[3,3]-sigmatropic rearrangements of fluorinated allyl (thio)cyanates - A to ol for the synthesis of fluorinated (thio)ureas

Article abstract of DOI:10.2533/chimia.2014.436

The first (thio)cyanate to iso(thio)cyanate rearrangements based on 2-fluoroallylic alcohols are presented. Long-chain 2-fluoroallylic alcohols were converted to corresponding N-unsubstituted carbamates by treatment with trichloroacetyl isocyanate. Dehydration using trifluoroacetic anhydride in the presence of triethylamine formed intermediate allylic cyanates, which immediately underwent sigmatropic rearrangement to fluorinated allyl isocyanates. Without isolation the latter delivered fluorinated ureas by addition of amines. The thiocyanate to isothiocyanate rearrangements started from the same fluorinated allylic alcohols, which were first converted to mesylates. Heating in THF with potassium thiocyanate led to fluorinated allyl isothiocyanates, via [3,3]-sigmatropic rearrangement of intermediate allyl thiocyanates. The formed products were further reacted with amines to fluorinated thioureas. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2014.436

436 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
doi:10.2533/chimia.2014.436
Chimia 68 (2014) 436–441 © Schweizerische Chemische Gesellschaft
[3,3]-Sigmatropic Rearrangements of
Fluorinated Allyl (Thio)cyanates – A Tool
for the Synthesis of Fluorinated
(Thio)ureas
Daniel C. Ramb, Lisa Kost, and Günter Haufe*
Dedicated to Professor Klaus Schulze on the occasion of his 80th birthday
Abstract: The first (thio)cyanate to iso(thio)cyanate rearrangements based on 2-fluoroallylic alcohols are
presented. Long-chain 2-fluoroallylic alcohols were converted to corresponding N-unsubstituted carbamates
by treatment with trichloroacetyl isocyanate. Dehydration using trifluoroacetic anhydride in the presence of
triethylamine formed intermediate allylic cyanates, which immediately underwent sigmatropic rearrangement to
fluorinated allyl isocyanates. Without isolation the latter delivered fluorinated ureas by addition of amines. The
thiocyanate to isothiocyanate rearrangements started from the same fluorinated allylic alcohols, which were first
converted to mesylates. Heating in THF with potassium thiocyanate led to fluorinated allyl isothiocyanates, via
[3,3]-sigmatropic rearrangement of intermediate allyl thiocyanates. The formed products were further reacted
with amines to fluorinated thioureas.
Keywords: Cyanates · 2-Fluorallylic alcohols · Fluorinated ureas and thioureas · Isocyanates ·
Isothiocyanates · [3,3]-Sigmatropic rearrangements · Thiocyanates
isothiocyanates can be rearranged to thio- 1,1-difluorinated allyl esters have been
cyanates when the formed carbon skeleton published.[14] Fewer examples were known
for [3,3]-sigmatropic rearrangements in-
The thermal rearrangement of allyl
1. Introduction
becomes more stable.[7]
In contrast, the allyl cyanate to allyl volving monofluorinated double bonds.[15]
isocyanate rearrangement became avail- In systematic studies we have shown that
able to organic chemists much later due a variety of [3,3]-sigmatropic rearrange-
to the lack of pathways to synthesize al- ments such as the Johnson-Claisen, the
lyl cyanates and to very easy formation of Ireland-Claisen, the ester enolate, the
cyclic trimers, the trialkyl cyanurates.[8] Eschenmoser and the Overman rearrange-
Simple allyl cyanates are about 5 kcal/mol ments based on 2-fluoroallylic alcohols are
less stable than the sulfur analogues[6b] and useful methods to synthesize fluorinated,
practically unisolable[9] due to the very γ,δ-unsaturated carboxylic acids, esters,
low activation barrier of isomerization to amino acids, carboxylic acid amides, or
the allyl isocyanates of 15–20 kcal/mol.[6,9] allylamines, respectively.[16] Here we dis-
thiocyanates to allyl isothiocyanates (mus-
tard oils) is a very well-known method[1]
for the preparation of key intermediates,
for the synthesis of e.g. thioureas and thio-
carbamates for agrochemical and pharma-
ceutical purposes[2] and for organocata-
lytic applications due to their high hydro-
gen bonding activity.[3] As early as 1885
Billeter and independently Gerlich dis-
covered the reaction and in 1925 Billeter
proposed a cyclic transition state for the
rearrangement despite not having any sup-
porting evidence.[4] Later, the concept was
supported by experimental evidence[5] and
more recently the reaction was confirmed
by further experimental and theoretical
investigations to proceed as a [3,3]-sig-
matropic rearrangement.[6] In general the
reaction is irreversible because isothio-
cyanates are thermodynamically more
stable, but under particular circumstances,
The evolution, development and synthetic
close our first results on [3,3]-sigmatropic
applications of this [3,3]-sigmatropic rear- rearrangements of fluorinated allyl (thio)
rangement have been reviewed a couple of cyanates.
years ago[8b,10] and the mechanism was con-
firmed again by recent quantum chemical
calculations.[6b] Like the isothiocyanates, 2. Results and Discussion
also the cyanates play an important role as
intermediates for the synthesis of biologi-
The starting material for the rearrange-
cally active compounds and particularly as ment precursors, the 2-fluoroallylic alco-
monomers for polymerization reactions.[11] hols 1 and 2, were synthesized according
In recent years, [3,3]-sigmatropic rear- to our well-known three-step procedure
rangements of fluorine-containing allylic of bromofluorination of 1-alkenes, HBr
systems have become a powerful tool to elimination from the formed 1-bromo-
generate new fluorinated molecules by car- 2-fluoroalkanes and subsequent allylic ox-
bon–carbon or carbon–heteroatom bond idation of the vinylfluorides with selenium
formation. By way of example, Claisen re- dioxide to give the target compounds in
arrangements of polyfluorinated allylvinyl 28-35% overall yield (Scheme 1).[17] The
ethers,[12] Johnson-Claisen rearrangements non-fluorinated allylic alcohol 3 was syn-
of terminal 1,1-difluoroallylic alcohols,[13] thesized by allylic oxidation of hexadec-
and Ireland-Claisen rearrangements of 1-ene.
*Correspondence: Prof. Dr. G. Haufe
Organisch-Chemisches Institut Münster
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster, Germany
Tel.: +49 251 83 33281
E-Mail: haufe@uni-muenster.de

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 437
Scheme 2.
O
H
N
Unsuccessful syn-
thesis of isocyanates
using cyanogen bro-
BrC
N
C
O
H
O
Base
R
R
C H
3 27
N
1
C H
3 27
X
C H
3 27
1
1
C
X
O
mide.
X
X
solvent
1 (R =C H ,X=F)
1
3 2
2(R =CH 7,X=F)
1 (X =F)
3(X =H)
7 1
5
3(R =C H ,X=H)
1
3 27
Scheme 1. Synthesis of 2-fluoroallylic alcohols
1-3.
Scheme 3. Synthesis
of allylic carbamates
7-9.
O
O
O
O
H
2.1 Cyanate to Isocyanate
Rearrangement
In one of the early reports on cyanate
to isocyanate rearrangement, Overman
used cyanogen chloride to synthesize cya-
Cl3CC(O)N
C
O
K2CO3
O
N
CCl3
O
NH2
H
R
CH2Cl2
0°CtoRT, 4h
H O, MeO
H
2
R
R
X
RT,3h
X
4-6
X
7-9
1-3
nates from allylic alcohols.[9b] The major
drawback of cyanogen chloride is the high
toxicity and difficult handling of the gas.
Table 1. Results of the synthesis of allylic carbamates 7-9.
Therefore, we first tried to replace cy-
Substrates
R
X
F
Products [yield]a
4 [98%]
Products [yield]a
7 [99%]
anogen chloride with the solid cyanogen
bromide. Unfortunately all attempts with
different bases or solvents failed to convert
1 to the target cyanate or the rearranged
isocyanate (Scheme 2).
1
2
3
C13H27
C13H27
C13H27
F
5 [98%]
8 [91%]
H
6 [97%]
9 [65%]
Also all attempts with the fluorine-free
a
allylic alcohol 3 failed. Thus, the lower
Isolated yields
reactivity of the reagent BrCN and not
the decreased nucleophilicity of the al-
lylic alcohol function due to the electron
withdrawing effect of the adjacent fluorine
atom seems to be the reason for the failure.
Therefore, we next investigated Ishikawa’s
Scheme 4. Reaction
pathway forming
isocyanates by dehy-
dration reaction of 8
and subsequent rear-
rangement.
O
N
C
O
N 2
H
T
F
A
A, NEt3
O
C H
3 27
N
1
C
CH2Cl2
C H
C H
13 27
1
3 2
7
F
O
F
8
F
method of dehydration of allyl carbamates
leading to cyanates, which do rearrange
immediately.[18]
Similarly to a literature procedure,[19]
the allylic alcohols 1–3 were first trans-
formed to the target carbamates 7–9 via
the mixed imides 4–6 in good to excellent
Table 2. Conditions for the dehydration reaction of 8.
Entry Equiv NEt3 Equiv TFAA Temperature Result
yields (Scheme 3, Table 1).
Next we optimized the reaction condi-
tions for the dehydration reaction using 8
as model compound (Scheme 4). The re-
action was controlled by TLC. IR spectra
1
2
1
1
3
3
–78°C to r.t.
no reaction
0 °C to r.t.
incomplete conversion
3
3
3
0 °C to r.t.
full conversion
of the crude reaction mixture showed the
typical peak of the isocyanate moiety at
2259 cm–1. Attempts to isolate the isocya-
Scheme 5. Strategy
for the synthesis of
fluorinated and non-
fluorinated ureas
10-15.
O
nate or the amine after aqueous workup
O
T
NH
2
FAA, NEt3
O
failed (Table 2).
Nu
R
N
C
R
N
Nu
X
O
Thus the intermediate isocyanates were
H
DCM
R
X
directly treated with aniline or piperidine
forming the corresponding ureas in moder-
ate to good yield over three steps (Scheme
X
7-9
10-15
5, Table 3).
The rearrangement to the isocyanate
Table 3. Results for the synthesis of the fluorinated and non-fluorinated ureas 10-15.
occurred via a six-membered transition
state and hence gave the trans-configured
ureas exclusively. This configuration was
C13H27 Piperidine 10 79
Entry
R
X
Nu
Product
Yield [%]
confirmed by the typical large 3JH,F = 36 Hz
1
F
coupling constant. The moderate yields for
2
3
4
5
6
C13H27
C13H27
C13H27
C7H15
C7H15
F
H
H
F
Aniline
Piperidine
Aniline
11
12
13
14
15
30
78
73
76
35
aniline adducts are due to difficult isola-
tion. A diisocyanate addition product was
never observed. No significant influence
of the fluorine atom was observed as yet
but further investigations with broader va-
riety of allylic alcohols and amines are in
progress.
Piperidine
Aniline
F

438 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
Scheme 6. Possible
reaction pathways
for nucelophilic
substitution with the
ambident thiocyanate
anion on the particu-
lar allylic system.
2.2 Thiocyanate to Isothiocyanate
N
C
Rearrangement
OLG
S
S
[3,3]
MSCN
The thiocyanate to isothiocyanate rear-
C
a)
R
N
R
R
rangement in principle should be accom-
plished by initial transformation of the
OH-group in the 3-position to a leaving
group and its subsequent nucleophilic sub-
stitution with the ˉSCN anion to a thiocya-
nate followed by [3,3]-sigmatropic rear-
rangement. However the particular allylic
system and the ambident reactivity of the
thiocyanate anion create the dilemma of
different possible reaction pathways:
a) SN2 reaction with nucleophilic attack
of the sulfur atom of the ˉSCN anion on the
most electrophilic carbon atom forming an
allylic thiocyanate I and subsequent rear-
rangement to the primary isothiocyanate II
(Scheme 6a).
F
II
F
F
I
S
OLG
C
N
[3,3]
MSCN
R
S
b)
c)
R
C
R
F
N
F
F
IV
III
S
OLG
C
S
N
NCSM
C
R
R
N
R
F
F
F
IV
II
b) SN2' reaction with a nucleophilic at-
tack of the thiocyanate’s sulfur atom at the
spectrum are assigned to the thiocyanate (19F NMR). These compounds could not
23, which is supported by the weak band at be separated from each other and from the
terminal position. The resulting primary
thiocyanate could then rearrange to the
secondary isothiocyanate (Scheme 6b).
2157 cm–1 in the IR spectrum of the crude two not fully characterized products 22/23
product mixture. Furthermore, the quartet and 24/25, respectively, by column chro-
at δ = –111 ppm in the 19F NMR spectrum matography.
c) Furthermore, due to the ambident
and the doublet of triplet at δ = 5.32 ppm
In addition to the weak band of allylic
reactivity of the SCN anion a nucleophilic
attack of the thiocyanate anion with the ni-
trogen atom is also possible. Calculations
by Mayr et al. have shown a more nucleo-
philic character of the sulfur atom but an
attack of the nitrogen atom cannnot be
excluded.[20a,b] A competitive SN2' and SN2
reaction might result in two regioisomeric
isothiocyanates IV and II (Scheme 6c).
Consequently, we synthesized the
mesylates 16 and 17, which were stable
enough to be isolated and characterized.
For the substitution reaction and subse-
quent rearrangement we tested differ-
ent reaction conditions. Best results for
the formation of isothiocyanate 19 were
achieved by heating of mesylate 17 with
in the 1H NMR spectrum suggest the pres- thiocyanate 23 at 2157 cm–1, the IR spec-
ence of compound 25 in the crude product trum contains the intense broad band for
mixture.
The regioisomers 18/19 and 20/21
were formed in ratios of 82–83 and 6–7% at the beginning of the reaction, we ana-
isothiocyanates at 2054 cm–1. In order to
find out whether the thiocyanate is formed
O
Ms
N
C
S
SCN
NCS
KSCN
R
NCS
+
R
+
R
+
R
R
T
HF
F
F
F
F
F
60 °C,26h
18 (R =C H )
19 (R =CH 7)
20 (R =C H )
21 (R =CH 7)
16 (R =C H )
17 (R =CH 7)
24 (R =C H )
1
3 2
7 15
13 2
7 1
22 (R =C H )
1
7 1
3 2
5
1
3 2
25 (R =CH 7)
13 2
5
23 (R =CH 7)
7 1
5
7 1
5
82-83%
6-7%
1-6%
5-6%
Scheme 7. Synthesis of isothiocyanates 18, 19 and side products.
potassium thiocyanate in dry THF at 60 °C
for 26 h in a sealed tube (Scheme 7). Using
the tosylate, other solvents, temperatures
or microwave irradiation resulted in worse
product ratios. For instance, treating the
tosylate under the same reaction condi-
tions led to additional fluorinated products.
Under the optimal reaction conditions one
major product and three minor products
were formed. Based on our knowledge on
similar vinyl fluorides we assign the dou-
blet of triplet at –118 ppm in the 19F NMR
spectrum (Fig. 1) to compound 19 with a
fluorine atom attached to an 1,2-disubsti-
tuted double bond, while the doublet of
doublet of doublet at –109 ppm belongs
to a vinylic fluorine in 2-position at the
terminal double bond (compound 21).
Analogous results were obtained for the
rearrangement of the higher homologue
16. A similar substitution pattern with a
doublet of doublet of doublet at δ = –107
ppm in the 19F NMR spectrum and a dou-
blet of doublet at δ = 4.64 ppm and doublet
of doublet at δ = 4.87 ppm in the 1H NMR
19
23
21
25
Fig. 1. 19F NMR spectrum of the crude product mixture after heating of 17 with KSCN in THF.

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 439
lyzed aliquots of the crude product mix-
ture after short reaction times and found
the typical thiocyanate absorption at 2157
cm–1 which decreased due to the rearrange-
ment to the thermodynamically more sta-
N
C
S
NCS
1. MsCl/NEt3
toluene
reflux, 4h
61%
C H
5 31
OH
C H
5 31
SCN
1
1
C H
C H
15 31
1
5 3
1
2. K
SCN, MeCN
F
F
F
F
60 °C,3h
26
28
2:1
29
29
ble isothiocyanate. Thus pathway a) seems
Scheme 8. Inverse thiocyanate rearrangement.
to be preferred. A primary thiocyanate
III (pathway b) was not observed at any
4. Experimental Part
time of the reaction. Parallel pathway c),
the nucleophilic attack of the nitrogen of
the ambident anion SCN, is not excluded,
though a different ratio of products 19
and 25 might be expected. Moreover, ac-
cording to calculations on SN2-type reac-
tions,[20] the sulfur atom has the lower in-
trinsic barrier in the ambident thiocyanate
anion and hence this attack is favored. In
addition, the attack on the most electro-
philic carbon atom forming a thiocyanate
of type I results in a lower energy uptake
for reorganizing regarding atomic posi-
tion and electronic configuration, which
both would support pathway a) initiated
by a nucleophilic attack of the sulfur in a
SN2 reaction. Regarding the spectroscopic
data for both isothiocyanates 18 and 19 the
trans-configuration of the double bonds
is indicated by the big coupling constant
(3JH,F = 35 ppm), which is an additional ar-
gument for a [3,3]-sigmatropic rearrange-
ment.
Nucle
0 °C
W,1h
ophile
R
NCS
R
NHC(S)Nu
1
0
M
F
F
All commercial reagents were used
without further purification. Air-sensitive
reactions were conducted in flame-dried
flasks under argon atmosphere. Melting
points are uncorrected. NMR spectra were
recorded at 300 MHz (1H), at 75 MHz
(13C) and at 282 MHz (19F) and are re-
1
8 (R =C H )
30/31 (R =C H )
13 2
3
2/33 (R =CH 7)
13
2
1
9 (R =CH 7)
7
15
7 15
Scheme 9. Nucleophilic addition of 18 and 19
with different nucleophiles.
the corresponding tosylate) could not be ported in ppm downfield from TMS (1H
prepared due to elimination reaction. The
and 13C, CDCl3 as internal standard and
instability of allylic mesylates has already CFCl3, 19F). Signals were assigned with
1
been reported.[22] Surprisingly, the fluo- the help of H NMR (GCOSY), (1H and
rine stabilizes this leaving group in allylic 13C) with GHSQC and GHMBC. ESI mass
position and the resulting mesylates and spectra were recorded on a Finnigan MAT
tosylates could be stored for weeks.
4200S. Column chromatography (silica
gel Merck 60, 0.040–0.063 mm) was used
for purification. Fluorinated allylic alco-
hols were prepared according to ref. [17].
Carbamates were prepared according to
3. Conclusion
In conclusion, [3,3]-sigmatropic rear- ref. [19]. Methanesulfonyl- and toluene-
rangements of secondary allyl (thio)cya- sulfonyl compounds were prepared fol-
nates delivered different fluorinated and lowing standard procedures.
non-fluorinated primary allyl iso(thio)cya-
The structure of a type-III-thiocyanate
nates, which were further converted to the 4.1 General Procedure for the
corresponding (thio)ureas. We achieved a Synthesis of Ureas 10–15 from
selective allyl cyanate to allyl isocyanate Carbamates 7–9 by Dehydration,
rearrangement on fluorinated compounds [3,3]-Sigmatropic Rearrangement
(compound 28) and a type-IV-isothiocy-
anate (compound 29) was independently
confirmed by fluorine NMR data of prod-
ucts of an ‘inverse’ thiocyanate rearrange-
ment. Starting from the diastereomeric
fluorinated allyl alcohols 26 (2:1, synthe-
sized from the corresponding α-fluoro-
α,β-unsaturated esters[21]), the mesylates
27 were prepared and reacted with potas-
sium thiocyanate in acetonitrile at 60 °C
yielding a 2:1 mixture of isomers 28 (2:1)
and 29. Further heating in toluene for 4 h
completed the rearrangement of 28 to 29
for the first time. The mechanism of for-
and Addition of the Amine to the
mation of allyl isothiocyanates, however, Intermediate Isocyanates
is not fully approved yet, but we suspect
Under an argon atmosphere the corre-
that a [3,3]-sigmatropic rearrangement sponding carbamate (0.2 mmol, 1.0 equiv)
took place. Additional investigations on is dissolved in dry dichloromethane (3
the electronic structure of these fluori- mL) and cooled to 0 °C. Triethylamine
nated allylic systems will be necessary. (83 µL, 0.6 mmol, 3.0 equiv) and trifluo-
Furthermore, we were able to rearrange a roacetic acid anhydride (84 µL, 0.6 mmol,
fluorine-containing primary allyl thiocya- 3.0 equiv freshly distilled from P O ) are
nate to the secondary allyl isothiocyanate added slowly to the solution and t2he5mix-
(Scheme 8). The isothiocyanate 29 was
by heating. Finally microwave irradiation ture is stirred for two more hours at 0 °C.
formed as the sole product showing a dou-
blet of doublet of doublet at –109 ppm with
the same pattern as in compounds 20/21.
Signals similar to those of compounds 28
were not found in the crude product of
the reactions of 16 or 17 with KSCN (see
above).
Next the above prepared mixtures of
rearrangement products 18/19 (contami-
nated with the minor side products) were
treated with aniline and piperidine form-
ing fluorinated thioureas 30/31 and 32/33
in 40–54% isolated yields by microwave
of the fluorinated primary allyl isothiocya- After warming to room temperature the
nates with amines produced corresponding amine (1.3 equiv) is added and the solu-
fluorinated thioureas. We intend to investi- tion is stirred at room temperature over
gate potential applications of the prepared night. Water (5 mL) is added and the
fluorinated (thio)ureas as organocatalysts phases are separated. The aqueous phase
and to study the effect of the fluorine atom is extracted with dichloromethane (5 mL),
on the selectivity.
the combined organic phase is washed with
brine (15 mL) and dried over MgSO4. The
solvent and traces of trifluoroacetic acid
Table 4. Results for the synthesis of fluorinated thioureas 30-33.
irradiation for 1 h (Scheme 9, Table 4).
Entry
R
Nu
Product
30
Yield [%]
Products formed from the minor impuri-
ties were not detected in the final products
after purification.
Unfortunately, a potential influence of
the fluorine atom on the rearrangement
rate could not be investigated because the
fluorine-free analogue of mesylate 17 (or
1
2
3
4
C13H27
C13H27
C7H15
C7H15
Piperidine
Aniline
52
46
54
40
31
Piperidine
Aniline
32
33

440 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
are removed by distillation. The residue
gel the resulting methanesulfonate 17 mg, 1.9 mmol, 1.5 equiv). The mixture is
is purified by silica gel chromatography was obtained. Yield: 291 mg (1.11 mmol, heated to 60 °C over 26 h. Water (10 mL)
(pentane/diethyl ether, 1:1) affording the 56%), yellow oil.
fluorinated urea as colorless solid or oils.
and diethyl ether (10 mL) is added and the
1H NMR (300 MHz, CDCl3): δ = 0.87 phases are separated. The aqueous phase
(t, J = 6.7 Hz, 3 H, 10-CH ), 1.29 (m, is extracted four more times with diethyl
4.1.1 Exemplarily Data for Fluorinated 10 H, 5-CH – 9-CH2), 1.78–13.91 (m, 2 H, ether. The combined organic phases are
Ureas
4-CH ), 3.024 (s, 3 H, 11-CH3), 4.74 (dd, dried over MgSO4 and the solvent is evapo-
N-(2-Fluorohexadec-2-en-1-yl)-N',N'- J = 3.25 Hz, J = 47.5 Hz, 1 H, 1-CHA), 4.90 rated in vacuo. After column filtration on
pentamethylene urea (10): Yield: 62 mg (dd, J = 3.5 Hz, J = 16.0 Hz, 1 H, 1-CHB), silica gel the resulting isothiocyanates are
(79%), yellow oil.
1H NMR (300 MHz, CDCl3): δ = 0.87 3-CH). 13C NMR (75 MHz, CDCl3): δ =
(t, J= 6.7 Hz, 3 H, 10-CH3), 1.25–1.39 (m, 14.1 (C-10), 22.7 (C-9), 24.9 (C-5), 29.0– dec-2-ene (18):
4.90 (dt, J = 3.5 Hz, J = 15.9 Hz, 1 H, obtained as yellow oils.
trans-2-Fluoro-1-isothiocyanatohexa-
10 H, 5-CH2 – 9-CH2), 1.52–1.63 (m, 6 H, 31.9 (C-4 – C-9), 39.0 (C-11), 79.4 (d, J =
1H NMR (300 MHz, CDCl3): δ =
13-CH2 – 15 CH2), 2.03 (m, 2 H, 4-CH2), 29.6 Hz, C-3), 95.3 (d, J = 17.1 Hz, C-1), 0.87 (t, J = 6.7 Hz, 1H, 16-CH3), 1.26
3.33 (m, 4 H, 16/12 – CH2), 3.92 (dd, 160.8 (d, J = 261.8 Hz, C-2). 19F NMR (m, 22 H, 5-CH2-15-CH ), 2.08–2.15 (m,
J = 5.4, J = 16.0 Hz, 2 H, 1-CH2), 4.74 (282 MHz, CDCl3): δ = –112.7 (ddd, J = 2 H, 4-CH2), 4.30 (d, J 2= 13.7 Hz, 1 H,
(br s, 1 H, NH) 4.76 (dt, J = 7.5 Hz, J = 16.1 Hz, J = 18.3 Hz, J = 47.4 Hz). HRMS 2-CH2), 4.90 (dt, J = 7.6, J = 35.8 Hz, 1 H,
37.4 Hz, 1 H, 3-CH). 13C NMR (101 MHz, (ESI): m/z calcd for [M + Na]+: 252.1195; 3-CH).13C NMR (75 MHz, CDCl3): δ 14.1
CDCl3): δ = 14.1 (C-10), 22.6 (C-9), 23.4 found: 252.1197.
(d, J = 4.2 Hz, C-4), 24.6 (C-14), 25.6 (C-
(C-16), 22.6 (C-15), 22.3 (d, J = 3.6 Hz,
C-5), 28.9, 29.0, 29.3, 29.5 29.6 (C-6 –
C-14), 31.9 (C-4), 45.7 (d, J = 35.0 Hz,
C-1), 110.2 (d, J = 13.2 Hz, C-3), 151.3 (d,
13/15), 28.3, 28.7 (C-6 and C-7), 29.0– 4.2.2 Synthesis of the
29.2 (C-5 – C-7), 31.8 (C-8), 41.6 (d, J = Toluenesulfonate
31.1 Hz, C-1), 44.9 (C-12/16), 107.5 (d, J
The fluorinated allyl alcohol 1 (400
J = 254.6 Hz, C-2). 19F NMR (282 MHz,
= 14.4 Hz, C-3), 156.0 (d, J = 252.8 Hz, mg, 1.55 mmol, 1.0 equiv) was dissolved CDCl3): δ = -118.6 (dt, J = 13.6 Hz, J =
C-2), 157.1 (C-11). 19F NMR (282 MHz, in dichloromethane (15 mL) and cooled to 35.6 Hz). HRMS (ESI): m/z calcd for [M +
CDCl3): δ = –118.2 (dt, J = 16.1 Hz, J = 0 °C. Triethylamine (0.64 mL, 4.65 mmol,
37.4 Hz). HRMS (ESI): m/z calcd for [M + 1.8 equiv) and dimethylaminopyridine trans-2-Fluoro-1-isothiocyanatodec-
Na]+: 307.2156; found: 307.2156.
(DMAP) (19 mg, 0.15 mmol, 0.1 equiv) 2-ene (19):
N-(2-Fluorohexadec-2-en-1-yl)-N'- was added. p-Toluenesulfonyl chloride
1H NMR (400 MHz, CDCl3): δ = 0.88
phenylurea (11): Yield: 22 mg (30%). Mp (590 mg, 2.00 mmol, 1.5 equiv) was added (t, J = 6.7 Hz, 3 H, 10-CH3), 1.28–1.39
107 °C. and the mixture was stirred at room tem- (m, 10 H, 5-CH2 – 9-CH2), 2.09–2.14 (m,
Na]+: 322.1975; found: 322.1978.
1H NMR (300 MHz, methanol-d ): perature for 48 h (TLC control). Water (20
2 H, 4-CH2), 4.13 (d, J = 13.4. Hz, 2 H,
δ = 0.88 (t, J = 6.7 Hz, 3 H, 16-CH4), mL) was added and the phases were sepa- 1-CH2), 4.89 (dt, J = 7.6 Hz, J = 35.6 Hz,
1.24–1.37 (m, 22 H, 5-CH2 – 15-CH32), rated. The organic phase was washed with
1 H, 3-CH).13C NMR (101 MHz, CDCl3):
2.06 (m, 2 H, 4-CH2), 3.88 (dd, J = 5.5, J 2 n HCl (20 mL) and brine (20 mL). The
δ = 14.1 (C-10), 22.6, (C-9), 25.0 (C-5),
= 16.2 Hz, 2 H, 1-CH ), 4.78 (dt, J = 7.5 combined organic phases were dried over 28.9, 30.7, 31.8 (C-6 – C-8), 45.8 (d, J = 3
Hz, J = 37.5 Hz, 1 H,2 3-CH), 6.99 (m, 1 MgSO4. After column chromatography on 5.3), 110.2 (d, J = 13.2 Hz, C-1), 135.4 (s,
H, 21-CH), 7.25 (m, 2 H, 20/22-CH), 7.34 silica gel the resulting toluenesulfonate C-11), 151.4 (d, J = 254.4 Hz, C-2). 19F
(m, 2 H, 19/23-CH). 13C NMR (101 MHz, was obtained as yellow oil. Yield: 360 mg NMR (282 MHz, CDCl3): δ = –118.4 (dt,
methanol-d4): δ = 17.8 (C-16), 26.5 (C-15), (0.87 mmol, 56%).
27.2 (d, J = 4.4 Hz,C-4), 33.0–33.5 (C-5
1H NMR (300 MHz, CDCl3): δ = 0.86 m/z calcd for [M + Na]+: 238.1036; found:
– C-14), 35.7 (C-5), 44.2 (d, J = 32.6 Hz, (t, J = 6.6 Hz, 3 H, 16-CH3), 1.25 (m, 238.1032.
J = 13.4 Hz, J = 35.6 Hz). HRMS (ESI):
C-1), 111.1 (d, J = 14.3 Hz, C-3), 126.4 (C- 22 H, 5-CH2 – 15-CH2), 1.77 (m, 2 H,
cis/trans-2-Fluoro-1-thiocyanatoocta-
21), 122 (C-19/23), 132.7 (C-20/22), 143.1 4-CH2), 2.43 (s, 3 H, 23-CH ), 4.47 (dd, dec-2-ene (28):
(C-18), 159.6 (d, J = 253.1 Hz, C-2), 159.9 J = 3.4 Hz, J = 47.4 Hz, 13 H, 1-CH ),
In a sealed tube the 1:2 cis/trans-mix-
(C-17). 19F NMR (282 MHz, methanol-d4): 4H.63 (dd, J = 3.5 Hz, J = 16.1 Hz, 1 H,A1- ture of mesylate 27 (38 mg, 0.1 mmol) was
δ = –118.6 (dt, J = 16.3 Hz, J = 37.7 Hz). CHB), 4.87 (dt, J= 6.9 Hz, J = 17.0 Hz, dissolved in 2 mL MeCN and KSCN (11
HRMS (ESI): m/z calcd for [M + Na]+: 1 H, 3-CH), 7.31 (d, J = 8.0 Hz, 2 H, 19- mg, 0.15 mmol, 1.5 equiv). The mixture
399.2782; found: 399.2776.
CH), 7.77 (d, J = 8.4 Hz, 2 H, 18-CH). 13C was heated at 60 °C for 3 h. Water (5 mL)
NMR (75 MHz, CDCl3): δ = 14.2 (C-16), and diethyl ether (5 mL) was added and
21.7 (C-23), 22.8 (C-15), 24.7 (C-5), 29.1 the phases were separated. The aqueous
(C-4), 29.4–29.8 (C-7 – C-13), 31.9 (C-6), phase was extracted four more times with
4.2 General Procedures for the
Synthesis of Isothiocyanates
4.2.1 Synthesis of the
32.0 (C-14), 79.2 (d, J = 31.3 Hz, C-3), 94.5 diethyl ether. The combined organic phas-
(dd, J = 17.0 Hz, C-1), 127.9 (d, C-18/22), es were dried over MgSO and the solvent
Methanesulfonate 17
The fluorinated allyl alcohol 1 (348 mg,
129.8 (d, C-19/21), 134.2 (s, C-20), 144.9 was evaporated in vacuo4and the residue
2.00 mmol, 1.0 equiv) was dissolved in di- (s, C-17), 160.8 (d, J = 261.4 Hz, C-2). 19F was used without further purification for
chloromethane (5 mL) and cooled to 0 °C. NMR (282 MHz, CDCl ): δ = –112.7 (ddd, the rearrangement. The mixture contained
Triethylamine (0.55 mL, 3.60 mmol, 1.8
J = 16.6 Hz, J = 16.6 3Hz, J = 47.4 Hz). already 34% of the rearrangement product
equiv) and methanesulfonylchloride (0.23 HRMS (ESI): m/z calcd for [M + Na]+: 29.
mL, 3.00 mmol, 1.5 equiv) was added. The 435.2339; found: 435.2339.
mixture was warmed to room temperature –116.1 (m) (trans), –109.1 (m) (cis), cis/
19F NMR (282 MHz, CDCl3): δ =
and stirred for 30 min. Water (5 mL) was 4.2.3 Rearrangement of Thiocyanates trans 1:2; δ = –108.9 (29).
added and the phases were separated. The
to Isothiocyanates
2-Fluoro-3-isothiocyanatoocatadec-1-
In a sealed tube under argon atmo- ene (29):
aqueous phase was extracted three times
with dichloromethane (10 mL) and the sphere the methanesulfonyl derivative (1
combined organic phases were dried over equiv) is dissolved in dry THF (3 mL)
The crude reaction mixture of 28 was
dissolved in toluene (4 mL) and heated un-
MgSO4. After column filtration on silica and potassium thiocyanate is added (188 der reflux for 4 h. Following work up pro-

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 441
derivatives ’, Part 1, Ed. S. Patai, John Wiley
cedure is similar to other rearrangements. (dd, J = 5.0 Hz, J= 17.2. Hz, 2 H, 1-CH2),
& Sons, Chichester, 1977, pp 569–618. b)
The thiocyanate was obtained as yellow
4.85 (dt, J = 7.5 Hz, J = 37.5 Hz, 1 H,
D. E. Gilges, ‘Kinetics and mechanism of
oil. Yield: 20 mg (0.06 mmol, 61%).
3-CH), 5.61 (bs, 1 H, NH). 13C NMR (101
reactions of cyanates and related compounds’,
in: ‘The chemistry of cyanates and their thio
derivatives’, Part 1, Ed. S. Patai, John Wiley &
Sons, Chichester, 1977, pp 381–444.
1H NMR (300 MHz, CDCl3): δ = 0.88 MHz, CDCl3): δ = 14.1 (C-10), 22.6 (C-9),
(t, J = 6.7 Hz, 3 H, 18-CH3), 1.26 (m, 26 23.5 (d, J = 4.1, C-4), 24.2 (C-14), 25.4
H, 5-CH2 – 17-CH ), 1.72–1.80 (m, 2 H, (C-13/15), 28.9, 30.7, 31.8 (C-6 – C-8),
4-CH2), 4.14 (dt, J 2= 6.7 Hz, J = 11.7 Hz, 48.9 (d, J = 28.9, C-1), 48.9 (C12/16),
1 H, 3-CH), 4.55 (dd, J = 3.8 Hz, J = 47.6 109.3 (d, J = 13.2 Hz, C-1), 154.6 (d, J
Hz, 1 H, 1-CHA), 4.71 (dd, J = 3.7 Hz, J = = 252.9 Hz, C-2), 181.1 (C-11). 19F NMR
16.5 Hz, 1 H, 1-CH ). 13C NMR (75 MHz, (282 MHz, CDCl3): δ = –117.9 (dt, J =
[9] a) C. Christophersen, A. Holm, Acta Chem.
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CDCl ): δ = 13.1 (CB-18), 21.7 (C-17), 24.5 17.2 Hz, JH,F = 37.2 Hz). HRMS (ESI):
3
(C-5),329.7, 29.8, 29.9, 30.0, 30.3, 32.3 (C- m/z calcd for [M + Na]+: 323.1928; found:
4 and C-6 – C-16), 56.9 (dd, J = 31.1 Hz, 323.1929.
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C-3), 91.1 (dd, J = 17.8 Hz, C-1), 131.7
(C-19), 160.4 (dd, J = 260.9 Hz, C-2). 19F
Acknowledgements
[11] a) H. Ulrich, ‘Reactions of alkyl and aryl
Financial support by the Deutsche
NMR (282 MHz, CDCl3): δ = –108.9 (ddd,
isocyanates’, in: ‘The
Chemistry and
Forschungsgemeinschaft (DFG, Project Ha
2145/12-1) is gratefully acknowledged.
J = 11.6, J = 16.5, J = 47.6 Hz). HRMS
Technology of Isocyanates’, Wiley, 1996; b)
E. Delebecq. J. P. Pacault, B. Boutevin, F.
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found: 350.2288.
Received: April 3, 2014
203.
4.3 General Procedure for the
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[1] a) R. G. Guy, ‘Synthesis and preparative
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(0.2 mmol) is microwave irradiated to
100 °C with the amine (0.1 mL) for 1 h.
Dichloromethane (5 mL) and 2 n HCl (5
mL) is added and the phases are separated.
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and dried over MgSO . The resulting resi-
due is purified by sili4ca gel chromatogra-
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N-(2-Fluorohexadec-2-en-1-yl)-N'-
phenylthiourea (31):
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1H NMR (300 MHz, CDCl3): δ = 0.87
(t, J = 6.7 Hz, 1 H, 16-CH ), 1.25–1.36
(m, 22 H, 5-CH2-15-CH2), 23.02–2.10 (m,
2 H, 4-CH ), 4.37 (dd, J = 5.5, J = 16.4 Hz,
1 H, 2-CH2), 4.84 (dt, J = 7.5, J = 37.3 Hz,
1 H, 3-CH2), 6.19 (bs, C-1-NH), 7.21–7.24
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46.2C(d, J = 30.0, C-1), 109.6 (d, J = 13.8
Hz, C-1), 125.2 (C-19/23), 127.5 (C-15),
130.3 (C-20/22), 135.8 (C-118), 153.7 (d,
J = 252.8 Hz, C-2), 180.8 (C-17). 19F NMR
(282 MHz, CDCl3): δ = –118.1 (dt, J = 16.5
Hz, J = 37.4 Hz). HRMS (ESI): m/z calcd
for [M + Na]+: 415.2554; found: 415.1554.
N-(2-Fluorodec-2-en-1-yl)-N',N'-
pentamethylene-thiourea (32):
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(t, J = 6.7 Hz, 3 H, 10-CH3), 1.27–1.37
(m, 10 H, 5-CH2 – 9-CH ), 1.61–1.68 (m,
6 H, 13/14/15-CH2), 2.025–2.11 (m, 2 H,
4-CH2), 3.79 (m, 4 H, 12/16-CH2), 4.41
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