A convenient one-pot synthesis of α-isothiocyanatoethers and unusual course of some of its nucleophilic displacement reactions

Article abstract of DOI:10.1135/cccc19971491

A simple new method has been devised for the preparation of α-isothiocyanatoethers 1a-1f in good yields by reaction of PO(NCS)₃ or (PhO)₂PONCS with an equimolar mixture of aldehydes and alcohols. The course of nucleophilic additions of methanol, amines and hydrazine to 1a-1f is described.

Full text of DOI:10.1135/cccc19971491

One-Pot Synthesis of α-Isothiocyanatoethers
1491
A CONVENIENT ONE-POT SYNTHESIS OF α-ISOTHIOCYANATOETHERS
AND UNUSUAL COURSE OF SOME OF ITS NUCLEOPHILIC
DISPLACEMENT REACTIONS
1,
2
3
Juraj BERNAT, Pavol KRISTIAN *, Jana GUSPANOVA , Jan IMRICH
and Tatiana BUSOVA
4
Department of Organic Chemistry, P. J. Safarik University, 041 67 Kosice, Slovak Republic;
e-mail: 1 kristian@kosice.upjs.sk, 2 guspan@oci.unizh.ch, 3 jimrich@kosice.upjs.sk,
4 busova@kosice.upjs.sk
Received January 6 , 1997
Accepted May 14, 1997
A simple new method has been devised for the preparation of α-isothiocyanatoethers 1a–1f in good
yields by reaction of PO(NCS)3 or (PhO)2PONCS with an equimolar mixture of aldehydes and alcohols.
The course of nucleophilic additions of methanol, amines and hydrazine to 1a–1f is described.
Key words: Isothiocyanates; Thiocarbamates; Thioureas; Thiosemicarbazides.
The high chemical reactivity of the N=C=S group1 made chemists look for various
types of isothiocyanates as suitable reagents for organic synthesis. In this respect bi-
functional isothiocyanates containing some additional reactive centre in the molecule
such as halogenoisothiocyanates, acylisothiocyanates or vinylisothiocyanates2 are inte-
resting compounds. This group of isothiocyanates also includes α-isothiocyanatoethers,
which can undergo addition as well as cyclization reactions. One of the best known
methods of their preparation is the halogen displacement by an alkali thiocyanates in
α-halogenoethers3. A recent approach to their synthesis showed that the reaction of
trimethylsilyl isothiocyanate with acetals in the presence of ZnCl2 gives the desired
α-isothiocyanatoethers, whereas the reaction with aldehydes at similar conditions gives
α,α′-diisothiocyanatoethers4. This paper deals with a new method for the preparation of
isothiocyanatoethers and their application in nucleophilic addition reactions.
In contrast to the previous report4, the method herein describes a one-pot process
consisting of the reaction of an aldehyde with an equimolar amount of alcohol and the
subsequent action of isothiocyanate agents PO(NCS)3 and/or (PhO)2PONCS on the
hemiacetal formed. Both the isothiocyanates give the same yields but PO(NCS)3 has the
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

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Bernat, Kristian, Guspanova, Imrich, Busova:
advantage of being prepared directly by a reaction of POCl3 with KSCN. The advantage
of this method – over the previous preparation from α-halogenoethers – is its broader
application possibilities. Hemiacetals and the isothiocyanate reagents used are more
reactive and are synthetically more accessible than many α-halogenoethers. The phos-
phorus-containing isothiocyanates were also employed in our previous work5 concern-
ing the synthesis of isothiocyanates from alcohols or carboxylic acids where a direct
substitution of an –OH group by an –NCS group took place. The resulting α-isothio-
cyanatoethers 1a–1f (Scheme 1) are pale yellow liquids sensitive to moisture. They
decompose on prolonged standing, which can be prevented by keeping them in dry
1
ether. Their structure was confirmed by H NMR and 13C NMR spectra and by the
intensive IR spectral band νasym(NCS) at 2 050 cm–1.
1
1
OR
CH
OH
OR
CH
PO(NCS)
3
1
R
CH
O
+
R OH
R
R
or (PhO) PONCS
2
NCS
1a-1f
1
1
R
R
R
R
1
1
a
b
c
d
e
f
Et Et
Me Et
Et Me
Et iPr
Pr Et
Ph Et
SCHEME 1
It is well known that isothiocyanates readily react with alcohols, amines and hydra-
zines1,6 to give thiocarbamates, thioureas and thiosemicarbazides, respectively. These
products have found applications as biologically active substances1,7, analytical rea-
gents8 and synthons in heterocyclic chemistry9–11. It was interesting to investigate the
reaction of α-isothiocyanatoethers with the previously mentioned nucleophiles
(Schemes 2–4). The reaction of isothiocyanate 1a with sodium methoxide gives methyl
OEt
OEt
MNO
MeONa
Et CH
1a
Et CH
NHCOOMe
NHCSOMe
3
2
H
OEt
Et
MeOCS
MeOCS
MeOCS
Et
OEt
H
Et
EtO
H
H
H
H
A
B
C
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

One-Pot Synthesis of α-Isothiocyanatoethers
1493
1
N-(1-ethoxypropyl)thiocarbamate 2 whose H and 13C NMR spectra showed double
resonance signals in the ratio of 2.14 : 1, which are in accord with the structure 2.
Heating of thiocarbamate 2 to 130 °C in dideuterio-1,1,2,2-tetrachloroethane causes the
resonance signals to coalesce, whereas the spectrum assumes the original form on cool-
ing the sample. The largest differences in chemical shifts of pairs of signals (0.51 and
0.33 ppm) are exhibited by the CH and NH protons. One of possible interpretations is
the presence of conformations B and C in the reaction mixture; their analogous gauche
arrangement of hydrogens at CH–NH bond is indicated by the identical values of their
coupling constants (ca 9.5 Hz) (Scheme 2). The reaction of thiocarbamate 2 with
mesitylnitriloxide (MNO) gave methyl N-(1-ethoxypropyl)carbamate (3, Scheme 2)
which, in contrast to its sulfur analogue 2, shows no resonance doubling of signals in
1H NMR spectra even after cooling to –100 °C.
α-Isothiocyanatoethers react with amines at 0 °C to give the corresponding thioureas.
In the case of the reaction of propan-1-amine with 1-ethoxypropyl isothiocyanate (1a),
the addition of the amine to the N=C=S group is accompanied by substitution of the
ethoxy group, hence the final product is N-propyl-N′-[1-(propylamino)propyl]thiourea (4).
Secondary amines react with α-isothiocyanatoethers 1a and 1d to give the correspond-
ing N,N,N′-trisubstituted thioureas 5a–5c (Scheme 3).
NHPr
Et CH
NH CS NHPr
1a + PrNH
2
4
1
2
OEt
CH
OEt
CH
R R
R
5
1
2
+
R R NH
R
R
a
b
c
Et (CH )
2 5
1
2
NHCSNR R
NCS
Me (CH )
2 5
Me Et, Et
1a, 1d
5a-5c
SCHEME 3
The reaction of isothiocyanate 1a with hydrazine took place at –30 °C yielding the
expected product 4-(1-ethoxypropyl)thiosemicarbazide (6) and a minor product 1-pro-
pylidene-4-(1-ethoxypropyl)thiosemicarbazide (7) which could be isolated from the re-
action mixture. The course of this reaction was not studied. It is possible that it results
from autocondensation of two molecules of compound 6 with elimination of ethanol
and thiosemicarbazide (Scheme 4).
OEt
OEt
+
NH
Et CH
Et CH
1a
+ NH
2
2
NHCSNHNH
NH CS NH N CHEt
2
7
6
SCHEME 4
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Bernat, Kristian, Guspanova, Imrich, Busova:
EXPERIMENTAL
Spectral Measurements
The 1H NMR spectra were measured on a Tesla BS 587 spectrometer (80 MHz) and JEOL Alpha
400 instrument (399.65 MHz) in deuteriochloroform using tetramethylsilane as internal standard. To
1
1
assign the conformational structures of thiocarbamate 2, the homonuclear H, H COSY method was
used. The 13C NMR spectra were measured with a Tesla BS 567 spectrometer (25 MHz) in deuterio-
chloroform. The chemical shifts are given in ppm (δ-scale).The infrared spectra were recorded on a
Specord 75 IR instrument (Zeiss, Jena) in chloroform. The elemental analyses were performed on a
Perkin–Elmer CHN 2400 analyzer. PO(NCS)3 and (PhO)2PONCS were obtained by refluxing POCl3
and (PhO)2POCl with KSCN in benzene and acetonitrile, respectively5. The amines and hydrazine
were commercial products (Aldrich). TLC was carried out on a Merck silica gel 60 (230–400 mesh).
General Procedure for Preparation of α-Isothiocyanatoethers (1)
To the respective aldehyde (0.1 mol), constantly stirred at 0 °C, the equivalent amount of alcohol
(0.1 mol) was added. The reaction mixture was left to stand at room temperature for 1 h and then
cooled again to 0 °C, whereupon a solution of (PhO)2PONCS (0.1 mol) or PO(NCS)3 (0.037 mol) in
hexane (20 ml) was added dropwise. The reaction mixture was left to stand for 15 h and distilled
under reduced pressure. In the case of reaction with PO(NCS)3, only the hexane layer was separated
and distilled.
1-Ethoxypropyl isothiocyanate (1a): b.p. 59–62 °C/2.1 kPa; yield 65%. For C6H11NOS (145.2) cal-
culated: 49.62% C, 7.63% H, 9.65% N; found: 49.27% C, 7.51% H, 9.52% N. IR spectrum: 2 066
1
(NCS). H NMR spectrum: 1.03 t, 3 H, J = 7.8 (CH3, Pr); 1.26 t, 3 H, J = 7.1 (CH3, EtO); 1.70–1.99 m,
2 H (CH2, Pr); 3.53 dq and 3.89 dq, 2 H, J = 9.3, 7.1 (CH2, EtO); 4.80 t, 1 H, J = 5.3 (CH, Pr). 13C NMR
spectrum: 8.6 (CH3, Pr); 14.7 (CH3, EtO); 30.2 (CH2, Pr); 65.3 (CH2, EtO); 89.8 (CH, Pr); 137.6
(NCS).
1-Methoxypropyl isothiocyanate (1b): b.p. 31–32 °C/2.1 kPa (reported4 72–73 °C/7.3 kPa); yield
44%. IR spectrum: 2 063 (NCS). 1H NMR spectrum: 1.01 t, 3 H (CH3); 1.62–2.05 m, 2 H (CH2);
3.27 s, 3 H (CH3O); 4.75 t, 1 H (CH).
1-Isopropoxypropyl isothiocyanate (1c): b.p. 41–43 °C/2.0 kPa; yield 35%. For C7H13NOS (159.3)
calculated: 52.79% C, 8.23% H, 8.79% N; found: 51.96% C, 8.05% H, 8.73% N. IR spectrum: 2 056
1
(NCS). H NMR spectrum: 1.13 t, 3 H (CH3, Pr); 1.19 d and 1.21 d, 6 H (2 × CH3, iPr); 1.69–2.00 m,
2 H (CH2, Pr); 3.83–4.28 m, 1 H (CH, iPr); 4.87 t, 1 H (CH, Pr). 13C NMR spectrum: 8.7 (CH3, Pr);
21.2 (CH3, iPr); 22.9 (CH3, iPr); 30.6 (CH2, Pr); 71.3 (CH, iPr); 87.8 (CH, Pr).
1-Ethoxyethyl isothiocyanate (1d): b.p. 48–50 °C/2.4 kPa (reported4 84–85 °C/8.0 kPa); yield 57%.
IR spectrum: 2 037 (NCS). 1H NMR spectrum: 1.27 t, 3 H, J = 7.2 (CH3, EtO); 1.57 d, 3 H, J = 6.0 (CH3);
3.47–4.05 m, 2 H (CH2, EtO); 5.07 q, 1 H, J = 6.0 (CH). 13C NMR spectrum: 14.7 (CH3, EtO); 23.2
(CH3); 65.2 (CH2, EtO); 85.1 (CH); 138.1 (NCS).
1-Ethoxybutyl isothiocyanate (1e): b.p. 55–56 °C/2.7 kPa; yield 64%. For C7N13NOS (159.2) cal-
culated: 52.79% C, 8.23% H, 8.79% N; found: 52.31% C, 8.16% H, 8.72% N. IR spectrum: 2 050
1
(NCS). H NMR spectrum: 0.96 t, 3 H, J = 6.4 (CH3, Bu); 1.25 t, 3 H, J = 7.2 (CH3, EtO); 1.35–2.00 m,
4 H (CH2CH2, Bu); 3.40–4.05 m, 2 H (CH2, EtO); 4.91 t, 1 H, J = 5.7 (CH, Bu). 13C NMR spectrum:
13.5 (CH3, Bu); 14.7 (CH3, Et); 17.7 (CH2, Bu); 38.9 (CH2, Bu); 65.4 (CH2, Et); 88.6 (CH, Bu); 137.5
(NCS).
1-Ethoxybenzyl isothiocyanate (1f): b.p. 59–61 °C/2.1 kPa; yield 45%. For C10H11NOS (193.3)
calculated: 62.15% C, 5.74% H, 7.25% N; found: 61.46% C, 5.69% H, 7.06% N. IR spectrum: 1 992
1
(NCS). H NMR spectrum: 1.34 t, 3 H (CH3); 3.60–4.00 m, 2 H (CH2); 5.92 s, 1 H (CH); 7.40–7.75 m,
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One-Pot Synthesis of α-Isothiocyanatoethers
1495
5 H (Ph). 13C NMR spectrum: 14.7 (CH3); 65.3 (CH2); 88.8 (CH); 126.0 (2 CH-ortho); 128.7 (2 CH-meta);
129.4 (CH-para); 137.2 (C-ipso).
Methyl N-(1-Ethoxypropyl)thiocarbamate (2)
1-Ethoxypropyl isothiocyanate (1a, 1.45 g, 0.01 mol) was added dropwise to a suspension of sodium
alkoxide (0.54 g, 0.01 mol) in dry ether under nitrogen at room temperature with constant stirring.
The reaction mixture was left to stand overnight, then neutralized with dilute hydrochloric acid, the
ether layer was separated and dried with sodium sulfate. Ether was evaporated and the residue was
subjected to chromatography (silica gel; petroleum ether–ether 5 : 1). The product was recrystallized
from hexane. M.p. 48–50 °C; yield 1.15 g (65%). For C7H15NO2S (177.3) calculated: 47.43% C,
8.53% H, 7.90% N; found: 47.02% C, 8.50% H, 7.88% N. IR spectrum: 3 400 (NH); 1 490 (NHCS).
1H NMR spectrum for the major conformer: 0.97 t, 3 H, J = 7.3 (CH3, Pr); 1.19 t, 3 H, J = 7.1 (CH3,
EtO); 1.70 m, 2 H (CH2, Pr); 3.60 m, 1 H and 3.73 m, 1 H (CH2, EtO); 3.98 s, 3 H (CH3O); 5.49 dt,
1 H, J = 9.5; 6.1 (CH); 6.51 d, 1 H, J = 9.5 (NH); for the minor conformer: 0.94 t, 3 H, J = 6.7
(CH3, Pr); 1.18 t, 3 H, J = 7.1 (CH3, EtO); 1.62 m, 2 H (CH2, Pr); 3.43 m, 1 H and 3.62 m, 1 H
(CH2, EtO); 4.08 s, 3 H (CH3O); 4.98 dt, 1 H, J = 9.4; 6.1 (CH); 6.84 d, 1 H, J = 9.4 (NH). 13C NMR
spectrum for the major conformer: 9.0 (CH3, Pr); 15.2 (CH3, EtO); 28.6 (CH2, Pr); 56.9 (CH3O);
64.2 (CH2, EtO); 86.9 (CH); 191.6 (CS); for the minor conformer: 9.0 (CH3, Pr); 15.0 (CH3, EtO);
28.6 (CH2, Pr); 58.3 (CH3O); 63.8 (CH2, EtO); 84.0 (CH); 191.3 (C=S).
Methyl N-(1-Ethoxypropyl)carbamate (3)
A solution of mesitylnitriloxide (1.61 g, 0.01 mol) in acetonitrile (20 ml) was added dropwise to a
solution of thiocarbamate 2 (1.77 g, 0.01 mol) in anhydrous acetonitrile (20 ml) at room temperature
with constant stirring. The reaction mixture was stirred for 1 h, the solvent was evaporated, and the
crude product was recrystallized from an acetone–hexane mixture. Oil; yield 1.34 g (83%). For
(C7H15NO3) (161.2) calculated: 52.16% C, 9.38% H, 8.69% N; found: 52.32% C, 9.27% H, 8.51% N.
1
IR spectrum: 3 440 (NH); 1 725 (CO). H NMR spectrum: 0.93 t, 3 H (CH3, Pr); 1.16 t, 3 H (CH3,
EtO); 1.60 m, 2 H (CH2, Pr); 3.53 m (CH2, EtO); 3.68 s, 3 H (CH3O); 4.88 m (CH, NH). 13C NMR
spectrum: 9.2 (CH3, Pr); 15.2 (CH3, EtO); 29.0 (CH2, Pr); 52.1 (CH3O); 63.3 (CH2, EtO); 83.3 (CH, Pr);
156.7 (C=O).
General Procedure for Preparation of Thioureas 4 and 5a–5c
A solution of the respective amine (0.1 mol) in ether (40 ml) was gradually added to a solution of
α-isothiocyanatoether 1a–1d (0.1 mol) in dry ether (40 ml) with stirring at 0 °C. After the isothio-
cyanate had reacted (TLC monitoring), ether was evaporated and hexane was added to the residue.
The separated crystalline thiourea was collected by suction and dried in air.
N-Propyl-N′-[1-(propylamino)propyl]thiourea (4): m.p. 148–150 °C; yield 60%. For C10H23N3S
1
(217.4) calculated: 55.25% C, 10.67% H, 19.33% N; found: 54.86% C, 10.41% H, 19.28% N. H NMR
spectrum: 0.98, 9 H (3 CH3); 1.66 m, 6 H (3 CH2); 3.53 m, 4 H (2 CH2); 6.05 m, 1 H (CH); 7.34 s,
2 H (2 NH); 8.65 s, 1 H (NH). 13C NMR spectrum: 9.6 (CH3); 11.4 (2 CH3); 22.2 (2 CH2); 28.8
(CH2); 47.3 (2 CH2N); 64.6 (CH); 180.6 (C=S).
N-[N-(1-Ethoxypropyl)thiocarbamoyl]piperidine (5a): m.p. 76–78 °C; yield 72%. For C11H22N2OS
(230.4) calculated: 57.35% C, 9.63% H, 12.16% N; found: 57.08% C, 9.56% H, 12.09% N. IR spectrum:
1
3 430 (NH); 1 510 (NHCS). H NMR spectrum: 1.05 t, 3 H (CH3, Pr); 1.25 m, 3 H (CH3, EtO); 1.73 m,
8 H (CH2, Pr; CH2, skel.); 3.88 m, 6 H (CH2NCH2, CH2O); 5.78 d, 1 H (NH); 6.08 m, 1 H (CHO).
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

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Bernat, Kristian, Guspanova, Imrich, Busova:
N-[N-(1-Ethoxyethyl)thiocarbamoyl]piperidine (5b): m.p. 97–99 °C; yield 77%. For C10H20N2OS
(216.4) calculated: 55.52% C, 9.32% H, 12.95% N; found: 55.36% C, 9.27% H, 12.79% N. IR spec-
trum: 3 430 (NH); 1 510 (NHCS). 1H NMR spectrum: 1.25 t, 3 H (CH3, EtO); 1.46 d, 3 H (CH3);
1.73 m, 6 H (CH2, skel.); 3.84 m, 6 H (CH2NCH2, CH2O); 5.88 d, 1 H (NH); 6.25 m, 1 H (CHO).
13C NMR spectrum: 15.3 (CH3); 22.1 (CH3); 24.3 (CH2); 25.5 (2 CH2); 48.9 (CH2NCH2); 63.7
(CH2O); 83.2 (CHO); 180.6 (C=S).
N,N-Diethyl-N′-(1-ethoxyethyl)thiourea (5c): m.p. 35–38 °C; yield 45%. For C9H20N2OS (204.3)
calculated: 52.90% C, 9.87% H, 13.71% N; found: 51.98% C, 9.79% H, 13.68% N. IR spectrum: 3 425
(NH); 1 500 (NHCS). 1H NMR spectrum: 1.25 m, 12 H (CH3); 3.68 m, 6 H (CH2); 5.50 d, 1 H
(NH); 6.05 dq, 1 H (CHO).
Preparation of 4-(1-Ethoxypropyl)thiosemicarbazide (6) and 1-Propylidene-4-(1-ethoxypropyl)thio-
semicarbazide (7)
A solution of isothiocyanate 1a (1 g, 7 mmol) in ether (10 ml) was added dropwise to a solution of
35% hydrazine (0.63 g, 7 mmol) in ethanol (10 ml) with constant stirring under nitrogen at –30 °C.
The temperature of reaction mixture was allowed to increase to room temperature. The crude product
obtained upon evaporation of the solvent was submitted to chromatography (silica gel; heptane–ether
1 : 1) to give compounds 6 and 7.
4-(1-Ethoxypropyl)thiosemicarbazide (6): m.p. 67–70 °C (heptane); yield 38%. For C6H15N3OS
1
(177.3) calculated: 40.65% C, 8.53% H, 23.70% N; found: 40.17% C, 8.47% H, 23.34% N. H NMR
spectrum: 0.98 t, 3 H (CH3, Pr); 1.20 t, 3 H (CH3, EtO); 1.68 m, 2 H (CH2, Pr); 3.66 m, 2 H (CH2,
EtO); 3.84 s, 2 H (NH2); 5.38 dt, 1 H (CH); 7.62 d, 1 H (NH); 8.13 s, 1 H (NH). 13C NMR spec-
trum: 9.1 (CH3); 15.3 (CH3); 28.9 (CH2); 63.8 (CH2O); 85.3 (CH); 182.1 (C=S).
1-Propylidene-4-(1-ethoxypropyl)thiosemicarbazide (7): m.p. 187–188 °C; yield 23%. For
C9H19N3OS (217.3) calculated: 49.74% C, 8.81% H, 19.23% N; found: 49.15% C, 8.69% H,
1
19.13% N. H NMR spectrum: 0.99 t, 3 H (CH3, Pr); 1.11 t, 3 H (CH3, Pr); 1.21 t, 3 H (CH3, EtO);
1.72 m, 2 H (CH2, Pr); 2.30 m, 2 H (CH2, Pr); 3.68 m, 2 H (CH2, EtO); 5.69 dt, 1 H (CH); 7.30 t,
1 H (CH=N); 7.48 d, 1 H (NH); 9.85 s, 1 H (NH). 13C NMR spectrum: 9.0 (CH3); 10.5 (CH3); 15.2
(CH3); 25.7 (CH2); 29.0 (CH2); 64.0 (CH2); 85.5 (CH); 148.4 (C=N); 177.4 (C=S).
This study was supported by the Grant Agency for Science of the Slovak Ministry of Education (Registr.
No. 96/5195/553).
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