 7.2 Hz, H-8), 4.92–5.02 (2 H, m, H-1), 5.79
(1 H, ddt, J = 17.1, 10.3, 5.1 Hz, H-2).
13C NMR (75 MHz, CDCl3): d = 16.9 (CH2, C-8), 25.1 (CH2, C-7),
28.0 (CH2), 28.3 (CH2), 33.4 (CH2), 40.8 (CH2, C-3), 114.3 (CH2,
C-1), 119.6 (C, C-9), 138.5 (CH, C-2).
8-Nonenoic Acid:20 The above crude 8-nonenenitrile was dissolved
in a 3:2 mixture of EtOH–H2O (7 mL). NaOH (209 mg, 5.24 mmol)
was added and the resulting solution heated to reflux overnight. Af-
ter concentration, the solution was hydrolyzed (2 mL). The aqueous
layer was first extracted with CH2Cl2 (2 × 10 mL) and then neutral-
ized with 1 M aq HCl. This aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The organic layers were successively washed
with H2O (10 mL) and brine (10 mL). After drying (MgSO4) and fil-
tration, the solvent was removed by concentration, and the pale yel-
low oil obtained was used without further purification.
1H NMR (300 MHz, CDCl3): d = 1.34–1.41 (6 H, m, H-4, H-5, H-
6), 1.63 (2 H, br quint, J = 7.1 Hz, H-7), 2.03 (2 H, br q, J = 6.6 Hz,
H-3), 2.35 (2 H, t, J = 7.4 Hz, H-8), 4.91–5.01 (2 H, m, H-1), 5.80
(1 H, ddt, J = 16.9, 10.1, 5.0 Hz, H-2).
IR (neat): 914, 993, 1265, 1439, 1640, 2154, 2936, 2977, 3078
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51 (4 H, br quint, J = 7.4 Hz, H-
3), 1.84 (4 H, br quint, J = 7.4 Hz, H-4), 2.02–2.08 (4 H, m, H-2),
2.94 (4 H, t, J = 7.2 Hz, H-5), 5.39–5.42 (2 H, m, H-1).
13C NMR (75 MHz, CDCl3): d = 28.8 (2 CH2), 29.8 (2 CH2), 32.2
(2 CH2), 34.1 (2 CH2), 112.4 (2 C, C-6), 130.3 (2 CH, C-1).
HRMS: m/z calcd for [C12H18N2S2 + H]+: 255.0990; found:
255.0989.
Thiocyanatin B (4)
GC/MS analysis of the crude product: C14 = 2.0%, C15 = 3.5%,
C16 = 3.9%, C17 = 27.2%, C18 = 57.3%, C19 = 6.1%.
Data for the major compound (C18) obtained, C18H30N2S2: colorless
oil.
IR (neat): 968, 1462, 2154, 2854, 2928 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.31–1.35 (12 H, m, H-4, H-5, H-
6), 1.39–1.45 (4 H, m, H-3), 1.82 (4 H, quint, J = 7.3 Hz, H-7),
1.95–2.01 (4 H, m, H-2), 2.94 (4 H, t, J = 7.3 Hz, H-8), 5.36–5.39
(2 H, m, H).
13C NMR (75 MHz, CDCl3): d = 28.0 (2 CH2), 28.8 (2 CH2), 28.9
(2 CH2), 29.5 (2 CH2), 29.9 (2 CH2), 32.5 (2 CH2), 34.1 (2 CH2),
112.5 (2 C, C-9), 130.4 (2 CH, C-1).
13C NMR (75 MHz, CDCl3): d = 24.6 (CH2), 28.7 (CH2), 28.8
(CH2), 28.9 (CH2), 33.7 (CH2), 34.1 (CH2), 114.3 (CH2, C-1), 138.9
(CH, C-2), 180.7 (C, C-9).
8-Nonen-1-ol: The above crude 8-nonenoic acid was dissolved in
anhyd Et2O (7 mL). LiAlH4 (99 mg, 2.62 mmol) was carefully add-
ed to the solution at 0 °C. The resulting suspension was stirred over-
night at r.t. and successively treated with H2O (10 mL), 1 M aq
NaOH (10 mL), and H2O (20 mL). After drying (MgSO4), filtration,
and concentration, the resulting pale yellow oil was used without
further purification.
1H NMR (300 MHz, CDCl3): d = 1.32 (8 H, br s, H-4, H-5, H-6, H-
7), 1.56 (2 H, br quint, J = 6.8 Hz, H-8), 2.03 (2 H, br q, J = 6.9 Hz,
H-3), 3.63 (2 H, t, J = 6.5 Hz, H-9), 4.90–5.02 (2 H, m, H-1), 5.80
(1 H, ddt, J = 16.9, 10.1, 6.6 Hz, H-2).
HRMS: m/z calcd for [C18H30N2S2 + H]+: 339.1929; found:
339.1930.
Cross-Coupling of 6-Bromohex-1-ene
Conditions A: A solution of 6-bromohex-1-ene (0.05 mL, 0.40
mmol) dissolved in CH2Cl2 (2 mL) was deoxygenated with an argon
stream. After addition of Hoveyda–Grubbs catalyst (3 mol%), the
mixture was submitted to MW activation (100 °C, 20 min). Addi-
tional small amount of the same catalyst (1 mol%) was added fol-
lowed by heating under MW for 10 min. After cooling and
concentration, the mixture was submitted to chromatography on sil-
ica gel (eluent: EtOAc–hexanes, 5:95). GC/MS analysis revealed
the following composition: ratio: C7 = 2.1%, C8 = 11.2%,
C9 = 32.6%, C10 = 45.9%, C11 = 8.1% and C12 = 0.1%.
13C NMR (75 MHz, CDCl3): d = 25.7 (CH2), 28.8 (CH2), 29.1
(CH2), 29.3 (CH2), 32.7 (CH2), 33.8 (CH2), 62.6 (CH2, C-9), 114.1
(CH2, C-1), 139.1 (CH, C-2).
Conditions B: A solution of 6-bromohex-1-ene (0.05 mL, 0.40
mmol) dissolved in CH2Cl2 (2 mL) was deoxygenated with an argon
stream. After addition of Grubbs II catalyst (8 mg, 0.01 mmol), the
mixture was heated to reflux for 4 h. After cooling and concentra-
tion, the mixture was submitted to chromatography on silica gel
(eluent: EtOAc–hexanes, 5:95). GC/MS analysis revealed the fol-
lowing composition: ratio: C8 = 3.7%, C9 = 24.1%, C10 = 71.3%,
C11 = 0.8% and C12 = 0.1%.
Non-8-enyl 4-Methylbenzenesulfonate (14)21
To a solution of the above crude 8-nonen-1-ol in CH2Cl2 (7 mL) was
added TsCl (324 mg, 1.70 mmol) and Et3N (0.24 mL, 1.70 mmol).
The mixture was heated under reflux overnight. After hydrolysis
with sat. aq NH4Cl (20 mL), the aqueous phase was extracted with
Et2O (3 × 10 mL). The combined organic layers were washed with
H2O (10 mL) and brine (10 mL). After drying (MgSO4) and filtra-
tion, the solution was concentrated under vacuum. Purification by
flash chromatography on silica gel (eluent: EtOAc–hexanes, 5:95)
Conditions C: A solution of 6-bromohex-1-ene (0.05 mL, 0.40
mmol) dissolved in CH2Cl2 (2 mL) was deoxygenated with an argon
stream. After addition of Grubbs II catalyst (17 mg, 0.02 mmol), the
Synthesis 2010, No. 2, 233–238 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Cross-Metathesis of Unsaturated Thiocyanates
237
gave 15 (120 mg, 0.41 mmol) as a colorless liquid; yield: 31% over
4 steps.
EtOAc–hexanes, 5:95) to give 16 (243 mg, 0.91 mmol, 83%) as a
colorless liquid.
1H NMR (300 MHz, CDCl3): d = 1.23–1.29 (8 H, m, H-4, H-5, H-
6, H-7), 1.65 (2 H, br quint, J = 6.6 Hz, H-8), 2.01 (2 H, br q, J = 6.9
Hz, H-3), 2.44 (3 H, s, H-14), 4.01 (2 H, t, J = 6.4 Hz, H-9), 4.90–
5.01 (2 H, m, H-1), 5.78 (1 H, ddt, J = 16.9, 10.1, 6.6 Hz, H-2), 7.34
(2 H, d, J = 8.3 Hz, H-12), 7.78 (2 H, d, J = 8.3 Hz, H-11).
1H NMR (300 MHz, CDCl3): d = 1.29–1,34 (4 H, m, H-4, H-5),
1.62–1.66 (2 H, m, H-6), 1.98–2.00 (2 H, m, H-3), 2.44 (3 H, s, H-
12), 4.01 (2 H, t, J = 6.4 Hz, H-7), 4.90–4.99 (2 H, m, H-1), 5.74 (1
H, ddt, J = 17.1, 10.3, 6.6 Hz, H-2), 7.34 (2 H, d, J = 8.2 Hz, H-10),
7,78 (2 H, d, J = 8,2 Hz, H-9).
13C NMR (75 MHz, CDCl3): d = 21.6 (CH3, C-14), 25.3 (CH2), 28.7
(CH2), 28.8 (CH2), 28.9 (2 CH2), 33.7 (CH2), 70.7 (CH2, C-9), 114.3
(CH2, C-1), 127.9 (2 CH), 129.8 (2 CH), 133.2 (C, C-10), 139.0
(CH, C-2), 144.7 (C, C-13).
13C NMR (75 MHz, CDCl3): d = 21.6 (CH3, C-12), 24.8 (CH2), 28.1
(CH2), 28.7 (CH2), 33.5 (CH2), 70.6 (CH2, C-7), 114.6 (CH2, C-1),
127.9 (2 CH), 129.8 (2 CH), 133.2 (C, C-8), 138.5 (CH, C-2), 144.7
(C, C-11).
(E)-16-{[(4-Methylphenyl)sulfonyl]oxy}hexadec-8-enyl 4-Meth-
ylbenzenesulfonate (15)21
(6E,10E)-9-Hydroxy-16-{[(4-methylphenyl)sulfonyl]oxy}hexa-
deca-6,10-dienyl 4-Methylbenzenesulfonate (17)
Tosylate 14 (236 mg, 0.80 mmol) was dissolved in CH2Cl2 (4 mL).
After bubbling with an argon stream for 15 min, second-generation
Grubbs catalyst (34 mg, 0.04 mmol) was added at once. The result-
ing solution was stirred at r.t. for 4 h. Additional amount of catalyst
(17 mg, 0.02 mmol) was added. After stirring overnight, the solvent
was removed by concentration and the crude mixture was purified
by flash chromatography on silica gel (eluent: EtOAc–hexanes,
5:95) to afford 15 (177 mg, 0.31 mmol, 79%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.23–1.28 (16 H, m, H-3, H-4, H-
5, H-6), 1.62 (4 H, br quint, J = 7.1 Hz, H-7), 1.91–1.94 (4 H, m, H-
2), 2.44 (6 H, s, H-13), 4.01 (4 H, t, J = 6.5 Hz, H-8), 5.32–5.35 (2
H, m, H-1), 7.34 (4 H, d, J = 8.1 Hz, H-11), 7.78 (4 H, d, J = 8.1 Hz,
H-10).
A solution of tosylate 16 (1.221 g, 4.55 mmol) and hexa-1,15-dien-
3-ol (0.05 mL, 0.45 mmol) in CH2Cl2 (45 mL) was bubbled with an
argon stream for 5 min. After addition of Grubbs II catalyst, the re-
sulting solution was stirred at r.t. for 5 h. After TLC monitoring, ad-
ditional amount of the catalyst (9 mg, 0.01 mmol) was added. After
stirring for an additional 1 h at r.t., the solution was concentrated.
The crude mixture was purified by flash chromatography on silica
gel (eluent: EtOAc–hexanes, 10:90 then 20:80). Compound 17 was
isolated as a colorless oil (263 mg, 0.45 mmol, 99%).
1H NMR (300 MHz, CDCl3): d = 1.29–1.34 (8 H, m, H-3, H-4, H-
13, H-14), 1.60–1.65 (4 H, m, H-2, H-15), 1.96–1.99 (4 H, m, H-5,
H-12), 2.12–2.25 (2 H, m, H-9), 2.44 (6 H, s, H-12), 4.01 (5 H, t,
J = 6.4 Hz, H-1, H-8, H-16), 5.36–5.62 (4 H, m), 7.34 (4 H, d,
J = 8.2 Hz, H-19), 7.79 (4 H, d, J = 8.2 Hz, H-18).
13C NMR (75 MHz, CDCl3): d = 21.7 (2 CH3, C-13), 25.3 (2 CH2),
28.8 (2 CH2), 28.9 (2 CH2), 29.0 (2 CH2), 29.5 (2 CH2), 32.5 (2
CH2), 70.7 (2 CH2, C-8), 127.9 (4 CH), 129.9 (4 CH), 130.3 (2 CH),
133.3 (2 C, C-9), 144.7 (2 C, C-12).
13C NMR (75 MHz, CDCl3): d = 21.7 (2 CH3, C-21), 24.9 (2 CH2),
28.5 (2 CH2), 28.7 (2 CH2), 31.9 (CH2), 32.4 (CH2), 41.0 (CH2, C-
9), 70.6 (CH2, C-1 or C-16), 70.7 (CH2, C-1 or C-16), 72.0 (CH, C-
8), 126.0 (CH), 127.9 (4 CH), 129.9 (4 CH), 131.2 (CH), 132.7
(CH), 133.2 (2 C, C-17), 133.8 (CH), 144.8 (2 C, C-20).
Thiocyanatin B (4)4
To a solution of ditosylate 15 (68 mg, 0.12 mmol) in EtOH (1mL)
was added KSCN (35 mg, 0.36 mmol). The resulting solution was
heated overnight. After cooling and concentration, the residue was
partitioned between H2O and Et2O (1:1, 10 mL). The aqueous layer
was extracted with Et2O (3 × 5 mL). The combined organic layers
were washed with H2O (5 mL) and brine (5 mL). After drying
(MgSO4), filtration, and concentration, the crude mixture was puri-
fied by flash chromatography on silica gel (eluent: EtOAc–hexanes,
5:95). Compound 4 (38 mg, 0.11 mmol, 94%) was isolated as a col-
orless oil.
9-Hydroxy-16-{[(4-methylphenyl)sulfonyl]oxy}hexadecyl
4-Methylbenzenesulfonate (18)
To a solution of ditosylate 17 (263 mg, 0.45 mmol) in EtOAc (3
mL), was added PtO2 (6 mg, 0.02 mmol). The resulting suspension
was hydrogenated (1 atm) at r.t. for 1 h. The catalyst was removed
by filtration over Celite. After concentration, compound 18 (215
mg, 0.37 mmol, 81%) was isolated as a white solid and used without
further purification; mp 74.1 °C.
1H NMR (300 MHz, CDCl3): d = 1.21–1.28 (22 H, m, H-3, H-4, H-
5, H-6, H-7, H-9, H-10, H-11, H-12, H-13, H-14), 1.63 (4 H, br
quint, J = 6.4 Hz, H-2, H-15), 2.44 (6 H, s, H-21), 3.56 (1 H, br s,
H-8), 4.01 (4 H, t, J = 6.5 Hz, H-1, H-16), 7.34 (4 H, d, J = 8.2 Hz,
H-19), 7.78 (4 H, d, J = 8.2 Hz, H-18).
IR (neat): 739, 1176, 1265, 1463, 2155, 2856, 2929 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25–1.32 (12 H, m), 1.39–1.44 (4
H, m), 1.82 (4 H, quint, J = 7.3 Hz, H-7), 1.98 (4 H, br s, H-2), 2.94
(4 H, t, J = 7.3 Hz, H-8), 5.38 (2 H, br s, H-1).
13C NMR (75 MHz, CDCl3): d = 28.0 (2 CH2), 28.8 (2 CH2), 28.9
(2 CH2), 29.5 (2 CH2), 29.9 (2 CH2), 32.5 (2 CH2), 34.1 (2 CH2),
112.4 (2 C, SCN), 130.4 (2 CH, C-1).
HRMS: m/z calcd for [C30H46O7 + Na]+: 605.2583; found:
605.2584.
Thiocyanatin A (3)4
HRMS: m/z calcd for [C18H30N2S2 + H]+: 339.1929; found:
339.1929.
To a solution of ditosylate 18 (215 mg, 0.37 mmol) in EtOH (2 mL)
was added KSCN (108 mg, 1.11 mmol). The solution was heated to
reflux and stirred overnight. The resulting mixture was concentrated
and partitioned between Et2O and H2O (1:1, 20 mL). The aqueous
phase was extracted with Et2O (3 × 10 mL), and the combined or-
ganic layers were washed with H2O (10 mL) and the brine (10 mL).
After drying (MgSO4), the solution was filtered, and concentrated.
The residue was purified by flash chromatography on silica gel (elu-
ent: EtOAc–hexanes, 20:80). Compound 3 (81 mg, 0.23 mmol,
62%) was isolated as a colorless liquid.
Thiocyanatin A (3) via Tosylate 16
Hept-6-enyl 4-Methylbenzenesulfonate (16)
To a solution of hept-6-en-1-ol (124 mg, 1.09 mmol) in CH2Cl2 (5
mL) were successively added Et3N (0.20 mL, 1.41 mmol) and TsCl
(269 mg, 1.41 mmol). The solution was kept under reflux overnight.
After hydrolysis with sat. aq NH4Cl (10 mL), the aqueous layer was
extracted with Et2O (3 × 5 mL). The combined organic layers were
washed with H2O (5 mL) and brine (5 mL). After drying (MgSO4)
and filtration, the solvent was removed by distillation. The crude
product was purified by flash chromatography on silica gel (eluent:
IR (neat): 738, 1099, 1266, 1459, 2154, 2856, 2930, 3412 cm–1.
Synthesis 2010, No. 2, 233–238 © Thieme Stuttgart · New York

238
F. Cros et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.32 (14 H, br s), 1.43 (8 H, br s),
1.82 (4 H, quint, J = 7.1 Hz, H-2, H-15), 2.94 (4 H, t, J = 7.3 Hz, H-
1, H-16), 3.58 (1 H, br s, H-8).
13C NMR (75 MHz, CDCl3): d = 25.5 (CH2), 25.6 (CH2), 27.8
(CH2), 27.9 (CH2), 28.8 (CH2), 28.9 (CH2), 29.4 (CH2), 29.6 (2
CH2), 29.9 (2 CH2), 34.1 (CH2), 34.2 (CH2), 37.4 (CH2), 37.5 (CH2),
71.8 (CH, C-8), 112.4 (2 C, SCN).
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Acknowledgment
We thank the Université de Lyon 1 and CNRS for financial support.
F.C. acknowledges the ‘Ministère de la Recherche et de l’Enseigne-
ment Supérieur’ for a PhD grant. We thank Dr. D. Bouchu (ICBMS
Lyon) for GC/MS analyses.
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Synthesis 2010, No. 2, 233–238 © Thieme Stuttgart · New York