Synthesis of substituted 1-thiocyanatobutadienes and their application in a Diels-Alder/[3,3] sigmatropic rearrangement tandem reaction

Article abstract of DOI:10.1007/s00706-004-0258-7

The retrosynthetic analysis of Ibogamine, a natural psychotropic alkaloid with exceptional anti-addictive properties found in both enantiomeric forms, requires an efficient access to a racemic cyclohexene. This cyclohexene can be obtained via the sequence Diels-Alder/[3,3] sigmatropic rearrangement reaction starting from substituted 1-thiocyanatobutadienes. An efficient synthesis of the enone, a stable precursor of 1-thiocyanatobutadienes, is reported. Enolisation of this enone was studied to find the optimal conditions to get the desired 1-thiocyanatobutadienes with good Z-selectivity. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-004-0258-7

Monatshefte f€ur Chemie 136, 597–607 (2005)
DOI 10.1007/s00706-004-0258-7
Synthesis of Substituted
1-Thiocyanatobutadienes and their
Application in a Diels-Alder=[3,3] Sigmatropic
Rearrangement Tandem Reaction
ꢀ
^ ^
Institute of Chemistry, University of Neuchatel, CH-2007 Neuchatel, Switzerland
´ `
Sebastien Lanaspeze and Reinhard Neier
Received August 9, 2004; accepted August 30, 2004
Published online January 24, 2005 # Springer-Verlag 2005
Summary. The retrosynthetic analysis of Ibogamine, a natural psychotropic alkaloid with excep-
tional anti-addictive properties found in both enantiomeric forms, requires an efficient access to a
racemic cyclohexene. This cyclohexene can be obtained via the sequence Diels-Alder=[3,3] sig-
matropic rearrangement reaction starting from substituted 1-thiocyanatobutadienes. An efficient
synthesis of the enone, a stable precursor of 1-thiocyanatobutadienes, is reported. Enolisation of
this enone was studied to find the optimal conditions to get the desired 1-thiocyanatobutadienes
with good Z-selectivity.
Keywords. Enols; Ibogamine; Rearrangements; Tandem reactions; Total synthesis.
Introduction
The number of synthetic steps in a total synthesis strongly influences the efficiency.
An attractive way to reduce the length of a synthetic pathway is to combine several
transformations into one-pot reactions so called tandem, domino, or cascade
reaction [1–3]. The tandem process Diels-Alder reaction=[3,3] sigmatropic rear-
rangement combines two well-known pericyclic reactions in one single synthetic
step, which allows to obtain interesting synthetic building blocks efficiently [4].
Starting from (E)-1-thiocyanatobuta-1,3-diene (1) and acryloyl chloride led to a
cis=trans 85:15 mixture of diastereoisomers of 1,4-substituted cyclohexene 3 in
84% yield [5] (Scheme 1). The cyclohexene 3 is a precursor for the preparation of
the skeleton of Iboga-type alkaloids. The isothiocyanate 3 can be easily trans-
formed in three steps to the 2-azabicyclo[2.2.2]oct-5-ene 4 [5] (Scheme 1). This
ꢀ
Corresponding author. E-mail: reinhard.neier@unine.ch

ꢀ
S. Lanaspeze and R. Neier
598
Scheme 1
bicyclic compound has been used by Trost et al. for the synthesis of desethylibo-
gamine (5) [6, 7].
Ibogamine (6a), as other Iboga-type alkaloids, has been isolated from an African
plant Tabernanthe iboga [8], which has well-known psychotropic activities.
Studies on rodents have proven that 6a shows exceptional multi-drug anti-addictive
properties [8–10]. Unfortunately, despite the encouraging results described by
Lotsof [11] about treatment of opioid withdrawal with ibogaine (6b) on human
patients, systematic clinical studies have not been carried out. Since the first total
synthesis of 6a by B€uchi [12] in 1965, eleven other total synthesis have been
reported [7, 13–21] but none of them is cost- and material-efficient enough to
allow the production of this compound or of derivatives of this compound in large
scale industrial production.
In most of the reported total syntheses of ibogamine (6a), the crucial step is the
formation of the C–C bond between the carbons C(2) corresponding to the
ꢀ-position of the indole ring and C(16) one of the ꢀ-positions of the bridgehead
carbon connected to the N-atom. In the total synthesis reported by Trost et al. this
crucial C–C bond was formed using a palladium-catalysed Heck-type C–C cou-
pling, in the presence of stoechiometric amounts of a silver salt [7]. The goal of our
studies is to develop an alternative procedure for the synthesis of the strategic C–C
bond avoiding use of stoechiometric quantities of a silver salt. Introducing a triflate
protected enolate on carbon C(16) should allow to test different catalytic C–C

Synthesis of Substituted 1-Thiocyanatobutadienes
599
Scheme 2
coupling conditions. Ibogamine (6a), contrary to the model compound desethyli-
bogamine (5), possesses an additional ethyl group in a pseudo-equatorial position
on carbon C(20). The retrosynthetic analysis of 6a based on the formation of the
strategic C–C bond described above leads to two major building blocks of similar
size: the indole derivative 7 (M¼B(OH)2, ZnCl) and the isoquinuclidine ring rac-8.
We propose to obtain the isoquinuclidine ring rac-8 via our tandem process Diels-
Alder reaction=[3,3] sigmatropic rearrangement starting from the 2,4-substituted
1-thiocyanatobuta-1,3-diene 10. In this paper the synthesis of diene 10 via a
Z-enolisation of the enone 11 is reported and the stereoselectivity of this enolisa-
tion is studied.
Results and Discussions
The initial step of the synthesis of enone 11 is the preparation of the phosphorane 13.
According to the procedure described by Hudson et al. [22], we started our syn-
thesis from the highly toxic, commercially available 1,3-dichloroacetone 12. Accord-
ing to the literature procedure the intermediate salt formed from the SN2 reaction
between the dichloroketone and triphenylphosphine was isolated in 85% yield. The
salt was then deprotonated in a separate step to get the ylide 13. To improve the yield
and to reduce the time of exposure to toxic ꢀ-chloroketones, we developed a one-pot
Scheme 3

ꢀ
S. Lanaspeze and R. Neier
600
Scheme 4
process. Using this one-pot procedure the ylide 13 could be isolated in almost quan-
titative yield. Displacement of the first chlorine atom of 1,3-dichloroacetone 12 by
triphenylphosphine was monitored by the disappearance of the 31P signal of triphe-
nylphosphine (ꢁP ¼ ꢁ4.4 ppm) in its 31P NMR (Scheme 3). The second SN2 reaction
replacing the chloride by nucleophilic attack of the sulphur atom of the thiocyanate
anion was carried out in ethanol. In order to accelerate the reaction, the presence of
a catalytic quantity of iodide was needed, as has been reported by Sapi et al. [23].
Thus, the thiocyanate 14 was obtained in very good yield and satisfactory purity so
that the raw material could be used in the following step without further purification.
The Wittig reaction was assumed to be E-selective due to the stabilisation of ylide
14 by the adjacent carbonyl group. As assumed the E-enone 11 was obtained as
a consequence of the thermodynamic equilibrium between the more stable trans-
oxaphosphetane 15 and its cis-diastereoisomer during the Wittig reaction (Scheme 4).
Propionaldehyde was both the solvent and the reactant of our Wittig reaction.
The progress of the reaction was monitored by the growth of the 31P signal of tri-
phenylphosphine oxide (ꢁP ¼ 30.1 ppm) in 31P NMR. The ꢀ,ꢂ-unsaturated ketone
11 is probably undergoing unwanted polymerisations, which make the purification
difficult. Thus, after filtration on a short silica gel column, the enone 11 was
purified by a bulb-to-bulb distillation (100ꢂC, 10ꢁ1 mbar). By this straight forward
three-steps process enone 11 could be obtained in 65% total yield starting from
1,3-dichloroacetone 12.
In order to optimize the reaction conditions for the enolisation model 16b was
chosen. Synthesis of thiocyanate 16b was carried out using a similar procedure as
for the synthesis of 14 starting from commercially available phenacyl chloride 16a
(Scheme 5).
Scheme 5

Synthesis of Substituted 1-Thiocyanatobutadienes
601
Scheme 6
The enolisation of ꢀ-halogenoketones usually leads to the kinetic (Z)-dia-
stereoisomer [24]. The ꢀ-thiocyanatoketones can be viewed as pseudohalogen ana-
logues of ꢀ-halogenoketones. The stereoselectivity of the enolisation can be explained
using ꢃ-bonds, also called ‘‘banana’’ bonds or bent bonds [25–28]. Using a Newman
projection to describe the most stable ground state conformation of the ꢀ-halogen-
oketone, the strongest electron withdrawing substituent in the ꢀ-position of the car-
bonyl group (the halogen or the pseudohalogen) has to be in a syn-coplanar position
relative to the C–O ꢃ-bond (Scheme 6). In this conformation all bonds are staggered,
the two hydrogen atoms, which are the best donor atoms, are in a anti-periplanar
position compared to the two strongly electron attracting C–O ꢃ-bonds (Scheme 6).
Having the precursors for our enolates in hand, we studied the stereoselectivity
of the enolisation process of our enone 11 under thermodynamic conditions, using
triethylamine or H€unig’s base. With our model compound 16b, an excellent stereo-
selectivity of the enolisation was observed under our experimental conditions.
Compound 17 was obtained as a (Z)=(E)-mixture with a diastereoselectivity of
Table 1. Study of stereoselectivity of the enolisation of enone 11 under thermodynamic conditions
10
R
Procedure
(ZE)=(EE)d
Yield
a
b
c
TMS
TBDMS
Ms
Aa
Aa
Bb
Bb
Cc
87:13
62:38
100:0
85:15
65:35g
78%
e
–
71%
f
d
e
Ts
–
Tf
72%h
a
Procedure A: 2.2 eq triethylamine þ 2 eq electrophile þ 1 eq enone 11 in ether as solvent at rt for 1 h;
procedure B: 2–10 eq triethylamine þ 1.2–5 eq electrophile þ 1 eq enone 11 in CH2Cl2 as solvent at
b
0ꢂC for 30 min; c procedure C: 1.4 eq diisopropylethylamine þ 1.25 eq electrophile þ 1 eq enone 11 in
CH2Cl2 as solvent at 0ꢂC for 30 min; d stereoselectivity estimated by 1H NMR analysing the product
of the Diels-Alder reaction; only the (ZE)-diastereoisomer can react in a Diels-Alder reaction; e under
the conditions of procedure A, the diene 10b could not be isolated, due to hydrolysis; the stereo-
selectivity was tentatively assigned based on the analysis of the raw material; f diene 10c was isolated
but not purified; g both diastereoisomers (ZE) and (EE) could be separated by chromatography on a
silica gel column and the diasteriomeric ratio was estimated by 19F NMR; h the synthesis of diene 10e
was also carried out under kinetic conditions resulting in a better stereoselectivity

ꢀ
S. Lanaspeze and R. Neier
602
Scheme 7
99:1 (Scheme 5). As described in Table 1, four different electrophiles were used to
trap the enol, applying three different experimental procedures (Table 1).
As predicted for the formation of the 1(Z),3(E)-diastereoisomers was favoured
compared to the formation of the 1(E),3(E)-diastereoisomers. Using the procedure B
and mesyl chloride as an electrophile the best diastereoselectivity was observed
(de>99%). A NOESY experiment showed a crosspeak between H-C(1) and H-C(4)
(Scheme 7) proving the structure of compound 10c. The observed NOESY crosspeak
is only compatible with the s-cis conformation of the 1(Z), 3(E)-diastereoisomer.
Applying the conditions D for the enolisation of enone 11 under kinetic
control the dienes 10b and 10e were obtained. The lithium enolate 17 is formed
under low-temperature conditions. The enolate is then quenched by various elec-
trophiles to get the desired substituted 1-thiocyanatobuta-1,3-diene 10b and 10e.
As indicated in Table 2 very good yields were obtained under these conditions. A
satisfactory diastereoselectivity was observed with TBDMSCl as an electrophile
(de ¼ 60% in favour of 1(Z),3(E)-diastereoisomer of the silylated 1-thiocyanato-
hexa-1,3-diene 10b). Using triflic anhydride as an electrophile, the influence of ad-
dition of DMPU as a co-solvent on diastereoselectivity was studied. A good
diastereoselectivity (de ¼ 78%) was observed without the use of the co-solvent. Ad-
dition of DMPU (20% in THF) improved the diastereoisomeric excess to de ¼ 95%.
Table 2. Stereoselectivity of the enolisation of enone 11 under kinetically controlled condition
10
R
Procedure
THF=DMPU
(ZE)=(EE)b
Yield
b
e
e
TBDMS
Da
Da
Da
10:0
10:0
8:2
80:20
89:11c
97.5:2.5c
90%
50%d
85%
Tf
Tf
a
Procedure D: 1.1 eq LiHMDS in THF=DMPU as solvent at ꢁ80ꢂC for 45 min þ 1.1 eq electro-
b
1
phile þ 1 eq enone 11 in THF as solvent at 0ꢂC for 1 h; stereoselectivity estimated by H NMR
analysing the product of the Diels-Alder reaction; only the (ZE)-diastereoisomer can react in a Diels-
d
Alder reaction; the diastereomeric ratio was estimated by 19F NMR; non optimised
c

Synthesis of Substituted 1-Thiocyanatobutadienes
603
Conclusions
An efficient three-step synthesis of enone 11 has been developed giving 11 in 65%
total yield. The stereoselectivity of the enolisation of 11 was studied under thermo-
dynamically controlled conditions using different electrophiles to trap the enolate.
Excellent diastereoisomeric excesses were observed and the best diastereoselectivity
was found using mesyl chloride as an electrophile (de>99%) yielding the 1(Z),3(E)-
1-thiocyanatohexa-1,3-dien-2-yl methanesulfonate (10c). Under kinetically con-
trolled conditions the 1-thiocyanatobuta-1,3-dienes 10b and 10e could be obtained.
The addition of DMPU as a co-solvent was studied in the case of the 1-thiocyana-
tobuta-1,3-diene 10e. The diastereoselectivity (de ¼ 78%) could be improved using
DMPU (de ¼ 95%). Efficient synthesis of five different substituted 1-thiocyanato-
buta-1,3-dienes 10a–10e are reported in good total yields. Their efficiency in our
Diels-Alder=[3,3] sigmatropic rearrangement tandem reaction will be studied in
view of the development of a new total synthesis of (rac)-Ibogamine (6a).
Experimental Part
All moisture-sensitive reactions were carried out under Ar and N2 using oven-dried glassware. All
reagents were of commercial quality if not specifically mentioned. Solvents were freshly distilled prior
to use. Flash chromatography (FC): Brunschwig silica gel 60, 0.032–0.063 mm; under positive pres-
sure. TLC: Merck precoated silica gel thin-layer sheets 60F 254, detection by UV and treatment with
basic KMnO4 sol. Mp: Gallenkamp MFB-595. IR spectra: Perkin Elmer Spectrum One FT-IR, in
cmꢁ1. NMR spectra: Bruker Avance-400 (400 MHz (1H), 162MHz (31P), and 100 MHz (13C)) and
Varian Gemini-2000 (188MHz (19F)), at rt, chemical shifts ꢁ in ppm rel. to SiMe4 (¼0 ppm) as
internal reference, coupling constants J in Hz. ESI-MS Finnigan LCQ. Elemental analyses of novel
compounds agreed favourably with calculated values.
1-Chloro-3-(triphenyl-5ꢄ-phosphanylidene)propan-2-one (13)
Triphenylphosphine (52.90 g, 200.9mmol) in 75 cm3 of dry THF was added to a solution of 25.12 g of
1,3-dichloroacetone (197.8 mmol) in 25 cm3 of dry THF. The mixture was heated to reflux for 4 h and
the solvent was then removed. The resulting white salt was dissolved in 100cm3 of methanol, and an
aqueous solution (1.55 M) of 10.48 g of Na2CO3 (98.9 mmol) was added. The mixture was allowed
to stand for 30 min and the white precipitate was dried in air to provide a white powder of pure 13
(67.58 g, 191.6mmol, 97%). Ylide 13 has been described by Hudson et al. [22]. Mp 179–180ꢂC
(Ref. [22] 178–179ꢂC); Rf ¼ 0.25 (CH2Cl2=MeOH 97=3); 31P NMR (162MHz, CDCl3): ꢁ ¼ 16.9 ppm;
1H NMR (400 MHz, CDCl3): ꢁ ¼ 7.68–7.62 (m, 6H, H-52), 7.60–7.54 (m, 3H, H-54)), 7.50–7.45 (m,
6H, H-53), 4.28 (d, 2J(3-P)¼23.9 Hz, 1H, H-3), 4.02 (s, 2H, H-1) ppm; 13C NMR (100MHz, CDCl3):
ꢁ ¼ 185.1 (s, 1C, C-2), 133.1 (s, 6C, C-53), 133.0 (s, 3C, C-54), 128.9 (d, 3J(52-P)¼12.5Hz, 6C, C-52),
126.2 (d, 1J(51-P)¼91.3Hz, 3C, C-51), 51.4 (d, 1J(3-P)¼114.5 Hz, 1C, C-3), 47.3 (d, 3J(1-P)¼
16.1Hz, 1C, C-1) ppm.
1-Thiocyanato-3-(triphenyl-5ꢄ-phosphanylidene)propan-2-one (14, C22H18NOPS)
Ylide 13 (64.42g, 182.6mmol) in 300 cm3 of ethanol was added to a solution of 21.30 g of potassium
thiocyanate (219.1mmol) in 350 cm3 of hot ethanol and 3.03g of KJ (18.3 mmol) were added. The
mixture was allowed to stir at 55ꢂC for 5 h and cooled to rt. The potassium salts were filtered off, most

ꢀ
S. Lanaspeze and R. Neier
604
of the solvent was evaporated in the rotavap, and 400 cm3 of CH2Cl2 were added. The potassium salts
were filtered off again and washed with cold CH2Cl2. The resulting solution was concentrated to
dryness to provide pure 14 (65.75 g, 175.1mmol, 96%), mp 146–148ꢂC. Rf ¼ 0.39 (CH2Cl2=MeOH
97=3); 31P NMR (162 MHz, CDCl3): ꢁ ¼ 16.1ppm; 1H NMR (400MHz, CDCl3): ꢁ ¼ 7.70–7.52
2
(m, 9H, H-52, H-54), 7.51–7.42 (m, 6H, H-53), 3.96 (d, J(3-P)¼24.0Hz, 1H, H-3), 3.92 (s, 2H,
H-1) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 181.5 (d, 2J(2-P)¼3.1 Hz, 1C, C¼O), 133.1 (d,
3
3
4J(53-P)¼9.9 Hz, 6C, C-53), 132.6 (d, J(54-P)¼3.0 Hz, 3C, C-54), 129.2 (d, J(52-P)¼12.7 Hz, 6C,
C-52), 125.7 (d, 1J(51-P)¼91.2Hz, 3C, C-51), 114.1 (SCN), 52.9 (d, 1J(3-P)¼108.5 Hz, 1C, C-3), 43.1
3
(d, J(1-P)¼19.1Hz, 1C, C-1) ppm; IR (KBr): ꢅꢁ¼ 2994, 2153, 1577, 1548, 1482, 1438, 1228, 1108,
764, 747, 719, 692, 518, 507 cmꢁ1
.
(E)-1-Thiocyanatohex-3-en-2-one (11, C7H9NOS)
A solution of 44.35 g of ylide 14 (118.1 mmol) in 86cm3 of freshly distilled propanal is allowed to stir
at 40ꢂC for 6 h under Ar and cooled to rt. The mixture was concentrated and quickly filtered on a short
silica gel column (200 g; n-hexane=CH2Cl2 1=1). The resulting brown oil was purified by bulb-to-bulb
distillation (100ꢂC at 10ꢁ1 mbar) to provide a malodorous pale yellow oil (12.80g, 82.5mmol, 70%).
1
3
Rf ¼ 0.42 (CH2Cl2); H NMR (400 MHz, CDCl3): ꢁ ¼ 7.03 (dt, J(4-3)¼16.0Hz, 3J(4-5)¼6.3 Hz,
1H, H-4), 6.19 (dt, 3J(3-4)¼16.0 Hz, 4J(3-5)¼1.7 Hz, 1H, H-3), 4.24 (s, 2H, H-1), 2.31 (qdd,
3J(5-6)¼7.4 Hz, J(5-4)¼6.3 Hz, J(5-3)¼1.7Hz, 2H, H-5), 1.10 (t, J(6-5)¼7.4Hz, 3H, H-6) ppm;
13C-NMR (100 MHz, CDCl3): ꢁ ¼ 190.5 (C¼O), 153.6 (C-4), 126.5 (C-3), 111.9 (SCN), 42.7 (C-1),
25.9 (C-5), 11.9 (C-6) ppm; IR (film): ꢅꢁ¼ 2972, 2935, 2878, 2158, 1687, 1626, 1460, 1392, 1341,
3
4
3
1297, 1245, 1180, 1109, 1081, 1015, 977, 909 cmꢁ1
.
1-Phenyl-2-thiocyanatoethanone (16b)
According to the procedure described for 14, 5.96g of phenacyl chloride (38.5mmol) were treated
with 4.70g of KSCN (48.4 mmol) and 0.66g of KJ (4.0mmol) giving 5.90 g of 16b (33.3 mmol, 86%)
as brown crystals. Thiocyanate 16b has been already isolated by Prakash et al. [29] as an oil. Re-
crystallisation in n-hexane=AcOEt 2=1 gave needle shaped yellow crystals. Mp 81–82ꢂC; Rf ¼ 0.38
1
3
4
(n-hexane=AcOEt 3=1); H NMR (400 MHz, CDCl3): ꢁ ¼ 7.96 (ddm, J(32-33)¼8.4 Hz, J(32-34)¼
1.3 Hz, 2H, H-32), 7.69 (tt, 3J(34-33)¼7.4 Hz, 4J(34-32)¼1.3 Hz, 1H, H-34), 7.55 (dd, 3J(33,32)¼8.4 Hz,
3J(33,34)¼7.4 Hz, 2H, H-33), 4.76 (s, 2H, H-2) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 190.9
(C¼O), 134.9 (C-34), 134.1 (C-31), 129.3 (C-33), 128.6 (C-32), 112.0 (SCN), 43.1 (C-2) ppm; IR
(KBr): ꢅꢁ¼ 2937, 2156, 1678, 1593, 1448, 1379, 1326, 1296, 1202, 998, 757, 687, 630 cmꢁ1
.
(Z)-1-Phenyl-2-thiocyanatovinyl methanesulfonate (17, C10H9NO3S2)
Triethylamine (141 mg, 1.4 mmol) was added to a solution of 177 mg of 16b (1.0mmol) in 5 cm3 of
dry CH2Cl2 under Ar. After cooling to 0ꢂC, 143 mg of methanesulfonyl chloride (1.25 mmol) were
slowly introduced at 0ꢂC (10 min). After warming to rt, the resulting mixture was stirred for additional
45min, diluted in 25cm3 of CH2Cl2, and washed with 25cm3 of H2O whose pH was adjusted to 3–5
with aqueous HCl (1M). The organic layer was then washed with brine, dried (MgSO4), and the
solvent was evaporated to dryness to provide a green powder of a mixture of the two stereoisomers
1
(Z)=(E) (99=1) 17 (102 mg, 0.4 mmol, 40%). Rf ¼ 0.21 (n-hexane=AcOEt 3=1); H NMR (400 MHz,
CDCl3): ꢁ ¼ 7.56–7.50 (m, 2H, H-33), 7.50–7.42 (m, 3H, H-32, H-34), 6.50 (s, 1H, H-2(E)), 6.44 (s,
1H, H-2(Z)), 3.15 (s, 3H, H-3(Z)), 3.01 (s, 3H, H-3(E)) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 151.0
(C-1), 132.2 (C-31), 131.2 (C-34), 129.3 (C-32), 126.2 (C-33), 109.5 (SCN), 105.9 (C-2), 39.9 (C-3)
ppm; IR (KBr): ꢅꢁ¼ 3068, 3036, 2934, 2164, 1681, 1622, 1354, 1264, 1172, 1008, 961, 864, 801, 779,
718, 524, 505 cmꢁ1
.

Synthesis of Substituted 1-Thiocyanatobutadienes
605
General Procedures for the Synthesis of the Substituted
1-Thiocyanatobutadienes 10a–10e
Procedure A: To a stirred 0.6M solution of 2.2 eq of triethylamine in diethylether at rt under Ar were
added dropwise 2.0 eq of the corresponding electrophile. 1.0eq of 11 was then added dropwise to the
solution for 5 min. The resulting mixture was magnetically stirred at rt for 1 h and the solvent was
evaporated. Freshly distilled n-pentane was added to the crude product, the salts were filtered off and
washed with freshly distilled n-pentane again. After evaporating the n-pentane in vacuo, the product
was isolated without further purification.
Procedure B: To a stirred 0.8M solution of 1.0 eq of 11 in CH2Cl2 at 0ꢂC under Ar were added
2.0–10.0eq of triethylamine. A 3.0 M solution of 1.2–5.0 eq of the corresponding electrophile in
CH2Cl2 was then added dropwise to the solution for 30min. The resulting mixture was magnetically
stirred at 0ꢂC for 30min and then diluted in CH2Cl2. The organic phase was then washed with H2O,
dried (MgSO4), and concentrated in vacuo to obtain the raw product that was then purified by
chromatography on a silica gel column.
Procedure C: To a stirred 0.2 M solution of 1.0 eq of 11 in CH2Cl2 at rt under Ar were added 1.4 eq
of diisopropylethylamine. After cooling to 0ꢂC, 1.25eq of the corresponding electrophile were added
dropwise to the solution during 5 min. The resulting mixture was magnetically stirred at 0ꢂC for 30min
and then diluted in CH2Cl2. The organic phase was washed with saturated aqueous NH4Cl, H2O,
dried (MgSO4), and concentrated in vacuo to get the product that was purified by chromatography on a
silica gel column.
Procedure D: A solution of 1.1eq of Li bis(trimethyldisilyl)amide (1M in THF) was diluted 3
times in a THF=DMPU mixture to get a 0.33 M solution, which was cooled to ꢁ90ꢂC. A 1.0 M
solution of 1.0 eq of 11 in freshly distilled THF was then added dropwise while maintaining the
temperature of the solution below ꢁ80ꢂC. The orange solution was then magnetically stirred at
ꢁ85ꢂC for 45 min and 1.1 eq of the corresponding electrophile were added dropwise maintaining
the temperature of the solution below ꢁ80ꢂC. The temperature was then allowed to warm slowly to
0ꢂC and the mixture was stirred for additional 1 h at 0ꢂC. After diluting three times the reactions
mixture with n-hexane, the solution was poured onto saturated aqueous NH4Cl. The organic phase was
washed with H2O and brine, dried (MgSO4), and concentrated in vacuo to get the product that was
purified by chromatography on a silica gel column.
Trimethyl((3E)-1-thiocyanatohexa-1,3-dien-2-yloxy)silane (10a, C10H17NOSSi)
Procedure A: Freshly distilled enone 11 (0.40 g, 2.58 mmol) was reacted with 0.56 g of trimethylchlo-
rosilane (5.15 mmol) to obtain 10a as a yellow oil (0.46 g, 2.02 mmol, 78%) and (ZE)=(EE) mixture
1
(87=13). Compound 10a was extremely sensitive towards hydrolysis. H NMR (200MHz, CDCl3):
ꢁ ¼ 6.65 (dt, 3J(3-4)¼15.4Hz, 4J(3-5)¼1.1 Hz, 1H, H-3(EE)), 6.37 (dt, 3J(4-3)¼15.3Hz, 3J(4-
3
3
3
5)¼6.2 Hz, 1H, H-4(EE), 6.08 (dt, J(4-3)¼15.3Hz, J(4-5)¼6.2 Hz, 1H, H-4(ZE), 5.89 (dt, J(3-
4
4)¼15.4Hz, J(3-5)¼1.1 Hz, 1H, H-3(ZE)), 5.25 (s, 1H, H-1(ZE)), 5.12 (s, 1H, H-1(EE)), 2.16 (qdd,
3J(5-6)¼7.4 Hz, J(5-4)¼6.3 Hz, J(5-3)¼1.1 Hz, 2H, H-5), 1.03 (t, J(6-5)¼7.4 Hz, 3H, H-6), 0.29
3
4
3
(s, 9H, H-21) ppm.
tert-Butyldimethyl((3E)-1-thiocyanatohexa-1,3-dien-2-yloxy)silane (10b, C13H23NOSSi)
Procedure D: Enone 11 (0.47 g, 3.00 mmol) was reacted with a 1.0 M solution of 0.50g of tert-
butyldimethylchlorosilane (3.31 mmol) in freshly distilled THF. After purification by quick filtration
on silica gel with n-hexane=AcOEt 95=5, compound 10b was obtained as yellow oil (0.73 g,
2.71mmol, 90%) and (ZE)=(EE) mixture (80=20) that could not be separated. Rf (ZE) ¼ 0.79,
1
3
Rf (EE) ¼ 0.89 (n-hexane=AcOEt 10=1); H NMR (400MHz, CDCl3): ꢁ ¼ 6.63 (dt, J(3-4)¼15.2Hz,
3
3
4J(3-5)¼1.6 Hz, 1H, H-3(EE)), 6.42 (dt, J(4-3)¼15.2Hz, J(4-5)¼6.5 Hz, 1H, H-4(EE), 6.07 (dt,

ꢀ
S. Lanaspeze and R. Neier
606
3
3
4
3J(4-3)¼15.5Hz, J(4-5)¼6.5 Hz, 1H, H-4(ZE)), 5.85 (dt, J(3-4)¼15.5 Hz, J(3-5)¼1.6 Hz, 1H, H-
3
3
3(ZE)), 5.23 (s, 1H, H-1(ZE)), 5.10 (s, 1H, H-1(EE)), 2.23 (qdd, J(5-6)¼ 7.4 Hz, J(5-4) ¼ 6.5 Hz,
4J(5-3)¼1.6 Hz, 2H, H-5(EE)), 2.13 (qdd, J(5-6)¼7.4 Hz, J(5-4)¼6.5 Hz, J(5-3)¼1.6 Hz, 2H, H-
5(ZE)), 1.07 (t, 3J(6-5)¼7.4Hz, 3H, H-6(EE)), 1.02 (t, 3J(6-5)¼7.4 Hz, 3H, H-6(ZE)), 1.00 (s, 9H, H-
23(ZE)), 0.96 (s, 9H, H-23(ZE)), 0.20 (s, 6H, H-21(EE)), 0.19 (s, 6H, H-21(ZE)) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 161.7 (C-2(EE)), 157.7 (C-2(ZE)), 141.4 (C-4(EE)), 137.8 (C-4(ZE)), 124.5
(C-3(ZE)), 120.7 (C-3(EE)), 112.0 (SCN(EE)), 111.5 (SCN(ZE)), 90.0 (C-1(ZE)), 85.8 (C-1(EE)), 25.8
(C-23(ZE)), 25.7 (C-5(ZE)), 25.6 (C-23(EE)), 25.4 (C-5(EE)), 18.5 (C-22(EE)), 18.3 (C-22(ZE)), 13.0
(C-6(ZE)), 13.0 (C-6(EE)), ꢁ3.4 (C-21(EE)), ꢁ4.4 (C-21(ZE)) ppm.
3
3
4
According to procedure A using a 1.0 M solution of tert-butyldimethylchlorosilane in diethylether,
a (ZE)=(EE) mixture (63=37) of impure 10b was obtained.
(1Z,3E)-1-Thiocyanatohexa-1,3-dien-2-yl methanesulfonate (10c, C8H11NO3S2)
Procedure B: Enone 11 (0.54 g, 3.48mmol) in 35cm3 of CH2Cl2 was reacted with a 0.5 M solution of
0.50g of methanesulfonylchloride (4.35 mmol) in CH2Cl2 and 1.34g of triethylamine (13.23 mmol).
1
Isolation according to A to get 10c as yellow oil (0.58 g, 2.49 mmol, 71%). Rf ¼ 0.20 (CH2Cl2); H
NMR (400MHz, CDCl3): ꢁ ¼ 6.36 (dtd, 3J(4-3)¼15.8Hz, 3J(4-5)¼6.6 Hz, 5J(4-1)¼0.5 Hz, 1H,
H-4), 6.18 (dd, 5J(1-4)¼0.5 Hz, 3J(1-3)¼0.5 Hz, 1H, H-1), 5.97 (dtd, 3J(3-4)¼15.8Hz, 4J(3-
5)¼1.3 Hz, 4J(3-1)¼0.5 Hz, 1H, H-3), 3.05 (s, 3H, H-21), 2.19 (qdd, 3J(5-6)¼7.4 Hz, 3J(5-
4
3
4)¼6.3 Hz, J(5-3)¼1.3Hz, 2H, H-5), 1.03 (t, J(6-5)¼7.4 Hz, 3H, H-6) ppm; 13C-NMR (100 MHz,
CDCl3): ꢁ ¼ 175.9 (C-2), 148.2 (SCN), 139.0 (C-4), 114.4 (C-3), 41.7 (C-21), 25.7 (C-5), 12.8 (C-6)
1
ppm; H NOESY: cross peak between ꢁ ¼ 6.36 and 6.18 ppm.
(3E)-1-Thiocyanatohexa-1,3-dien-2-yl 4-methylbenzenesulfonate (10d, C14H15NO3S2)
Procedure B: Enone 11 (0.31 g, 2.00 mmol) was reacted with a 0.4 M solution of 0.76 g of p-toluene-
sulfonyl chloride (4.00 mmol) in CH2Cl2 and 2.02g of triethylamine (20.00mmol). A (ZE)=(EE)
mixture (65=35) of impure 10d (0.50 g) was obtained by this procedure. Rf ¼ 0.14 (14% AcOEt in
n-hexane). ESI-MS: m=z ¼ 332.1 [Mþ Na]þ.
(3E)-1-Thiocyanatohexa-1,3-dien-2-yl trifluoromethanesulfonate (10e, C8H8F3NO3S2)
Procedure D: Enone 11 (130mg, 0.84 mmol) was reacted with a 1.0 cm3 of a 1 M LiHMDS solution
diluted with 2 cm3 of a 7=3 mixture of THF=DMPU. Triflic anhydride (0.16 cm3, 0.94 mmol) was
added. Compound 10e was obtained as yellow oil (205mg, 0.71mmol, 85%) and (ZE)=(EE) mixture
(97.5=2.5). Both diastereoisomers could be separated by chromatography on a silica gel column using
n-hexane=AcOEt 95=5 as an eluant. ESI-MS: m=z ¼ 310.0 [Mþ Na]þ.
1(Z),3(E)-Diastereoisomer: Rf ¼ 0.34 (n-hexane=AcOEt 95=5); 19F NMR (188MHz, CDCl3):
1
3
3
ꢁ ¼ ꢁ73.16 ppm; H NMR (400MHz, CDCl3): ꢁ ¼ 6.32 (dt, J(4-3)¼15.6Hz, J(4-5)¼6.5 Hz, 1H,
H-4), 6.09 (s, 1H, H-1), 6.02 (dt, 3J(3-4)¼15.6Hz, 4J(3-5)¼1.6 Hz, 1H, H-3), 2.24 (qdd, 3J(5-
6)¼7.4 Hz, 3J(5-4)¼6.5 Hz, 4J(5-3)¼1.6Hz, 2H, H-5), 1.07 (t, 3J(6-5)¼7.4 Hz, 3H, H-6) ppm;
13C NMR (100 MHz, CDCl3): ꢁ ¼ 150.3 (C-2), 141.7 (C-4), 120.1 (C-3), 116.9 (C(SCN)), 108.4
(C-21), 104.9 (C-1), 25.8 (C-5), 12.6 (C-6) ppm.
1(E),3(E)-Diastereoisomer: Rf ¼ 0.49 (n-hexane=AcOEt 95=5); 19F NMR (188MHz, CDCl3):
1
3
3
ꢁ ¼ ꢁ73.65 ppm; H NMR (400MHz, CDCl3): ꢁ ¼ 6.49 (dt, J(4-3)¼15.4Hz, J(4-5)¼6.5 Hz, 1H,
H-4), 6.35 (dt, 3J(3-4)¼15.4Hz, 4J(3-5)¼1.5Hz, 1H, H-3), 6.10 (s, 1H, H-1), 2.32 (m, 3J(5-6)¼7.4 Hz,
3J(5-4)¼6.5 Hz, 4J(5-3)¼1.5 Hz, 2H, H-5), 1.11 (t, 3J(6-5)¼7.4 Hz, 3H, H-6) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 151.3 (C-2), 144.8 (C-4), 126.0 (SCN), 116.9 (C-3), 108.3 (C-21), 103.0
(C-1), 26.3 (C-5), 12.6 (C-6) ppm.

Synthesis of Substituted 1-Thiocyanatobutadienes
607
The same procedure without the use of DMPU led to a (ZE)=(EE) mixture (89=11) of 10e in 50%
yield which was not optimised.
Procedure C: Enone 11 (0.40 g, 2.57 mmol) was reacted with triflic anhydride. Compound 10e was
then purified by chromatography on a silica gel column by using CH2Cl2 as an eluant to get a
(ZE)=(EE) mixture (65=35) (0.53 g, 1.85mmol) in 72% yield which was not optimised.
Acknowledgements
NMR Spectra (400MHz) were measured by H. Bursian and Dr. C. Saturnin, mass spectra by N.
Mottier and J. Jean-Denis, CHN analyses were made in the Ecole d’ingꢂenieurs et d’architectes de
^
Fribourg. We thank the University of Neuchatel and the Swiss National Science Foundation for
financial support.
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