A selective synthesis of β-isothiocyanato ketones through a Staudinger/aza-Wittig reaction of β-azido ketones

Article abstract of DOI:10.1007/s00706-012-0869-3

A novel selective two-step synthesis of β-isothiocyanato ketones from α,β-unsaturated ketones has been developed. The synthesis includes preparation of β-azido ketones followed by reaction with triphenylphosphine and carbon disulfide. Treatment of the obtained β-isothiocyanato ketones with ammonia or methylamine gives corresponding hexahydro-4-hydroxypyrimidine-2- thiones. The latter are also prepared directly from β-azido ketones without isolation of the intermediate β-isothiocyanato ketones.

Full text of DOI:10.1007/s00706-012-0869-3

Monatsh Chem (2013) 144:351–359
DOI 10.1007/s00706-012-0869-3
ORIGINAL PAPER
A selective synthesis of b-isothiocyanato ketones through
a Staudinger/aza-Wittig reaction of b-azido ketones
•
Anastasia A. Fesenko Ekaterina A. Dem’yachenko
•
•
Galina A. Fedorova Anatoly D. Shutalev
Received: 21 May 2012 / Accepted: 1 October 2012 / Published online: 1 December 2012
Ó Springer-Verlag Wien 2012
Abstract
A
novel selective two-step synthesis of
The most commonly used synthesis of b-isothiocyanato
aldehydes and ketones 1 involves the addition of thiocyanic
acid to the corresponding a,b-unsaturated carbonyl com-
pounds 2 (Scheme 1) [1, 18, 19]. However, reaction of
b-unsubstituted a,b-unsaturated aldehydes or ketones (2,
R2 = R3 = H) with thiocyanic acid proceeds with low
selectivity, resulting in mixtures of isomeric b-isothiocya-
nates 3 and b-thiocyanates 4 (up to 50 %) [20, 21], which are
difficult to separate because of similar physical properties.
This drawback confines the use of b-unsubstituted
b-isothiocyanato aldehydes and ketones in organic synthesis.
We hypothesized that a,b-unsaturated aldehydes and
ketones could be selectively transformed into respective
b-isothiocyanato carbonyl compounds 1 and 3 by the addi-
tion of HN3 to give b-azido aldehydes and ketones [22, 23]
followed by transformation of the azido group into
an isothiocyanato group using a Staudinger/aza-Wittig
sequence [24–30]. In our preliminary communication, an
example of the application of this methodology has been
described [31]. Herein, we report full details of the selective
synthesis of b-unsubstituted b-isothiocyanato ketones from
a,b-unsaturated ketones. We also describe further transfor-
mation of the obtained isothiocyanates into hardly accessible
6-unsubstituted hexahydro-4-hydroxypyrimidine-2-thiones
in high yields.
b-isothiocyanato ketones from a,b-unsaturated ketones
has been developed. The synthesis includes preparation of
b-azido ketones followed by reaction with triphenylphos-
phine and carbon disulfide. Treatment of the obtained
b-isothiocyanato ketones with ammonia or methylamine
gives corresponding hexahydro-4-hydroxypyrimidine-2-
thiones. The latter are also prepared directly from b-azido
ketones without isolation of the intermediate b-isothiocy-
anato ketones.
Keywords Azides Á Isothiocyanates Á
Carbonyl compounds Á Phosphorus compounds Á
Three-component reaction Á Pyrimidines
Introduction
b-Isothiocyanato aldehydes and ketones (e.g., 1), possess-
ing two reactive functional groups, have proved to be
versatile starting materials for the synthesis of a wide range
of nitrogen-containing acyclic and heterocyclic com-
pounds. Since the first representatives of 1 have been
described in 1946 [1], their chemistry was extensively
studied [2, 3]. They were used in preparation of various
pyrimidines [4–6], 1,3-thiazines [7, 8], 1,3-oxazines [9],
pyridines [10], nucleosides [11, 12], pyrroles [13], 1,2,4-
triazepines [14], condensed heterocycles [15–17], etc.
Results and discussion
Starting b-azido ketones 5a and 5b were prepared
according to the literature procedure based on the reaction
of methyl vinyl ketone (6a) and isopropenyl methyl ketone
(6b) with sodium azide in aqueous acetic acid at room
temperature (Scheme 2) [23]. b-Azido ketone 5c was first
synthesized following this procedure from phenyl vinyl
A. A. Fesenko Á E. A. Dem’yachenko Á G. A. Fedorova Á
A. D. Shutalev (&)
Department of Organic Chemistry, Moscow State University
of Fine Chemical Technologies, Moscow, Russian Federation
e-mail: shutalev@orc.ru
123

352
A. A. Fesenko et al.
R1
C
R1
Scheme 1
R1
R1
R2
R3
R
R
HNCS
HNCS
R2
R
R
+
N
O
S
S
O
N
R3
O
N
O
S
R2 or R3 = H
R2 = R3 = H
C
C
1
2
3
4
R1
R1
R1
R1
R1
NaN3
PPh3
- N2
CS2
R
R
R
R
R
N
O
S
N3
O
N
O
C
AcOH, H2O
N3
- Ph3PS
O
Ph3P
O
5a-5c
7a-7c
8a-8c
6a-6c
5a-5c
R1
R
7-9 a R = Me, R1 = H
b R = R1 = Me
5, 6 a R = Me, R1 = H; b R = R1 = Me; c R = Ph, R1 = H
N
- Ph3PO
c R = Ph, R1 = H
Scheme 2
9a-9c
ketone (6c). Previously, compound 5c was obtained by
reaction of 3-chloro-1-phenylpropan-2-one with sodium
azide [32] or treatment of 1-phenylcyclopropanol with
sodium azide in the presence of cerium (IV) ammonium
nitrate [33].
Scheme 3
1-azetine (9c) by the reaction of 5c with PPh3, however, in
very low yield.
The reactions between azides 5a, 5c and triphenyl-
phosphine (1 equiv.) with or without carbon disulfide in
CDCl3 were monitored by H and 13C NMR spectroscopy
Azides 5a–5c were isolated from reaction mixtures as
yellowish oils in 62–88 % yields after extraction with
diethyl ether followed by neutralization of ether extracts
with aqueous Na2CO3, drying and evaporation of solvent in
vacuum. The purity of the crude 5a–5c was excellent
([95 % according to 1H NMR data), and they were used in
further transformations without additional purification.
First, transformation of the azido group of compounds
5a–5c into an isothiocyanato group was examined using
azide 5a as a starting material. After treatment of this
compound with one equivalent of triphenylphosphine in dry
THF at room temperature, nitrogen evolution via the Stau-
dinger reaction was observed. Subsequent addition of excess
of carbon disulfide to the obtained solution of iminophos-
phorane 7a gave the target isothiocyanate 8a (Scheme 3).
The latter was isolated after solvent removal and extraction
of the residue with a petroleum ether–diethyl ether mixture
(1:1). However, the yield of 8a did not exceed 30 %.
A more convenient procedure of synthesis of 8a involved
treatment of a solution of 5a in THF-CS2 with triphenyl-
phosphine at room temperature for several hours. Yield of
8a increased when after cessation of nitrogen evolution, the
reaction mixture was refluxed for 1–1.5 h. Under optimal
conditions (THF-CS2, rt, 1.5 h, then reflux, 1 h), the yield
of oily 8a from azide 5a was 53 % after vacuum distillation.
Oily isothiocyanate 8b and solid isothiocyanate 8c were
prepared analogously from azides 5b and 5c in 82 and 52 %
yields, respectively. Notably, the products of intramolecular
aza-Wittig reaction of iminophosphoranes 7a–7c, azetines
9a–9c, were not detected in the studied reactions. Previ-
ously, Eguchi et al. [34] reported the formation of 2-phenyl-
1
at 25 °C. According to the 1H NMR spectroscopy data
(Table 1, Fig. 1), the reaction of 5a with PPh3 in CDCl3
was complete within 1.5 h to give iminophosphorane 7a
and methyl vinyl ketone (6a) in a 62:33 ratio, respectively.
Ketone 6a probably resulted from base-promoted elimi-
nation of hydrazoic acid from 5a under the action of 7a.
Strong basic properties of iminophosphoranes are well
documented in the literature [24–29]. The formation of
azetine 9a was not detected in the NMR experiment.
The structure of iminophosphorane 7a was confirmed by
1
1
its H and 13C NMR spectra. Thus, the H NMR spectrum
of 7a showed a singlet at 2.14 ppm because of the methyl
group, a doublet of triplets at 3.24 ppm (3J = 6.7 and
3JH,P = 10.1 Hz) and a triplet at 2.97 ppm (3J = 6.7 Hz)
assigned to the methylene groups of N–CH2–CH2 frag-
ment. In the 13C NMR spectrum the signals of the CH2–
CH2–C(O)–CH3 moiety were observed at 45.0 (d,
2JC,P = 11.6 Hz), 38.1 (d, JC,P = 2.2 Hz), 207.7 (s) and
3
30.2 (s) ppm, respectively.
Table 2 and Fig. 2 show the H NMR monitoring data
1
for the reaction between 5a, PPh3 (1 equiv.) and CS2 at
25 °C in a mixture of CDCl3–CS2. Under these conditions,
the rate of the formation of compound 8a was rather low.
After 39 min, azide 5a, isothiocyanate 8a, iminophos-
phorane 7a and methyl vinyl ketone 6a in a 38:45:10:7
ratio were observed. After 4 h, the amount of isothiocya-
nate 8a increased to 62 %. Two unidentified products (or
intermediates) were also formed in the reaction; however,
the overall amount of these products did not exceed 15 %.
123

A novel selective synthesis of b-isothiocyanato ketones
353
Compared with the literature method [1–3, 18, 19], the
above-described two-step methodology allows obtaining b-
unsubstituted b-isothiocyanato ketones from a,b-unsatu-
rated ketones with full chemoselectivity. The prepared
isothiocyanates 8a–8c were free from the corresponding
isomeric thiocyanates 4, whereas the previously described
8a, 8b [35] were mixtures of the b-isothiocyanato and b-
thiocyanato ketones in ratios of 50:50 and 65:35, respec-
tively [21].
Table 1 Reaction of 5a with PPh3 (CDCl3, 25 °C): dependence of
the product distribution on the reaction time
Time/min
Product distribution/%
5a
7a
6a
3
85
62
49
34
24
16
12
9
14
28
36
45
50
54
57
58
61
61
62
1
12
16
26
36
46
56
66
76
86
96
10
15
21
26
30
31
33
32
33
33
One of the most important reactions of b-isothiocyanato
ketones and aldehydes is that with ammonia or primary
amines to provide hexahydro-4-hydroxypyrimidine-2-
thiones or products of their further transformations generally
in good yields [2–6]. These compounds are currently of great
interest because of their remarkable biological activities
[36–38] and versatile synthetic applications [5, 8, 10, 39–
42]. However, the previously described reactions of com-
pounds 8a, 8b with ammonia and amines afforded the
products in rather low yields. For example, treatment of 8a
with ammonia in ethanol gave 1,2,3,4-tetrahydro-6-
methylpyrimidine-2-thione in only 40 % yield [43]. The
reaction of 8a with ammonia in diethyl ether afforded
hexahydro-4-methoxy-4-methylpyrimidine-2-thione in 18 %
yield after silica gel column chromatography of the obtained
7
6
5
A solution of 60.7 mg PPh3 (0.231 mmol) in 0.5 cm3 CDCl3 was
added at once to a 5-mm NMR tube charged with 26.2 mg 5a
(0.232 mmol). The solution obtained was shaken carefully (gas evo-
lution!). The progress of the reaction was monitored by 1H NMR
spectroscopy
Similar results as described for 5a were obtained from
NMR studies of the reactions between 5c and PPh3 with or
without CS2 in CDCl3.
Fig. 1 a–d 1H NMR spectra for
the reaction of 5a with PPh3
(CDCl3, 25 °C) after 12, 26, 46
1
and 66 min, respectively; e H
NMR spectra of 5a in CDCl3
123

354
A. A. Fesenko et al.
synthesis
of
6-unsubstituted
hexahydro-4-hydro-
Table 2 Reaction of 5a with PPh3 and CS2 (CDCl3, 25 °C):
dependence of the product distribution on the reaction time
xypyrimidine-2-thiones, we studied the reaction of pure
isothiocyanates 8a, 8b with ammonia and methylamine.
Prepared following our procedure, compounds 8a, 8b
readily reacted with concentrated aqueous ammonia (1.5
equiv.) in MeCN at room temperature for 1–1.5 h to pro-
vide the corresponding hydroxypyrimidines 10a, 10b in 78
and 89 % yields, respectively. Similarly, reaction of 8a
with concentrated aqueous methylamine (MeCN, rt, 1.5 h)
gave pyrimidine 10c in 82 % yield (Scheme 4).
Time/min
Product distribution/%
5a
8a
7a
6a
6
83
69
60
38
27
18
18
11
21
28
45
54
62
63
5
1
3
4
7
8
8
8
10
15
39
77
254
372
7
8
10
11
12
11
Hydroxypyrimidines 10a, 10b, 10d were conveniently
synthesized directly from azido ketones 5a, 5b without
purification of the intermediate isothiocyanates 8a, 8b. Thus,
the reaction of azide 5b with PPh3–CS2 in THF followed by
evaporation of solvent and extraction of the residue with
petroleum ether–diethyl ether mixture (1:1) gave a solution
of crude isothiocyanate 8b. Removal of solvent in vacuum,
treatment of the residue with concentrated aqueous ammonia
or methylamine in MeCN at room temperature, followed by
evaporation of solvent and treatment of the solid residue with
diethyl ether afforded chromatographically and spectro-
scopically pure hydroxypyrimidines 10b, 10d in 84 and
73 % overall yields, respectively. This procedure was also
used for the synthesis of hydroxypyrimidine 10a from azide
5a in 59 % overall yield.
A solution of 81.1 mg PPh3 (0.309 mmol) in 0.3 cm3 CDCl3 was
added at once to a 5-mm NMR tube charged with a solution of
34.2 mg 5a (0.302 mmol) in 0.3 cm3 CS2. The solution obtained was
shaken carefully (gas evolution!). The progress of the reaction was
1
monitored by H NMR spectroscopy
product using an ethyl acetate-methanol mixture as eluent
[42]. Isothiocyanate 8a reacted with methylamine in water to
give acyclic N-methyl-N’-(3-oxobut-1-yl)thiourea in 10 %
yield [44]. Obviously, the low purity of the starting iso-
thiocyanates, because of the presence of considerable
amounts of the isomeric thiocyanates, explains these poor
yields. Thus, with the aim of developing a preparative
Fig. 2 a–d 1H NMR spectra for
the reaction of 5a with PPh3 and
CS2 (CDCl3, 25 °C) after 6, 15,
77 and 254 min, respectively
123

A novel selective synthesis of b-isothiocyanato ketones
355
R1
R1
ratios of 84:7:9, 75:10:15, 72:11:17 and 61:14:25,
respectively.
R1
O
Me
NHR2
OH
Me
NR2
Me
R2-NH2
In summary, a novel chemoselective two-step approach
to b-isothiocyanato ketones starting from a,b-unsaturated
ketones was developed. The synthesis involved preparation
of b-azido ketones followed by reaction with triphenyl-
phosphine and carbon disulfide. This approach was
especially useful for synthesis of b-unsubstituted b-isothi-
ocyanato ketones, which cannot be prepared with sufficient
purity by commonly used procedures. Treatment of the
obtained b-isothiocyanato ketones with ammonia or
methylamine gave corresponding 6-unsubstituted hexahy-
dro-4-hydroxypyrimidine-2-thiones in high yields. These
heterocycles were also prepared directly from b-azido
ketones without intermediate purification of the b-isothio-
cyanato ketones.
HN
HN
N
O
S
C
S
S
10a-10d
8a, 8b
11a-11d
1. PPh3, CS2
2. R2-NH2
R1
10, 11 a R1 = R2 = H
b R1 = Me, R2 = H
c R1 = H, R2 = Me
d R1 = R2 = Me
Me
N3
O
5a, 5b
Scheme 4
According to IR spectroscopic data, all the obtained
pyrimidines 10a–10d exist exclusively in the cyclic form in
1
the solid state. These forms were also observed in H and
13C NMR spectra immediately after dissolution of 10a–10d
in DMSO-d6.
Experimental
1H NMR spectra showed that 10b, 10d were obtained as
mixtures of (4R*, 5R*) and (4R*, 5S*)-diastereomers with
overwhelming predominance of the former isomer (94:6
and 99.5:0.5 for 10b and 10d, respectively). In DMSO-d6
solutions, the major isomers adopted a conformation with
an axial orientation of the hydroxyl group and equatorial
orientation of the 5-Me group. It was confirmed by the
FT IR spectra were recorded using a Bruker Vector 22
spectrophotometer in Nujol for solid samples or in film for
liquid samples. Band characteristics in the IR spectra are
defined as very strong (vs), strong (s), medium (m), weak
1
(w) and shoulder (sh). H and proton-decoupled 13C NMR
spectra (solutions in DMSO-d6 or CDCl3) were acquired
using a Bruker DPX 300 spectrometer at 300.13 MHz (1H)
4
presence of the long range coupling constant JOH,5-
= 0.4–0.6 Hz because of a W-shaped arrangement of the
1
and 75.48 MHz (13C). H NMR chemical shifts are refer-
H
OH and 5-H protons and the high value of the vicinal
enced to the residual proton signal in DMSO-d6 (2.50 ppm)
or CDCl3 (7.25 ppm). In 13C NMR spectra, central signals
of DMSO-d6 (39.50 ppm) or CDCl3 (77.00 ppm) were
used as references. Multiplicities are reported as singlet (s),
doublet (d), triplet (t), quartet (q) and some combinations
coupling between 5-H and axial 6-H (for 10d). The long
4
range coupling JOH, 5-H = 0.3–0.8 Hz was also observed
1
in H NMR spectra of pyrimidines 10a, 10c in DMSO-d6,
proving an axial orientation of the hydroxyl group in these
1
of these, multiplet (m). Selective H-1H decoupling and
compounds.
According to 1H NMR spectra, the N-unsubstituted
pyrimidines 10a, 10b remained in cyclic form in DMSO-d6
solutions at room temperature for a prolonged time; how-
ever, their slow dehydration was observed. For example,
after 9 days, pyrimidine 10a converted into a mixture of
10a, 1,2,3,4-tetrahydro-6-methylpyrimidine-2-thione (12a)
and hexahydro-4-methylenepyrimidine-2-thione (13a) in a
85:10:5 ratio. After 2 and 9 days, (4R*, 5R*)-10b trans-
formed into mixtures of (4R*, 5R*)-10b, (4R*, 5S*)-10b,
1,2,3,4-tetrahydro-5,6-dimethylpyrimidine-2-thione (12b)
and hexahydro-5-methyl-4-methylenepyrimidine-2-thione
(13b) in ratios of 70:20:8:2 and 6:2:89:3, respectively. In
contrast to 10a, 10b, N-methyl-substituted pyrimidines
10c, 10d in DMSO-d6 solutions at room temperature
slowly gave equilibrium mixtures of 10c, 10d and their
acyclic isomers 11c, 11d. For example, after 14 days, the
1H NMR spectrum of 10c showed a 58:42 mixture of 10c
and 11c. After 2, 7, 9 and 21 days, 10d transformed into
mixtures of (4R*, 5R*)-10d, (4R*, 5S*)-10d and 11d in
DEPT-135 experiments were used to aid in the assignment
1
of H and 13C NMR signals. Elemental analyses (CHN)
were performed by using a Thermo Finnigan Flash EA1112
apparatus. The results were found to be in good agreement
( 0.3 %) with the calculated values. Thin-layer chroma-
tography (TLC) was carried out on Merck silica gel 60 F254
aluminum-backed plates in chloroform–methanol (9:1, v/v)
and chloroform–methanol (5:1, v/v) as solvent systems.
Spots were visualized with iodine vapors or UV light.
Column chromatography was performed with Merck silica
gel 60 (0.04–0.063 mm).
THF was dried over KOH pellets and then over Na-
benzophenone followed by distillation. All other reagents
and solvents were purchased from commercial sources and
used without further treatment. b-Azido ketones 5a, 5b
were prepared according to the literature procedure [23] as
yellowish oils with high purity in 62–63 % yields by
reaction of ketones 6a, 6b with NaN3 in aqueous acetic
acid at room temperature followed by extraction with
123

356
A. A. Fesenko et al.
4-Isothiocyanato-3-methylbutan-2-one (8b, C6H9NOS)
diethyl ether, neutralization with 7 % aqueous Na2CO3,
drying over MgSO4, filtration and removal of solvent in
vacuum. Azides 5a, 5b were used in further transforma-
tions without additional purification.
To a cooled ice bath a stirred solution of 16.30 g 4-azido-3-
methylbutan-2-one (5b, 0.128 mol) in 70 cm3 CS2 was
added dropwise over a period of 40 min a solution of
36.98 g PPh3 (0.141 mol) in 60 cm3 dry THF. The reaction
mixture was stirred for 2.3 h, while the temperature was
maintained at about 20 °C using a water bath. Then the
mixture was refluxed for 1 h and the solvent was removed
in vacuum. The residue was triturated with 40 cm3 diethyl
ether-petroleum ether mixture (1:1 v/v) until crystallization
was complete; the precipitate was filtered and washed with
diethyl ether–petroleum ether mixture (3 9 12 cm3, 1:1
v/v). The organic phases were combined, the solvent was
removed in vacuum, and the oily residue, containing 8b
and a small amount of Ph3PS, was distilled in vacuum to
give 15.06 g (82 %) 8b as a slightly yellow oil. B.p.:
89.5–92 °C (0.13 mbar); n2D0 = 1.5150; 1H NMR (CDCl3):
d = 3.74 (dd, 2J = 14.3, 3J = 6.5 Hz, 1H, CH(A) in
3-Azido-1-phenylpropan-1-one (5c)
To a stirred solution of 8.467 g vinyl phenyl ketone (6c,
64.07 mmol) in 70 cm3 AcOH was added dropwise a
solution of 12.504 g NaN3 (192.34 mmol) in 50 cm3 H2O
over 25 min at room temperature. The reaction mixture
was stirred for 4 h at room temperature and extracted with
diethyl ether (2 9 50 cm3 and 2 9 30 cm3). The combined
ether extracts were subsequently washed with 7 % aqueous
solution of Na2CO3 (to pH 9), water (to pH 7), brine and
dried over MgSO4. [Caution: generated hydrazoic acid
(HN3) is a very volatile, highly toxic and explosive com-
pound. All operations involving hydrazoic acid should be
carried out in an efficient fume hood following appropriate
precautions]. The solvent was removed in vacuum to give
9.882 g (88 %) 5c as yellowish oil. According to 1H NMR
analysis, the purity of the crude 5c was excellent, and it
was used in further transformations without additional
purification. The 1H NMR spectrum of the product is
essentially identical with the CDCl3 spectrum of this
compound described in Ref. [33].
2
3
CH2N), 3.53 (dd, J = 14.3, J = 6.5 Hz, 1H, CH(B) in
CH2N), 2.86 (tq, 3J = 7.3, 3J = 6.5, 3J = 6.5 Hz, 1H,
CHC=O), 2.21 (s, 3H, CH3C=O), 1.22 (d, 3J = 7.3 Hz, 3H,
CH3CH) ppm; 13C NMR (CDCl3): d = 208.24 (C=O),
131.23 (N=C=S), 46.83 (CHC=O), 46.30 (CH2N), 28.51
(CH3C=O), 14.45 (CH3CH) ppm.
3-Isothiocyanato-1-phenylpropan-1-one (8c,
C10H9NOS)
4-Isothiocyanatobutan-2-one (8a, C5H7NOS)
To a cooled ice bath a stirred solution of 1.634 g 3-azido-1-
phenylpropan-2-one (5c, 9.33 mmol) in 6 cm3 CS2 and
9 cm3 dry THF was added 2.508 g PPh3 (9.56 mmol). The
reaction mixture was stirred for 1.5 h at room temperature
and refluxed for 4 h, and the solvent was removed in
vacuum. The residue was triturated with 6 cm3 acetone–
petroleum ether mixture (8:5 v/v) until crystallization was
complete and cooled; the precipitate was filtered and
washed with an acetone–petroleum ether mixture (2 9
2 cm3, 8:5 v/v). The organic phases were combined and the
solvent was removed in vacuum. The residue was extracted
with diethyl ether (5 9 5 cm3), the solvent was removed,
and the residue was extracted with boiling hexane
(5 9 15 cm3). The aim of these subsequent extractions was
to remove Ph3PS as completely as possible without loss of
8c; the extraction with boiling hexane removed the yellow
coloring of the raw material. After evaporation of hexane,
the product was crystallized from CHCl3–hexane mixture
(1:4 v/v) to give 0.910 g (51 %) 8c as a white solid. (Note:
syntheses of 8c using more than 3 g of starting material 5c
are not recommended because the workup becomes labo-
rious). M.p.: 73.5–74 °C (CHCl3–hexane, 1:4 v/v); 1H
To a cooled ice bath a stirred solution of 3.650 g 4-azi-
dobutan-2-one (5a, 32.27 mmol) in 31 cm3 dry THF and
6 cm3 CS2 was added 8.463 g PPh3 (32.27 mmol) (caution:
vigorous evolution of nitrogen). The resulting solution was
stirred for 2.5 h at room temperature cooled ice bath a
stirred solution and the solvent was removed in vacuum.
The residue was triturated with 10 cm3 diethyl ether–
petroleum ether mixture (1:1 v/v) until crystallization
was complete; the precipitate was filtered and washed
with diethyl ether–petroleum ether mixture (3 9 5 cm3,
1:1 v/v). The organic phases were combined, the solvent
was removed in vacuum, and the oily residue, containing
8a and a small amount of Ph3PS, was distilled in vacuum to
give 2.656 g (64 %) 8a as a slightly yellow oil. A small
amount of 8a was also purified by column chromatography
on silica gel eluting with CHCl3–hexane mixtures (from
1:50 to 1:10) and then with CHCl3. B.p.: 88–90 °C
(0.13 mbar); n2D0 = 1.5193; 1H NMR (CDCl3): d = 3.73 (t,
3J = 6.5 Hz, 2H, CH2N), 2.81 (t, 3J = 6.5 Hz, 2H,
CH2C=O), 2.17 (s, 3H, CH3) ppm; 13C NMR (CDCl3):
d = 204.24 (C=O), 130.80 (N=C=S), 42.59 (CH2C=O),
ꢀ
39.34 (CH2N), 29.97 (CH3) ppm; IR (film): m = 2,196 s,
NMR (DMSO-d6): d = 7.97–8.02 (m, 2H, C(2)H and C(6)
H
2,121 vs (m N=C=S), 1,719 s (m C=O)/cm.
in Ph), 7.64–7.71 (m, 1H, C(4)H in Ph), 7.52–7.59 (m, 2H,
123

A novel selective synthesis of b-isothiocyanato ketones
357
3
C(3)H and C(5)H in Ph), 3.99 (t, J = 6.2 Hz, 2H, CH2N),
Pyrimidine 10a in DMSO-d6 solution at room temper-
ature slowly gave mixtures of 10a, 1,2,3,4-tetrahydro-6-
methylpyrimidine-2-thione (12a) and hexahydro-4-methy-
3.54 (t, 3J = 6.2 Hz, 2H, CH2C=O) ppm; 13C NMR
(DMSO-d6): d = 196.81 (C=O), 135.93 (Cquat in Ph),
133.62 (Cpara in Ph), 128.80 (Cortho in Ph), 128.01 (Cmeta in
Ph), 127.33 (N=C=S), 39.91 (CH2N), 37.78 (CH2C=O)
1
lenepyrimidine-2-thione (13a). H NMR spectrum of 12a
(DMSO-d6): d = 9.22 (br s, 1H, N(1)H), *8.25 (br s, 1H,
N(3)H, signals overlap with the N(3)H signal of 10a),
4.53–4.57 (m, 1H, 5-H), 3.72–3.75 (m, 2H, 4-H), 1.63–1.64
1
(m, 3H, 6-CH3) ppm. H NMR spectrum of 13a (DMSO-
ꢀ
ppm; IR (Nujol): m = 2,206 s, 2,125 vs (m N=C=S), 1,675
s (m C=O), 1,591 m (m CC in Ph), 752 s, 691 s (d CH in
Ph)/cm.
d6): d = 10.02 (br s, 1H, N(3)H), 8.52 (br s, 1H, N(1)H),
4.38 (unresolved t, 1H, = C–H), 3.94 (unresolved t, 1H, =
C–H), 3.10–3.15 (m, 2H, 6-H), 2.37–2.41 (m, 2H, 5-H)
ppm.
Hexahydro-4-hydroxy-4-methylpyrimidine-2-thione
(10a)
Method A: To a cooled ice bath a stirred solution of
1.990 g 4-isothiocyanatobutan-2-one (8a, 15.40 mmol) in
2 cm3 MeCN was added 1.6 cm3 28 % aqueous solution of
NH3 (density of 0.895 g/cm3), the reaction mixture was
stirred at room temperature for 1.5 h, and the solvent was
removed in vacuum. The residue was triturated with
petroleum ether, and the precipitate was filtered and dried
to give 1.755 g (78 %) 10a as a white solid. M.p.:
*111 °C (decomp., acetone) (rate of heating was 1 °C/3 s;
at lower rates of heating the compound decomposed
without melting and then melted with decomposition at
147.5–148 °C) (Ref. [42] 127–128 °C, Ref. [45] 151–
152 °C); 1H NMR (DMSO-d6): d = 8.22 (br s, 1H, N(3)H),
8.13 (unresolved d, 1H, N(1)H), 5.60 (d, 4JOH,5-H = 0.8 Hz,
1H, OH), 3.18–3.29 (m, 1H, 6-Ha), 3.00–3.09 (m, 1H, 6-
He), 1.66–1.75 (m, 1H, 5-He), 1.47–1.59 (m, 1H, 5-Ha),
1.35 (s, 3H, 4-CH3) ppm; 13C NMR (DMSO-d6):
d = 175.33 (C-2), 76.73 (C-4), 36.57 (C-6), 32.61 (C-5),
Hexahydro-4-hydroxy-4,5-dimethylpyrimidine-2-thione
(10b)
Method A: To a cooled ice bath a stirred solution of
15.057 g 8b (105.14 mmol) in 70 cm3 MeCN was added
dropwise 10 cm3 28 % aqueous solution of NH3 (density of
0.895 g/cm3), the reaction mixture was stirred for 10 min,
then the ice bath was removed and stirring was continued at
room temperature for 1 h. The solvent was removed in
vacuum. The residue was triturated with diethyl ether,
cooled, the precipitate was filtered, washed with cold die-
thyl ether and dried to give 15.010 g (89 %) 10b as a
mixture of (4R*, 5R*) and (4R*, 5S*)-diastereomers in a
ratio of 94:6. After crystallization from acetonitrile, the
diastereomeric ratio changed to 99:1. White solid, m.p.:
212–212.5 °C (decomp., MeCN) (Ref. [35] 187–188 °C);
1H NMR of the major diastereomer (DMSO-d6): d = 8.22
(d, 4JN(3)H, N(1)H = 2.0 Hz, 1H, N(3)H), 8.11 (unresolved m,
ꢀ
28.41 (4-CH3) ppm; IR (Nujol): m = 3,357 s, 3,219 br vs (m
4
NH, m OH), 1,564 s, 1,530 s (thioamide-II), 1,204 s, 1,163
s, 1,123 s/cm.
1H, N(1)H), 5.47 (d, JOH, 5-H = 0.6 Hz, 1H, OH), 2.85–
2.96 (m, 2H, 6-Ha and 6-He), 1.55–1.68 (m, 1H, 5-H), 1.29
3
Method B: To a cooled ice bath a stirred solution of
0.390 g 4-azidobutan-2-one (5a, 3.45 mmol) in 4 cm3 dry
THF and 2 cm3 CS2 was added 0.905 g PPh3 (3.45 mmol).
The resulting solution was stirred for 1.75 h at room tem-
perature and refluxed for 1.5 h, and the solvent was
removed in vacuum. The residue was triturated with diethyl
ether–petroleum ether mixture (1:1 v/v) until crystalliza-
tion was complete; the precipitate was filtered and washed
several times with diethyl ether–petroleum ether mixture
(1:1 v/v). The organic phases were combined, the solvent
was removed in vacuum, and the oily residue, containing
8a and small amount of Ph3PS, was disolved in 4 cm3
MeCN. Under stirring and cooling in an ice bath, to this
solution was added 0.35 cm3 28 % aqueous solution of
NH3 (density of 0.895 g/cm3). The obtained solution was
stirred at room temperature for 1 h and the solvent was
removed in vacuum. The residue was triturated with diethyl
ether until crystallization was complete, the precipitate was
filtered, washed with diethyl ether and dried to give
0.299 g (59 %) 10a as a white solid.
(s, 3H, 4-CH3), 0.84 (d, JCH 5ÀH = 6.7 Hz, 3H, 5-CH3)
3
ppm; 1H NMR of the minor diastereomer (DMSO-d6):
d = 8.06 (br s, 1H, N(1)H), 5.66 (s, 1H, OH), 3.40 (ddd, 2J6-
= 12.5, J6-Ha, 5-H = 4.4, J6-Ha, N(1)H = 1.3 Hz,
3
3
Ha, 6-He
1H, 6-Ha), 2.74 (ddd, 2J6-He, 6-Ha = 12.5, 3J6-He, 5-H = 3.8,
3J6-He, N(1)H = 3.8 Hz, 1H, 6-He), 1.68–1.78 (m, 1H, 5-H),
1.24 (s, 3H, 4-CH3), 0.80 (d, 3JCH ;5ÀH= 7.0 Hz, 3H, 5-CH3)
3
ppm, the signal of the N(3)H proton overlaps with signal of
the N(1)H proton of the major isomer; 13C NMR of the
major diastereomer (DMSO-d6): d = 175.16 (C-2), 78.76
(C-4), 42.98 (C-6), 34.83 (C-5), 25.69 (4-CH3), 11.80 (5-
CH3) ppm; 13C NMR of the minor diastereomer (DMSO-
d6): d = 174.81 (C-2), 79.92 (C-4), 43.38 (C-6), 33.75 (C-
5), 24.89 (4-CH3), 13.91 (5-CH3) ppm; IR (Nujol):
ꢀ
m = 3,345 s, 3,222 br vs, 3,138 m (m NH, m OH), 1,592 s,
1,532 s (thioamide-II), 1,213 s, 1,171 s, 1,036 s/cm.
Method B: Compound 10b (3.388 g, 84 %) was pre-
pared from 3.209 g 4-azido-3-methylbutan-2-one (5b,
25.24 mmol), 7.236 g PPh3 (27.59 mmol), 15 cm3 CS2,
20 cm3 dry THF, 16 cm3 MeCN and 2.5 cm3 28 %
123

358
A. A. Fesenko et al.
aqueous solution of NH3 (density of 0.895 g/cm3) as
described for 10a using method B.
methylamine (density of 0.902 g/cm3) as described for 10a
using method B. This compound was obtained as a mixture
of (4R*, 5R*)- and (4R*, 5S*)-diastereomers in a ratio of
99.5:0.5, respectively. After crystallization from acetoni-
trile the diastereomeric ratio did not change. White solid,
Pyrimidine (4R*, 5R*)-10b in DMSO-d6 solution at room
temperature slowly gave mixtures of (4R*, 5R*)-10b,
(4R*, 5S*)-10b, 1,2,3,4-tetrahydro-5,6-dimethylpyrimidine-
2-thione (12b) and hexahydro-5-methyl-4-methylenepyr-
imidine-2-thione (13b). 1H NMR spectrum of 12b (DMSO-
d6): d = 9.06 (br s, 1H, N(1)H), 8.16 (br s, 1H, N(3)H), 3.61–
3.63 (m, 2H, 4-H), 1.63–1.66 (m, 3H, 6-CH3), 1.47–1.49 (m,
1
m.p.: 116.5–117 °C (MeCN) (Ref. [35] 108–109 °C); H
NMR of the major diastereomer (DMSO-d6): d = 8.02 (dd,
= 4.1, JNH,6-Ha = 1.7 Hz, 1H, NH), 5.98 (d,
3
3JNH,
6-He
4JOH, 5-H = 0.4 Hz, 1H, OH), 3.16 (s, 3H, NCH3), 3.11
1
2
(ddd, J6-He,
3
= 12.8, J6-He,
3
= 4.9, J6-He,
3H, 5-CH3) ppm. H NMR spectrum of 13b (DMSO-d6):
d = 9.96 (br s, 1H, N(3)H), 8.49 (br s, 1H, N(1)H), 4.40–4.41
(m, 1H, = C–H), 3.99–4.01 (m, 1H, = C–H), 1.69–1.79 (m,
=
NH
6-Ha
5-H
2
4.1 Hz, 1H, 6-He), 2.77 (ddd, J6-Ha, 6-He = 12.8, J6-Ha,
3
3
= 10.1, J6-Ha, NH = 1.7 Hz, 1H, 6-Ha), 1.96 (dddq,
5-H
3
3
3
1H, 5-H), 1.04 (d, JCH ;5ÀH = 6.7 Hz, 3H, 5-CH3) ppm,
signals of the 6-H protons overlap with proton signals of
3J5-H, 6-Ha = 10.1, J5-H, J5ÀH;CH = 6.9, J5-H, 6-He = 4.9,
3
3
4J5-H, OH = 0.4 Hz, 1H, 5-H), 1.19 (s, 3H, 4-CH3), 0.90 (d,
3JCH ;5ÀH = 6.9 Hz, 3H, 5-CH3) ppm; 1H NMR of the
other compounds.
3
minor diastereomer (DMSO-d6): d = 8.14 (br s, 1H, NH),
5.85 (s, 1H, OH), 3.23 (s, 3H, NCH3), 1.77–1.89 (m, 1H, 5-
Hexahydro-4-hydroxy-3,4-dimethylpyrimidine-2-thione
(10c)
3
H), 1.38 (s, 3H, 4-CH3), 0.91 (d, JCH ;5ÀH = 6.7 Hz, 5-
3
CH3) ppm, signals of the 6-H protons overlap with protons
signals of the major isomer and the acyclic form 11d (see
below); 13C NMR of the major diastereomer (DMSO-d6):
d = 176.95 (C-2), 85.38 (C-4), 43.19 (C-6), 36.72 (C-5),
33.02 (N–CH3), 20.55 (4-CH3), 13.07 (5-CH3) ppm; IR
To a cooled ice bath a stirred solution of 1.839 g 8a
(14.23 mmol) in 3 cm3 MeCN was added 1.6 cm3 40 %
aqueous solution of methylamine (density of 0.902 g/cm3),
the reaction mixture was stirred at room temperature for
1.5 h, and the solvent was removed in vacuum. The solid
residue was triturated with petroleum ether; the precipitate
was filtered and dried to give 1.869 g (82 %) 10c as a white
solid. M.p.: 91–91.5 °C (acetone) (Ref. [35] 85–86 °C); 1H
NMR (DMSO-d6): d = 8.11 (unresolved br t, 1H, N(1)H),
6.05 (d, 1H, 4JOH, 5-H = 0.3 Hz, OH), 3.17 (s, 3H, NCH3),
2.97–3.19 (m, 2H, 6-Ha and 6-He), 1.82–1.96 (m, 2H, 5-Ha
and 5-He), 1.38 (s, 3H, 4-CH3) ppm; 13C NMR (DMSO-d6):
d = 177.56 (C-2), 81.74 (C-4), 36.23 (C-6), 35.32 (C-5),
ꢀ
(Nujol): m = 3,438 m, 3,290 vs, 3,237 vs (m NH, m OH),
1,553 s, 1,509 s (thioamide-II), 1,289 s, 1,079 s/cm.
Pyrimidine 10d (two diastereomers, 99.5:0.5) in DMSO-
d6 solution at room temperature slowly gave mixtures of
(4R*, 5R*)-10d, (4R*, 5S*)-10d, and its acyclic isomer
1
11d. H NMR spectrum of 11d (DMSO-d6): d = *7.41
(br s overlapped by the signals of the other NH group, 1H,
NHCH3), 7.41 (unresolved br t, 1H, NHCH2), 3.53 (very br
s, 1H, CH in CH2N), 3.38 (very br s, 1H, CH in CH2N),
2.79 (br s, 3H, N–CH3), 2.13 (s, 3H, CH3C=O), 0.99 (d,
3J = 7.1 Hz, CH3CH) ppm, signals of the CH proton in the
CHCH3 fragment overlap with proton signals of 10d.
ꢀ
33.17 (N–CH3), 26.46 (4-CH3) ppm; IR (Nujol): m = 3,346
s, 3,185 br vs (m NH, m OH), 1,534 s, 1,501 s (thioamide-II),
1,292 s, 1,156 s, 1,086 s/cm.
Pyrimidine 10c in DMSO-d6 solution at room temper-
ature slowly gave equilibrium mixtures of 10c and its
acyclic isomer 11c. 1H NMR spectrum of 11c (DMSO-d6):
d = 7.42 (very br s, 1H, NHCH3), 7.37 (unresolved br t,
1H, NHCH2), 3.50 (very br s, 2H, CH2N), 2.78 (br s, 3H,
Acknowledgments This research was supported by the Presidential
Grant for Young Scientists no. MK-4400.2011.3.
3
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N–CH3), 2.69 (t, J = 6.6 Hz, 2H, CH2C=O), 2.09 (s, 3H,
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38.46 br (CH2N), 30.60 br (N–CH3), 29.95 (CH3C=O)
ppm.
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