T3P - A Benign Desulfurating Reagent in the Synthesis of Isothiocyanates

Article abstract of DOI:10.1055/s-0036-1591842

A number of alkyl, aryl and bifunctional isothiocyanates are obtained in moderate to high yields (41-94%) in a two-step, one-pot reaction of the parent primary amines or their salts with carbon disulfide, followed by reaction of the thus formed dithiocarbamates with T3P (propane phosphonic acid anhydride) as a new and efficient desulfurating agent.

Full text of DOI:10.1055/s-0036-1591842

SYNTHESIS
0
0
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9
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8
8
1
1
4
3
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
A
en
Ł. Janczewski et al.
Paper
Synthesis
T3P® – A Benign Desulfurating Reagent in the Synthesis of
Isothiocyanates
Łukasz Janczewskia
Anna Gajdaa
Sebastian Frankowskia
Tomasz M. Goszczyńskib
Pr
O
P
O
P
O
P
O
Pr
O
Pr
O
Tadeusz Gajda*a
0
0
0
0
0-
0
0
3
0-
5
6
6
0-
5
1
0
T3P®
S
R
R
NH2
or
NH3X
B:
R
BH
R
NCS
N
S
CS2
a Institute of Organic Chemistry, Faculty of Chemistry,
Lodz University of Technology, 116 Stefan Żeromski St.,
90-924 Lodz, Poland
b Department of Experimental Oncology, Hirszfeld
Institute of Immunology and Experimental Therapy,
Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114
Wrocław, Poland
H
R = alkyl, functionalized alkyl, aryl
X = Cl, Br, TsO
26 examples
yield up to 94%
purity >97%
B = Et3N, NMM
tadeusz.gajda@p.lodz.pl
Received: 13.10.2017
Accepted after revision: 02.11.2017
Published online: 27.11.2017
All these facts have resulted in interest from the scien-
tific community in developing synthetic pathways to ITCs.
The most important of these are based on primary amines
or organic azides as starting materials, and the choice of the
method depends on the availability of the substrates and
the structure of the target isothiocyanate (Scheme 2).
DOI: 10.1055/s-0036-1591842; Art ID: ss-2017-n0458-op
Abstract A number of alkyl, aryl and bifunctional isothiocyanates are
obtained in moderate to high yields (41–94%) in a two-step, one-pot re-
action of the parent primary amines or their salts with carbon disulfide,
followed by reaction of the thus formed dithiocarbamates with T3P®
(propane phosphonic acid anhydride) as a new and efficient desulfurat-
ing agent.
R
N3
Ph3P
Ph3PBr2
Et3N
CS2
R
N
PPh3
Key words isothiocyanates, desulfuration, propane phosphonic acid
– Ph3PS
iminophosphorane
anhydride (T3P®), dithiocarbamates, amino acids, amines
CSCl2/B:
R
NH2
R
NCS
Isothiocyanates (ITCs) belong to the group of hetero-
cummulenes, which have been the focus of research for
many years. ITCs are employed in the synthesis of sulfur-
containing heterocycles,1 thioamides,2 thiourea-derived or-
ganocatalysts,3a,b chiral derivatizing auxiliaries,3c and thiourea
receptors,4 whilst several natural ITCs exhibit chemo-
preventive and anticancer activity.5 Natural ITCs are an ele-
ment of a plant’s defense system and their task is to deter
potential aggressors. In several cruciferous plants such as
broccoli, cauliflower and cabbage, isothiocyanates are pres-
ent in the form of inactive precursors – glucosinolates, and
just after ‘the aggressor’s attack’ they release biologically
active ITCs under the action of myrosinase followed by a
Lossen rearrangement (Scheme 1).6 Release of ITCs from
glucosinolates also occurs during damage to plants or in the
course of their digestion by human intestinal flora.7
CS2/B:
desulfurating
agent
R
NHCS2 BH
dithiocarbamate
Scheme 2 Selected synthetic approaches to isothiocyanates
According to Scheme 2, azides, which can be considered
as convenient amine precursors, are converted upon reac-
tion with triphenylphosphine into iminophosphoranes,
which, in turn, via a reaction with carbon disulfide, afford
the target ITCs under neutral conditions (the tandem
Staudinger/aza-Wittig reaction8). Alternatively, iminophos-
phoranes can be formed directly from amines and triphen-
ylphosphine dibromide9 (Scheme 2). The azide approach
has been applied to the efficient synthesis of structurally
OH
O
2
H2O
D-glucose
SO4
HO
HO
R
S
S
R
OH
O3SO
glucosinolate
R
N C S
myrosinase
Lossen
rearrangement
N
N
OSO3
isothiocyanate
Scheme 1 Enzymatic formation of ITCs
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
Ł. Janczewski et al.
Paper
Synthesis
diverse ITCs.10 The only restriction to this approach results
from the limited availability of the parent azides in some
cases, or the fact that the explosive character of low-molec-
ular-weight organic azides makes their preparation danger-
ous. Occasionally, separation of the target isothiocyanates
from the triphenylphosphine sulfide by-product formed in
these reactions can cause difficulties.
Because of their excellent availability, primary amines
are the most often used starting materials in the synthesis
of ITCs. Their reactions with thiophosgene, discovered by
Ratke11a in 1872, are still currently extensively used as a di-
rect and efficient route to this class of compounds4,11b–e
(Scheme 2). The advantage of this approach is the straight-
forwardness and reproducibility of the reactions; its main
disadvantages being the use of highly toxic thiophosgene,
its low tolerance to the presence of some functional groups
and thiophosgene’s foul odor. As an alternative, thiophos-
gene surrogates such as di(2-pyridyl) thionocarbonate,12
1,1′-thiocarbonyldiimidazole,13 and 1,1′-thiocarbonyldi-
2(1H)-pyridone14 are used.
A particularly important route to ITCs is a two-step, and
usually one-pot reaction of primary amines with carbon di-
sulfide leading to dithiocarbamic acid salts, followed by in
situ desulfuration of the thus formed dithiocarbamates
(Scheme 2). After its discovery by Hofmann,15 a number of
reagents have been exploited as desulfurating agents.
Amongst others, peptide coupling reagents,10a,16 tosyl chlo-
ride,17 mesyl chloride,18 hydrogen peroxide,16f,19 molecular
iodine,20 ethyl chloroformate,21 di-tert-butyl dicarbonate,22
2,4,6-trichloro-1,3,5-triazine,23 triphosgene,24 diethyl chlo-
rophosphate,25 phenyl chlorothionoformate,26 diacetoxy-
iodobenzene,27 and 1,1′-(ethane-1,2-diyl)dipyridinium bis-
tribromide28 have recently been employed as desulfurating
agents. However, some of these protocols suffer from diffi-
culties in the separation of by-products or inconvenient
work-up procedures.
To date, the dithiocarbamate approach to ITCs, in which
propane phosphonic acid anhydride (T3P®)29 (1) (Figure 1)
is used as a desulfurating agent, has not been described.
T3P® is a widely used peptide coupling reagent and dehy-
drating agent, which also finds applications in large-scale
syntheses.30 It is a stable, non-toxic, safe and user-friendly
‘green’ reagent. It is important from a preparative stand-
point that water soluble side products are formed during
reactions involving T3P®, which should be easily removable
during a standard work-up.
In this paper, we present the results of our investigation
into the general synthesis of structurally diverse isothiocy-
anates from their parent amines via a one-pot dithiocarba-
mate approach using T3P® as a desulfurating agent.
Initially, optimization of the reaction conditions was
performed with phenethylamine (2a) as a model substrate.
Treatment of 2a with carbon disulfide in the presence of
triethylamine readily afforded the intermediate dithiocar-
bamate 3a after one hour at room temperature, in dichloro-
methane as the solvent. Next, dithiocarbamate 3a was al-
lowed to react in situ with T3P® (1.1 equiv) to give the tar-
get, (2-isothiocyanatoethyl)benzene (4a), in 77% yield after
2 hours at room temperature (Table 1, entry 1; method A).
The use of 5 equivalents of Et3N is recommended to ensure
optimal conditions for both steps. We also demonstrated
that increasing and decreasing the time for the desulfura-
tion step in the presence of T3P® resulted in lower yields
(72% and 71%, respectively) of 4a [entry 1 (see footnote c)
and entry 2]. In turn, desulfuration by T3P® performed in
boiling DCM was complete in 15 minutes and the isothiocy-
anate 4a was obtained with a yield comparable to those
mentioned above [entry 3 (see footnote d); method B].
Next, other bases such as N-methylmorpholine (NMM),
N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) were tested. The reaction in
the presence of NMM led to a yield comparable to that with
Et3N (entry 4), whereas the reactions with DIPEA and DBU
delivered lower yields when compared to those of Et3N and
NMM (entries 1 and 4 vs entries 5 and 6). As the highest
yield was obtained in the presence of Et3N, we used this as
the base and next varied the ratio of 2a to T3P®. Decreasing
the 2a/T3P® ratio to 1:0.8 equivalents resulted in a negative
impact on the yield (entry 7). An inverse effect was ob-
served when the loading of T3P® was increased to 1.5
equivalents (entry 1 vs 8). After careful screening, we found
that setting the substrate ratio (2a/T3P®) to 1:1.8 resulted
in the best yield: 85% (entry 9). Subsequent increases in the
substrate ratio had no influence on the yield [entry 9 (see
footnote e)]. We also showed that desulfuration was com-
patible with microwave (MW) conditions. After short ex-
perimentation (see the Supporting Information, Table S1),
we found that performing reactions in a pressure vial under
microwave-assisted conditions for 5 minutes at 80 °C
afforded the target 4a in 83% yield [entry 10 (see footnote
f); method C]. A plausible mechanistic pathway for the
above transformation (Table 1) involves formation of mixed
dithiocarbamate–phosphoric anhydride 5a as a result of a
reaction between 3a and T3P® (1), followed by the base-
mediated desulfuration of 5a to give the target isothiocya-
nate 4a and thiopyrophosphate 6 as a side product. At-
tempts to confirm the presence of 5a by 31P NMR spectros-
copy under the reaction conditions failed. However, a sin-
glet at 96 ppm displayed in the 31P NMR spectrum of the
reaction mixture after quenching and subsequent hydroly-
O
P
O
P
O
P
O
O
O
1
Figure 1 Propane phosphonic acid anhydride (T3P®) (1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
Ł. Janczewski et al.
Paper
Synthesis
sis of intermediate 6 and unreacted T3P® (1), could be as-
signed to the propanephosphonothioic salt,31 which con-
firms in part this mechanistic hypothesis.
benzene (4p) were prepared in good yields from 4-me-
thoxyaniline (2o) and 4-fluoroaniline (2p), respectively
(entries 15 and 16). However, attempts to obtain 1-isothio-
cyanato-4-nitrobenzene from strongly electron-deficient 4-
nitroaniline were unsuccessful. As the use of ammonium
salts is often more advantageous compared with free
amines, we screened several ammonium salts 2a and 2h–
m, and proved that they were also convenient starting ma-
terials in this synthesis [entry 1 (see footnote c) and entries
8–13]. For ammonium salts, double the amount of Et3N (10
equiv) had to be used to achieve good yields of isothiocya-
nates 4a and 4h–m. Unfortunately, volatile, low-molecular-
weight isothiocyanate 4m (entry 13) and more sterically
demanding 4k and 4l (tertiary α-carbon) (entries 11 and
12) were isolated in low yields under the applied condi-
tions. Pure ITCs were easily obtained after flash chromatog-
raphy through a short pad of silica gel by simple elution of
the products with hexane or pentane, followed by careful
evaporation of the eluate.
With optimized reaction conditions in hand, the scope
of the transformation was evaluated. Structurally diverse
alkyl and aryl isothiocyanates 4a–p were obtained in high
yields from the parent amines 2a–g,n–p under the condi-
tions shown in Table 2 (entries 1–7 and 14–16). Further
studies revealed that the method was also compatible with
optically active amines with a stereogenic center on the α-
carbon atom. Thus, enantiopure (R)- and (S)-(1-isothiocy-
anatoethyl)benzene (4b)16e and (4c)32 were isolated in 84%
and 83% yields from their optically pure precursors (R)-2b
and (S)-2c, respectively (entries 2 and 3). The protocol
worked for an aromatic amine and with examples possess-
ing electron-donating or electron-withdrawing groups.
Thus, isothiocyanatobenzene (4n) was obtained in 92%
yield from aniline (2n) (entry 14), whilst 1-isothiocyanato-
4-methoxybenzene (4o) and 1-isothiocyanato-4-fluoro-
Table 1 Optimization of the Reaction Conditionsa and a Plausible Mechanism
H
+
BH
N
S
NCS
NH2
1. T3P® , temp
B: (5 equiv), CS2 (3 equiv), DCM
S
rt, 1 h
time, (MW)
2. H2O, 30 min
2a
3a
4a
T3P®
H2O
B:
H
S
O
P
O
O
O
P
O
P
O
P
O
O
P
O–
N
S
P
O
O
O–
Pr
Pr
Pr
Pr
Pr
Pr
S
6
5a
Entry
Base (B)
T3P® (equiv)
Time (h)
Yield (%)b
1
2
Et3N
Et3N
Et3N
NMM
DIPEA
DBU
Et3N
Et3N
Et3N
Et3N
1.1
1.1
1.1
1.1
1.1
1.1
0.8
1.5
1.8e
1.8
2c
77
71
72
72
64
57
63
80
85
83
24
3
0.25d
4
2
5
2
6
2
7
2
8
2
9
2
10
5 minf
a Method A: 2a (2 mmol), CS2 (6 mmol, 3 equiv), base (10 mmol, 5 equiv), 1 h, r.t., then T3P® (50% w/w in EtOAc) was added at 4 °C and the reaction mixture was
stirred at r.t. for the time given in Table 1.
b Yields of isolated products after flash chromatography (hexane).
c Decreasing the reaction time with T3P® to 1 h resulted in a 72% yield.
d Method B: reaction was carried out at reflux for 15 min.
e Reaction with 2.1 equiv of T3P® had no influence on the yield.
f Method C: microwave-assisted reaction, pressure vial, 5 min at 80 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Ł. Janczewski et al.
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Synthesis
Table 2 Preparation of Alkyl and Aryl Isothiocyanates via T3P®-
Table 2 (continued)
Mediated Desulfuration of Dithiocarbamatesa
Entry
Substrate
Product
Yield (%)b
41
1. Et3N (5 or 10 equiv), CS2 (3 equiv), DCM, rt, 1 h
R
NH2
or
R
NH3X
R
NCS
4a–p
NH3OTs
NCS
4m
NCS
2. T3P® (1.8 equiv), 4 °C to rt, 2 h
3. H2O, 30 min
13
2a–g,n–p
2h–m
2m
R = alkyl, aryl; X = Cl, TsO
NH2
14d
15
92
82
Entry
1c
Substrate
Product
Yield (%)b
85
2n
4n
NH2
NCS
NH2
NCS
MeO
MeO
2a
4a
2o
4o
NCS
NH2
NH2
NCS
2
3
84
83
16e
72
F
F
2b
4b
2p
4p
a Reaction conditions: 2a–p (2 mmol), CS2 (6 mmol, 3 equiv), Et3N
(10 mmol, 5 equiv) for 2a–g,o–p or Et3N (20 mmol, 10 equiv) for
ammonium salts 2h–m, 1 h, r.t.; then, T3P® (50% w/w in EtOAc) was added
at 4 °C, followed by 2 h at r.t.
NH2
NH2
NCS
NCS
2c
2d
4c
4d
b Yields of pure products after flash chromatography (hexane or pentane).
c Product 4a was obtained in 77% yield starting from 2-phenylethylammo-
nium chloride.
d The following reaction conditions were applied: 2n (2 mmol), CS2 (8
mmol, 4 equiv), Et3N (16 mmol, 8 equiv), first step 22 h at r.t. (see ref.17b),
then T3P® was added at 4 °C, followed by 2 h at r.t.
4
5
83
94
e First step: 20 h at r.t., then T3P® was added at 4 °C, followed by 2 h at r.t.
NH2
NCS
2e
4e
To expand the synthetic utility of our protocol we fo-
cused on the preparation of bifunctional isothiocyanates.
The results demonstrate that the established conditions al-
lowed the reactions to proceed with a variety of bifunction-
al isothiocyanates and that the reaction was compatible
with a variety of functional groups. 1,6-Diisothiocyanato-
hexane (4q) was obtained in 60% yield from parent diamine
2q (Table 3, entry 1). N-Boc-1,2-diaminoethane (2r) and 6-
bromohexylammonium bromide (2s) were also found to be
good starting materials, giving the isothiocyanates 4r and
4s in 60% and 55% yields, respectively (entries 2 and 3). In
the light of the antiproliferative activity of some isothiocy-
anatoalkylphosphonates,10a,e,16f diethyl aminoalkylphos-
phonate hydrochlorides were also examined as potential
substrates. We found that aminophosphonate hydrochlo-
rides 2t–w afforded the corresponding products, diethyl (2-
isothiocyanatoheptyl)phosphonate (4t), diethyl (3-cyclo-
hexyl-2-isothiocyanatopropyl)phosphonate (4u), diethyl
[isothiocyanato(4-methoxyphenyl)methyl]phosphonate
(4v) and diethyl (isothiocyanatomethyl)phosphonate (4w)
in good yields (entries 4–7). Unfortunately, when this pro-
tocol was applied to methyl (S)-phenylalanate, (S)-alanate
and (R)-alanate hydrochlorides 2x–z as starting materials,
partly racemized (as confirmed by a substantial decrease in
the specific rotation) isothiocyanates 4x–z were obtained.
Fortunately, after a short experimentation (see the Sup-
porting Information, Table S3) we found that to ensure the
NCS
4f
6
7
8
82
72
75
NH2
2f
NH2
NCS
4g
2g
NH3Cl
NCS
4h
2h
+
NH3OTs
NCS
9
79
74
2i
4i
NCS
NH3OTs
2j
10
4j
NCS
NH3OTs
11
12
55
45
4k
2k
NH3OTs
NCS
2l
4l
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Ł. Janczewski et al.
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Yield (%)
51
Synthesis
reaction was free of racemization the replacement of Et3N
by a limited amount of NMM (3 equiv) was necessary. In
addition, release of the free amino esters from their hydro-
chlorides, the formation of the corresponding dithiocarba-
mates in the first step, and also the addition of T3P® to the
reaction mixture should be carried out at –5 °C. Thus modi-
fied, the protocol allowed us to obtain enantiopure methyl
(S)-2-isothiocyanato-3-phenylpropionate (4x), methyl (S)-
2-isothiocyanatopropionate (4y), and methyl (R)-2-isothio-
cyanatopropionate (4z) from their optically pure amino
acid counterparts in 72%, 63% and 62% yields (entries 8–10).
Racemization depends on the strength of the amine used. It
is highly probable that it occurs during the second step of
the transformation. As proof, we subjected optically pure
isothiocyanate 4y (>99.9:0.1 er), derived from amino acid
2y, to 5 equivalents of Et3N or NMM under the standard re-
action time/temperature (2 h, r.t.). Significant racemization
was observed only when Et3N was used (52:48 er), while al-
most no racemization took place on exposure to NMM
(99:1 er).
Entry Substrate
Productb
OMe
OMe
O
EtO
P
O
EtO
P
EtO
EtO
6
NCS
4v
NH3Cl
2v
O
EtO
P
O
P
EtO
EtO
NCS
NH3Cl
7
50
72
EtO
2w
4w
O
O
OMe
OMe
8d
NH3Cl
NCS
4x
2x
O
O
OMe
OMe
OMe
OMe
9d
63
62
NH3Cl
NCS
4y
2y
Isothiocyanates derived from α-amino acids are valu-
able chiral building blocks, and among numerous applica-
tions, they have recently been employed in the synthesis of
peptidomimetics17d,e,33 and chiral carboxylate receptors.4
O
O
10d
NH3Cl
NCS
2z
4z
a Reaction conditions: 2q–z (2 mmol) [for 2q,s–w Et3N (20 mmol, 10 equiv)
was used, for 2r Et3N (10 mmol, 5 equiv) was applied, for 2x–z NMM
(6 mmol, 3 equiv) was used], CS2 (6 mmol, 3 equiv), T3P® (3.6 mmol, 1.8
equiv).
Table 3 Preparation of Bifunctional Isothiocyanates via T3P®-
Mediated Desulfuration of Dithiocarbamatesa
R
NH2
2q–r
or
b Yields of pure products after flash chromatography.
c Double amounts of reagents were used: Et3N (20 mmol, 10 equiv), CS2
(12 mmol, 6 equiv), T3P® (7.2 mmol, 3.6 equiv).
1. Et3N (5–10 equiv) or NMM (3 equiv), CS2 (3 or 6 equiv),
DCM, rt, 1–2 h
R
NCS
2. T3P® (1.8 or 3.6 equiv), –5 °C or 4 °C then rt, 2 h
d CS2, NMM and T3P® were added at –5 °C and the first step was continued
for 2 h at r.t.
4q–z
R
NH3X 3. H2O, 30 min
2s–z
X = Cl, Br
Entry Substrate
Productb
Yield (%)
60
In order to compare the effectiveness of the proposed
methodology with previously reported methods, the con-
version of the model amine 2a into isothiocyanate 4a was
study using selected reagents. For this purpose, the dithio-
carbamate was generated in the reaction of 2a with carbon
NH2
NCS
H2N
SCN
1c
2q
NH2
4q
NCS
Boc
N
Boc
N
H
2
60
55
H
disulfide and then desulfurated to give 4a using either
2r
4r
16f,19
TsCl,17b Boc2O,22 I2,20 or H2O2
(Table 4, entries 2–5). Ad-
ditionally, the reaction of 2a with thiophosgene was carried
out (entry 6). The results were compared with the T3P®
protocol presented in this work (entry 1). Table 4 presents
the yields of isolated, pure isothiocyanate 4a after flash
chromatography. Thiophosgene (entry 6) afforded the high-
est yield of (2-isothiocyanatoethyl)benzene (4a) (90%), but
handling problems and the toxicity relevant to this reagent
discouraged its use. In turn, the reaction involving H2O2 was
the lowest yielding (77%) compared to the others (entry 5).
The dithiocarbamate approach to 4a in which either T3P®
or TsCl were applied as desulfurating agents were found to
be equally attractive (entries 1 and 2, 85% yields), while
Boc2O and I2 were slightly less effective (entries 3 and 4,
82% and 81%, respectively).
NCS
NH3Br
Br
Br
3
4
4s
2s
O
EtO
P
NCS
O
P
NH3Cl
EtO
EtO
63
53
EtO
4t
2t
O
EtO
P
NCS
O
P
NH3Cl
EtO
EtO
EtO
5
4u
2u
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Ł. Janczewski et al.
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Synthesis
Table 4 A Comparative Study of the Reagents Used for the Synthesis
of 4a from 2a
bromide was prepared according to the procedure given by Obika et
al.35 Aminophosphonate hydrochlorides 2t–w were obtained accord-
ing to the procedure described by Zwierzak et al.36 The temperatures
of the reaction mixtures were measured with an external infrared
sensor. Flash chromatography was performed with a glass column
packed with Baker silica gel (30–60 μm). For TLC, silica gel on alumi-
num-backed TLC plates (Sigma-Aldrich) with indicator 254 mm were
used. A monomode microwave reactor (CEM Discover SP) equipped
with an IntelliVent pressure control system was used. The standard
method was applied, and the maximum pressure was set to 250 psi.
Melting points were obtained using a Büchi SMP-20 apparatus. Opti-
cal rotations were measured at 25 °C on a PolaAAr 3001 Polarimeter
Entry
Reagents
Yield (%)
1a
CS2, Et3N, anhyd DCM, T3P®
CS2, Et3N, THF, TsCl
85
85
82
81
77
90
217b
322
420
CS2, Et3N, EtOH, cat. DMAP, Boc2O
CS2, Et3N, MeCN, I2
516f,19
CS2, Et3N, THF, 30% H2O2
NaHCO3, CHCl3/H2O, CSCl2
64,11b–e
25
at λ = 589 nm, and are reported as follows: [α]D (c = g/100 mL sol-
a This work.
vent). Isothiocyanates were assessed for purity with a HPLC Gilson
Prep ELS™ II Detector, UV-VIS-156 using a reverse phase Kromasil
100-5C18 250 × 4.6 mm E64911 analytical column (detection at 254
nm), in various MeCN/H2O gradients: A: 0–1 min 20% MeCN, 10–20
min 70% MeCN, 25–30 min 80% MeCN; B: 0–1 min 20% MeCN, 10–20
min 70% MeCN, 25–30 min 90% MeCN; C: MeCN/H2O, 90%:10%; D: 0–
1 min 20% MeCN, 5–15 min 70% MeCN, 20–30 min 80% MeCN. Sam-
ples were prepared by dissolution of 0.5–1 mg in 1 mL of eluent
(H2O/MeCN, 80:20 or H2O/MeCN, 10:90 for 4t–w). Flow rate: 1
mL/min. Software: Trilution. The enantiomeric ratios (er) of 4b,c and
4x–z, and of the reactions between compound 4y with Et3N and
NMM were determined by chiral stationary phase HPLC using a Daicel
Chiralpak ID column for compounds 4b,c (hexane), a Daicel Chiralpak
IF column for compound 4x (hexane/i-PrOH, 99:1), and a Daicel Chi-
ralpak IC column for compounds 4y,z (hexane/i-PrOH, 98:2); column
temperature: 30 °C; flow rate: 1.0 mL/min. IR spectra were measured
To illustrate the practical application of the established
protocol, a gram-scale experiment was conducted (Scheme
3). We found that the reaction could be performed using
1.22 g (10 mmol) of phenethylamine (2a) to give 1.36
grams of isothiocyanate 4a in 83% yield, being comparable
to that of the small-scale experiment.
NH2
NCS
1. Et3N (5 equiv), CS2 (3 equiv), DCM, rt, 1 h
2. T3P® (1.8 equiv), 4 °C then rt, 2 h
3. H2O, 30 min
2a
1.22 g (10 mmol)
4a
1.36 g (83% yield)
on an FT-IR Alpha Bruker (ATR) instrument and are reported in cm–1
.
Scheme 3 A gram-scale experiment
NMR spectra were measured on a Bruker Avance II Plus spectrometer
(700 MHz for 1H NMR, 176 MHz for 13C NMR and 283 MHz for
31P NMR) and a Bruker Avance DPX spectrometer (250.13 MHz for
1H NMR) in CDCl3 solution. 1H and 13C NMR spectra are referenced ac-
cording to the residual peak of the solvent based on literature data.
31P NMR chemical shifts are reported in ppm downfield from 85%
H3PO4 as an external standard. Chemical shifts (δ) are reported in
ppm and coupling constants (J) in Hz. 31P and 13C NMR spectra are
proton-decoupled. A Bruker MicrOTOF-Q II spectrometer (Bruker Dal-
tonics, Germany) equipped with an Apollo II electrospray ionization
source with an ion funnel was used for the acquisition of the high-
resolution electrospray ionization (MS-ESI) spectra. An AutoSpec Pre-
mier (Waters) spectrometer with a HP 7890 (Agilent) gas chromato-
graph and an advanced autosampler was used for recording the high-
resolution electron ionization (MS-EI) spectra.
All the synthesized isothiocyanates, except for new
compounds 4t and 4u, are described in the literature. How-
ever, full spectroscopic data have not been reported for
compounds 4e, 4g, 4k, 4l, 4s, and 4z until now.
In conclusion, an efficient one-pot protocol for the syn-
thesis of structurally diverse alkyl, aryl and bifunctional
isothiocyanates has been developed. The reaction is broad
in scope, and the target isothiocyanates are obtained in
high and reproducible yields. The method is compatible
with a variety of protecting groups and the reactions occur
without racemization for the investigated groups of com-
pounds. The key element of this protocol is the application
of propane phosphonic acid anhydride (T3P®) — an easily
available, green and safe reagent — for in situ desulfuration
of the intermediate dithiocarbamates obtained from the
parent primary amines and carbon disulfide. In our opin-
ion, the established protocol makes a valuable contribution
to those already described for the synthesis of isothiocya-
nates.
Isothiocyanates 4a–w; Method A
Et3N (1.4 mL, 10 mmol for amines 2a–g,o–p,r, or 2.8 mL, 20 mmol for
diamine 2q and ammonium salts 2h–m,s–w, or 2.23 mL, 16 mmol for
2n) and CS2 (0.36 mL, 6 mmol for 2a–w, or 0.72 mL, 12 mmol for 2q,
or 0.48 mL, 8 mmol for 2n) were added in one portion to a solution of
primary amine 2a–g,n–r or ammonium salt 2h–m,s–w (2 mmol) in
anhyd DCM (10 mL) and placed in a 50 mL two-neck round-bottomed
flask equipped with a magnetic stir bar, a rubber septum, and a ther-
mometer and secured from moisture with a syringe filled with CaCl2.
The solution was stirred for 1 h at r.t. (22 h at r.t. for 2n or 20 h at r.t.
for 2p). Next, the reaction mixture was cooled to 4 °C and T3P® (2.12
mL, 3.6 mmol for 2a–p and 2r–w, or 4.24 mL, 7.2 mmol for 2q) was
added over 5 min in three portions. Thereafter, the solution was al-
lowed to reach r.t. and was stirred for 2 h at this temperature. Next,
the mixture was hydrolyzed with H2O (10 mL) for 30 min and diluted
with DCM (50 mL). The organic layer was separated and washed suc-
All reagents and solvents were purchased from Sigma-Aldrich
(Poland) and used as obtained. 1-Propanephosphonic acid anhydride
(50% in EtOAc) (T3P®) was purchased from Fluorochem. Methyl (S)-
phenylalanate, (S)-alanate and (R)-alanate hydrochlorides and 1,6-di-
aminohexane were purchased from Sigma-Aldrich. N-Boc-1,2-diami-
noethane was prepared from 1,2-diaminoethane according to the
procedure described by Famulok et al.34 6-Bromohexylammoium
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
Ł. Janczewski et al.
Paper
Synthesis
cessively with H2O (2 × 5 mL), 1 M HCl (2 × 5 mL), H2O (2 × 5 mL),
saturated NaHCO3 (2 × 5 mL), H2O (5 mL) and brine (5 mL) and then
dried over anhydrous MgSO4. The crude products were purified by
flash chromatography on silica gel using hexane or pentane as elu-
ents. Pure isothiocyanates 2a–w were isolated after careful evapora-
tion of the solvent and removal of volatile residues under reduced
pressure.
IR (ATR): 2079 (NCS), 1495, 1450, 1306, 1019, 757, 696 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.40–7.38 (m, 2 H, CHAr), 7.34–7.32 (m,
3 H, CHAr), 4.91 (q, JHH = 6.8 Hz, 1 H, CHNCS), 1.68 (d, JHH = 6.8 Hz, 3 H,
CH3).
13C NMR (176 MHz, CDCl3): δ = 140.3 (s, CAr), 132.5 (s, NCS), 129.0 (s,
CArH), 128.3 (s, CArH), 125.5 (s, CArH), 57.1 (s, CHNCS), 25.0 (s, CH3).
The analytical data are in agreement with those reported previously
in the literature.32
Amino Acid Derived Isothiocyanates 4x–z; Method A
N-Methylmorpholine (NMM) (0.66 mL, 6 mmol) and CS2 (0.36 mL, 6
mmol) were added dropwise to a cooled (–5 °C) suspension of amino
acid methyl ester hydrochloride 2x–z (2 mmol) in anhyd DCM (10
mL). The solution was stirred for 2 h at r.t. and then cooled to –5 °C
again. T3P® (2.12 mL, 3.6 mmol) was added over 5 min in three por-
tions, and the solution was stirred for 2 h at r.t. The isothiocyanates
4x–z were then isolated using the same procedure as described above
for ITCs 4a–w.
(Isothiocyanatomethyl)benzene (4d)
Colorless oil. Yield: 0.247 g, 1.66 mmol (83%) after flash chromatogra-
phy (hexane). Purity determined by HPLC was 99%, gradient A, tR
17.73 min.
IR (ATR): 2163 (NCS), 2068 (NCS), 1495, 1453, 1345, 694 cm–1
1H NMR (700 MHz, CDCl3): δ = 7.41–7.39 (m, 2 H, CHAr), 7.36–7.34 (m,
1 H, CHAr), 7.33–7.31 (m, 2 H, CHAr), 4.71 (s, 2 H, CH2NCS).
=
.
13C NMR (176 MHz, CDCl3): δ = 134.3 (s, CAr), 132.4 (s, NCS), 129.0 (s,
CArH), 128.5 (s, CArH), 126.9 (s, CArH), 48.8 (s, CH2NCS).
(2-Isothiocyanatoethyl)benzene (4a)
Colorless oil. Yield: 0.279 g, 1.7 mmol (85%) after flash chromatogra-
phy (hexane). Purity determined by HPLC was 98%, gradient A, tR
18.47 min.
The analytical data are in agreement with those reported previously
in the literature.17b,39
=
IR (ATR): 2180 (NCS), 2079 (NCS), 1495, 1453, 1346, 748, 698 cm–1
.
2-Isothiocyanatooctane (4e)40
1H NMR (700 MHz, CDCl3): δ = 7.36–7.34 (m, 2 H, CHAr), 7.30–7.27 (m,
1 H, CHAr), 7.23–7.21 (m, 2 H, CHAr), 3.73 (t, JHH = 7.0 Hz, 2 H, CH2NCS),
3.00 (t, JHH = 7.0 Hz, 2 H, CH2).
13C NMR (176 MHz, CDCl3): δ = 137.0 (s, CAr), 130.8 (s, NCS), 128.7 (s,
CArH), 128.6 (s, CArH), 127.1 (s, CArH), 46.3 (s, CH2NCS), 36.4 (s, CH2).
Colorless oil. Yield: 0.320 g, 1.87 mmol (94%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 98%, gradient B, tR
31.18 min.
IR (ATR): 2083 (NCS), 1456, 1378, 1334 cm–1
1H NMR (700 MHz, CDCl3): δ = 3.77–3.72 (m, 1 H, CHNCS), 1.65–1.60
(m, 1 H, H from CH2), 1.57–1.52 (m, 1 H, H from CH2), 1.48–1.43 (m, 1
H, H from CH2), 1.38–1.33 (m, 1 H, H from CH2, d, JHH = 6.5 Hz, 3 H,
CH3CH), 1.32–1.25 (m, 6 H, 3 × CH2), 0.89 (t, JHH = 7.0 Hz, 3 H, CH3).
13C NMR (176 MHz, CDCl3): δ = 129.9 (s, NCS), 54.1 (s, CHNCS), 37.6 (s,
CH2), 31.6 (s, CH2), 28.8 (s, CH3CH), 26.0 (s, CH2), 22.6 (s, CH2), 21.8 (s,
CH2), 14.1 (s, CH3).
=
.
The analytical data are in agreement with those reported previously
in the literature.37
(R)-(1-Isothiocyanatoethyl)benzene (4b)
Colorless oil. Yield: 0.272 g, 1.68 mmol (84%) after flash chromatogra-
phy (hexane). Purity determined by HPLC was 99%, gradient A, tR
20.30 min.
=
EI-MS: m/z [M•]+ calcd for C9H17NS: 171.1082; found: 171.1078.
The er was determined by HPLC using a Chiralpak ID column (hex-
ane); tmajor = 7.40 min, tminor = 6.82 min (>99.9:0.1 er).
3-Isothiocyanatopentane (4f)
25
25
20
[α]D –17.9 (c 1.0, CHCl3); [α]D –5.7 (c 1.0, acetone) [Lit.16e [α]D
Colorless oil. Yield: 0.211 g, 1.63 mmol (82%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
20.76 min.
IR (ATR): 2137 (NCS), 2088 (NCS), 2049 (NCS), 1458, 1346, 821 cm–1
1H NMR (700 MHz, CDCl3): δ = 3.53–3.49 (m, 1 H, CHNCS), 1.66–1.61
(m, 4 H, 2 × CH2), 1.02 (t, JHH = 7.4 Hz, 6 H, 2 × CH3).
13C NMR (176 MHz, CDCl3): δ = 129.9 (s, NCS), 61.9 (s, CHNCS), 28.6 (s,
2 × CH2), 10.6 (s, 2 × CH3).
–4.3 (c 1.0, acetone)].
IR (ATR): 2077 (NCS), 2039 (NCS), 1493, 1452, 1306, 1020, 756, 695
cm–1
.
.
1H NMR (700 MHz, CDCl3): δ = 7.40–7.38 (m, 2 H, CHAr), 7.34–7.32 (m,
3 H, CHAr), 4.92 (q, JHH = 6.8 Hz, 1 H, CHNCS), 1.68 (d, JHH = 6.8 Hz, 3 H,
CH3).
13C NMR (176 MHz, CDCl3): δ = 140.3 (s, CAr), 132.5 (s, NCS), 129.0 (s,
CArH), 128.3 (s, CArH), 125.5 (s, CArH), 57.1 (s, CHNCS), 25.0 (s, CH3).
The analytical data are in agreement with those reported previously
in the literature.41
The analytical data are in agreement with those reported previously
in the literature.16e,38
1-Isothiocyanato-2-methylpropane (4g)42
(S)-(1-Isothiocyanatoethyl)benzene (4c)
Colorless oil. Yield: 0.166 g, 1.44 mmol (72%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 99%, gradient A, tR
17.48 min.
IR (ATR): 2170 (NCS), 2074 (NCS), 1466, 1444, 1343, 690 cm–1
1H NMR (700 MHz, CDCl3): δ = 3.33 (d, JHH = 6.2 Hz, 2 H, CH2NCS), 1.99
(sept, JHH = 6.3 Hz, 1 H, CH), 1.00 (t, JHH = 6.7 Hz, 6 H, 2 × CH3).
13C NMR (176 MHz, CDCl3): δ = 129.8 (s, NCS), 52.5 (s, CH2NCS), 29.7
(s, CH), 19.9 (s, 2 × CH3).
Colorless oil. Yield: 0.270 g, 1.66 mmol (83%) after flash chromato-
graphy (hexane). Purity determined by HPLC was 98%, gradient A, tR =
20.41 min.
=
.
The er was determined by HPLC using a Chiralpak ID column (hex-
ane); tmajor = 6.82 min, tminor = 7.40 min (>99.9:0.1 er).
25
25
20
[α]D +5.4 (c 1.0, acetone); [α]D +17.8 (c 1.0, CHCl3) [Lit.32 [α]D
+16.6 (c 1.02, CHCl3)].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Ł. Janczewski et al.
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Synthesis
EI-MS: m/z [M•]+ calcd for C5H9NS: 115.0456; found: 115.0454.
3-Isothiocyanato-3-methylpentane (4l)
Colorless oil. Yield: 0.128 g, 0.89 mmol (45%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
23.68 min.
(3-Isothiocyanatopropyl)benzene (4h)
Colorless oil. Yield: 0.266 g, 1.5 mmol (75%) after flash chromatogra-
phy (hexane). Purity determined by HPLC was 100%, gradient A, tR
IR (ATR): 2075 (NCS), 1458, 1176, 819 cm–1
.
=
21.60 min.
1H NMR (700 MHz, CDCl3): δ = 1.71–1.66 (m, 2 H, CH2), 1.61–1.56 (m,
2 H, CH2), 1.31 (s, 3 H, CCH3), 0.98 (t, JHH = 7.4 Hz, 6 H, 2 × CH3).
IR (ATR): 2181 (NCS), 2084 (NCS), 1495, 1451, 1344, 743, 697 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.33–7.31 (m, 2 H, CHAr), 7.24–7.22 (m,
1 H, CHAr), 7.20–7.19 (m, 2 H, CHAr), 3.50 (t, JHH = 6.5 Hz, 2 H, CH2NCS),
2.77 (t, JHH = 7.4 Hz, 2 H, CH2), 2.02 (quin, JHH = 7.0 Hz, 2 H, CH2).
13C NMR (176 MHz, CDCl3): δ = 140.0 (s, CAr), 130.5 (s, NCS), 128.7 (s,
CArH), 128.6 (s, CArH), 126.5 (s, CArH), 44.3 (s, CH2NCS), 32.6 (s, CH2),
31.5 (s, CH2).
13C NMR (176 MHz, CDCl3): δ = 129.8 (s, NCS), 65.2 (s, C), 33.0 (s, 2 ×
CH2), 25.2 (s, CH3), 8.5 (s, 2 × CH3).
EI-MS: m/z [M•]+ calcd for C7H13NS: 143.0769; found: 143.0770.
3-Isothiocyanatoprop-1-ene (4m)
Colorless oil. Yield: 0.08 g, 0.81 mmol (41%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
14.55 min.
The analytical data are in agreement with those reported previously
in the literature.17b
IR (ATR): 2164 (NCS), 2083 (NCS), 1435, 1416, 1341, 1324, 986, 920
1-Isothiocyanato-3-methylbutane (4i)
cm–1
.
Colorless oil. Yield: 0.204 g, 1.58 mmol (79%) after flash chromatogra-
1H NMR (700 MHz, CDCl3): δ = 5.84 (ddt, JHaHc = 16.9 Hz, JHaHb = 10.0
Hz, JHaHde = 4.9 Hz, 1 H, CHa), 5.40 (dtd, JHcHa = 16.9 Hz, JHcHde = 1.8 Hz,
phy (pentane). Purity determined by HPLC was 99%, gradient A, tR
=
20.43 min.
JHcHb = 0.5 Hz, 1 H, CHc), 5.28 (dtd, JHbHa = 10.2 Hz, JHbHde = 1.6 Hz, JHbHc
=
IR (ATR): 2173 (NCS), 2090 (NCS), 2064 (NCS), 1468, 1351, 1329 cm–1
.
0.6 Hz, 1 H, CHb), 4.14 (dt, JHdeHa = 4.9 Hz, JHdeHa,Hb = 1.7 Hz, 2 H, CH-
1H NMR (700 MHz, CDCl3): δ = 3.53 (t, JHH = 6.8 Hz, 2 H, CH2NCS), 1.75
(sept, JHH = 7.0 Hz, 1 H, CH), 1.59 (q, JHH = 6.9 Hz, 2 H, CH2), 0.93 (d,
JHH = 6.7 Hz, 6 H, 2 × CH3).
deNCS). For protons (a–e) labeling see Supporting Information.
13C NMR (176 MHz, CDCl3): δ = 132.4 (s, NCS), 130.4 (s, CH), 117.7 (s,
CH2=CH), 47.2 (s, CH2NCS).
13C NMR (176 MHz, CDCl3): δ = 129.7 (s, NCS), 43.4 (s, CH2NCS), 38.6
(s, CH2), 25.5 (s, CH), 22.1 (s, 2 × CH3).
The analytical data are in agreement with those reported previously
in the literature.46
The analytical data are in agreement with those reported previously
in the literature.43
Isothiocyanatobenzene (4n)
Colorless oil. Yield: 0.248 g, 1.83 mmol (92%) after flash chromatogra-
1-Isothiocyanatobutane (4j)
phy (pentane). Purity determined by HPLC was 99%, gradient A, tR =
20.45 min.
Colorless oil. Yield: 0.17 g, 1.48 mmol (74%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
17.72 min.
IR (ATR): 2169 (NCS), 2030 (NCS), 2019 (NCS), 1589, 1451, 924, 745,
680 cm–1
.
IR (ATR): 2173 (NCS), 2127 (NCS), 2089 (NCS), 1510, 1345, 771 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.36–7.34 (m, 2 H, CHAr), 7.29–7.27 (m,
1 H, CHAr), 7.23–7.22 (m, 2 H, CHAr).
13C NMR (176 MHz, CDCl3): δ = 135.5 (s, NCS), 131.4 (s, CArNCS), 129.6
(s, CArH), 127.4 (s, CArH), 125.8 (s, CArH).
1H NMR (700 MHz, CDCl3): δ = 3.51 (t, JHH = 6.6 Hz, 2 H, CH2NCS), 1.67
(quin, JHH = 7.7 Hz, 2 H, CH2), 1.45 (sext, JHH = 7.7 Hz, 2 H, CH2), 0.94 (t,
JHH = 7.4 Hz, 3 H, CH3).
13C NMR (176 MHz, CDCl3): δ = 129.7 (s, NCS), 44.8 (s, CH2NCS), 32.0
(s, CH2), 19.8 (s, CH2), 13.3 (s, CH3).
The analytical data are in agreement with those reported previously
in the literature.17b
The analytical data are in agreement with those reported previously
in the literature.44
1-Isothiocyanato-4-methoxybenzene (4o)
Colorless oil. Yield: 0.270 g, 1.64 mmol (82%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
19.68 min
1-Isothiocyanato-1-methylcyclohexane (4k)45
Colorless oil. Yield: 0.169 g, 1.09 mmol (55%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 99%, gradient A, tR
25.27 min.
=
IR (ATR): 2174 (NCS), 2035 (NCS), 1580, 1499, 1459, 1243, 926, 826
cm–1
.
IR (ATR): 2077 (NCS), 2039 (NCS), 1447, 1258, 1165, 951, 771 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.16 (d, JHH = 9.1 Hz, 2 H, CHAr), 6.85 (d,
JHH = 9.1 Hz, 2 H, CHAr), 3.80 (s, 3 H, CH3O).
13C NMR (176 MHz, CDCl3): δ = 158.7 (s, CArOCH3), 134.1 (s, NCS),
127.1 (s, CArH), 123.7 (s, CArNCS), 114.9 (s, CArH), 55.6 (s, CH3O).
1H NMR (700 MHz, CDCl3): δ = 1.89–1.86 (m, 2 H, CH2), 1.70–1.66 (m,
1 H, H from CH2), 1.63–1.55 (m, 4 H, 2 × CH2), 1.41–1.37 (m, 2 H, CH2),
1.37 (s, 3 H, CH3), 1.21–1.15 (m, 1 H, H from CH2).
13C NMR (176 MHz, CDCl3): δ = 130.0 (s, NCS), 61.8 (s, CNCS), 39.1 (s, 2
× CH2), 29.7 (s, CH3), 25.0 (s, CH2), 22.4 (s, 2 × CH2).
The analytical data are in agreement with those reported previously
in the literature.17b
EI-MS: m/z [M•]+ calcd for C8H13NS: 155.0769; found: 155.0776.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Ł. Janczewski et al.
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Synthesis
1-Fluoro-4-isothiocyanatobenzene (4p)
1H NMR (700 MHz, CDCl3): δ = 4.19–4.08 (m, 4 H, 2 × CH2O), 4.05–
4.00 (m, 1 H, CH), 2.15–2.09 (m, 1 H, Hα from PCH2), 2.01–1.96 (m, 1
H, Hβ from PCH2), 1.74–1.70 (m, 2 H, CH2), 1.52–1.46 (m, 1 H, Hα from
CH2), 1.43–1.37 (m, 1 H, Hβ from CH2), 1.35 (t, JHH = 7.0 Hz, 3 H,
CH3CH2O), 1.34 (t, JHH = 7.0 Hz, 3 H, CH3CH2O), 1.33–1.26 (m, 4 H, 2 ×
CH2), 0.89 (t, JHH = 7.1 Hz, 3 H, CH3).
13C NMR (176 MHz, CDCl3): δ = 131.8 (s, NCS), 62.2 (d, JCP = 6.5 Hz,
CH2O), 62.1 (d, JCP = 6.5 Hz, CH2O), 53.3 [s, C(2)H], 37.2 [d, JCP = 11.2 Hz,
C(3)H2], 35.5 [d, JCP = 142.5 Hz, PC(1)H2], 31.1 (s, CH2), 25.4 (s, CH2),
22.4 (s, CH2), 16.5 (2 × d, JCP = 5.5 Hz, 2 × CH3CH2O), 14.0 (s, CH3).
Colorless oil. Yield: 0.219 g, 1.43 mmol (72%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient A, tR =
19.65 min.
IR (ATR): 2187 (NCS), 2029 (NCS), 1497, 1250, 930, 830 cm–1
1H NMR (700 MHz, CDCl3): δ = 7.22–7.20 (m, 2 H, CHAr), 7.05–7.03 (m,
2 H, CHAr).
13C NMR (176 MHz, CDCl3): δ = 161.3 (d, JCF = 249.2 Hz, CArF), 136.2 (s,
NCS), 127.6 (s, CArNCS), 127.5 (d, JCF = 8.8 Hz, CArH), 116.8 (d, JCF = 23.3
Hz, CArH).
.
31P NMR (283 MHz, CDCl3): δ = 25.64.
ESI–MS: m/z [M + Na]+ calcd for C12H24NNaO3PS: 316.1107; found:
The analytical data are in agreement with those reported previously
in the literature.17b
316.1111.
1,6-Diisothiocyanatohexane (4q)
Diethyl (3-Cyclohexyl-2-isothiocyanatopropyl)phosphonate (4u)
Colorless oil. Yield: 0.240 g, 1.2 mmol (60%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient B, tR =
22.06 min.
IR (ATR): 2179 (NCS), 2071 (NCS), 1448, 1344 cm–1
1H NMR (700 MHz, CDCl3): δ = 3.53 (t, JHH = 6.5 Hz, 4 H, 2 × CH2NCS),
1.74–1.70 (m, 4 H, 2 × CH2), 1.48–1.45 (m, 4 H, 2 × CH2).
13C NMR (176 MHz, CDCl3): δ = 130.1 (s, NCS), 45.0 (s, 2 × CH2NCS),
29.8 (s, 2 × CH2), 25.9 (s, 2 × CH2).
Yellow oil. Yield: 0.338 g, 1.06 mmol (53%) after flash chromatogra-
phy (hexane/EtOAc, 3:2). Purity determined by HPLC was 97%, gradi-
ent C, tR = 4.28 min.
.
IR (ATR): 2082 (NCS), 1248, 1051, 1021 (P–O–C), 960 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 4.18–4.07 (m, 5 H, 2 × CH2O, CHNCS),
2.13–2.08 (m, 1 H, Hα from PCH2), 1.99–1.94 (m, 1 H, Hβ from PCH2),
1.80–1.75 (m, 1 H, Hα from CH2), 1.72–1.63 (m, 5 H, 5 × Hα from CH2),
1.52–1.45 (m, 2 H, Hβ from CH2, CH), 1.35 (t, 3 H, JHH = 6.9 Hz, CH3),
1.34 (t, 3 H, JHH = 6.9 Hz, CH3), 1.30–1.22 (m, 2 H, 2 × Hβ from CH2),
1.17–1.11 (m, 1 H, Hβ from CH2), 0.98–0.93 (m, 1 H, Hβ from CH2),
0.90–0.84 (m, 1 H, Hβ from CH2).
The analytical data are in agreement with those reported previously
in the literature.47
tert-Butyl (2-Isothiocyanatoethyl)carbamate (4r)
13C NMR (176 MHz, CDCl3): δ = 131.7 (s, NCS), 62.3 (d, JCP = 6.7 Hz,
CH2O), 62.2 (d, JCP = 6.4 Hz, CH2O), 51.0 (s, CHNCS), 45.0 (d, JCP = 10.8
Hz, CH2), 34.5 (s, CH), 33.6 (s, CH2), 33.1 (d, JCP = 142.6 Hz, PCH2), 32.1
(s, CH2), 26.4 (s, CH2), 26.2 (s, CH2), 25.9 (s, CH2), 16.6 (d, JCP = 6.1 Hz,
CH3), 16.5 (d, JCP = 6.1 Hz, CH3).
31P NMR (283 MHz, CDCl3): δ = 25.59.
ESI-MS: m/z [M + Na]+ calcd for C14H26NNaO3PS: 342.1263; found:
White solid; mp 92–93 °C (Lit.48 63–64 °C). Yield: 0.243 g, 1.2 mmol
(60%) after flash chromatography (hexane/EtOAc, 10:1). Purity deter-
mined by HPLC was 98%, gradient D, tR = 4.91 min.
IR (ATR): 2193 (NCS), 2096 (NCS), 1688 (CO), 1528, 1436, 1278, 1165
cm–1
.
1H NMR (250 MHz, CDCl3): δ = 4.88 (br s, 1 H, NH), 3.64 (t, JHH = 5.6 Hz,
2 H, CH2NCS), 3.37 (q, JHH = 5.9 Hz, 2 H, CH2NH), 1.45 [s, 9 H, (CH3)3].
342.1269.
13C NMR (176 MHz, CDCl3): δ = 155.7 (s, CO), 132.4 (s, NCS), 80.2 [s,
C(CH3)3], 45.5 (s, CH2), 40.7 (s, CH2), 28.4 [s, (CH3)3].
Diethyl [Isothiocyanato(4-methoxyphenyl)methyl]phosphonate
(4v)
The analytical data are in agreement with those reported previously
in the literature.48
Yellow oil. Yield: 0.321 g, 1.02 mmol (51%) after flash chromatogra-
phy (hexane/EtOAc, 7:4). Purity determined by HPLC was 97%, gradi-
ent C, tR = 3.44 min.
IR (ATR): 2188 (NCS), 2044 (NCS), 1511, 1305, 1012 (P–O–C), 969 cm–1
1H NMR (700 MHz, CDCl3): δ = 7.35 (dd, JHH = 8.5 Hz, JHP = 2.2 Hz, 2 H,
2 × CHAr), 6.91 (d, JHH = 8.5 Hz, 2 H, 2 × CHAr), 4.93 (d, JHP = 18.9 Hz, 1 H,
PCHNCS), 4.14–3.99 (m, 4 H, 2 × CH2O), 3.81 (s, 3 H, CH3O), 1.28 (2 ×
td, JHH = 7.1 Hz, JHP = 3.1 Hz, 6 H, 2 × CH3).
13C NMR (176 MHz, CDCl3): δ = 160.1 (d, JCP = 2.4 Hz, CArOMe), 137.1
(s, NCS), 128.8 (d, JCP = 5.2 Hz, 2 × CArH), 123.8 (d, JCP = 4.9 Hz, CAr),
114.3 (d, JCP = 2.1 Hz, 2 × CArH), 64.3 (d, JCP = 6.7 Hz, CH2O), 63.9 (d, JCP
= 6.6 Hz, CH2O), 57.5 (d, JCP = 152.2 Hz, PCHNCS), 55.4 (d, JCP = 2.0 Hz,
CH3O), 16.6 (d, JCP = 5.2 Hz, CH3), 16.5 (d, JCP = 5.2 Hz, CH3).
1-Bromo-6-isothiocyanatohexane (4s)49
.
Colorless oil. Yield: 0.244 g, 1.1 mmol (55%) after flash chromatogra-
phy (pentane). Purity determined by HPLC was 100%, gradient B, tR =
22.29 min.
IR (ATR): 2180 (NCS), 2082 (NCS), 1451, 1345 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 3.52 (t, JHH = 6.6 Hz, 2 H, CH2NCS), 3.41
(t, JHH = 6.7 Hz, 2 H, CH2Br), 1.90–1.86 (m, 2 H, CH2), 1.73–1.69 (m, 2 H,
CH2), 1.51–1.43 (m, 4 H, 2 × CH2).
13C NMR (176 MHz, CDCl3): δ = 130.1 (s, NCS), 45.1 (s, CH2NCS), 33.6
(s, CH2), 32.5 (s, CH2), 29.9 (s, CH2), 27.4 (s, CH2), 25.8 (s, CH2).
EI-MS: m/z [M•]+ calcd for C7H12BrNS: 220.9874; found: 220.9884.
31P NMR (283 MHz, CDCl3): δ = 15.62.
The analytical data are in agreement with those reported previously
in the literature.10a
Diethyl (2-Isothiocyanatoheptyl)phosphonate (4t)
Colorless oil. Yield: 0.366 g, 1.25 mmol (63%) after flash chromatogra-
phy (hexane/EtOAc, 3:2). Purity determined by HPLC was 97%, gradi-
ent C, tR = 5.11 min.
IR (ATR): 2078 (NCS), 1239, 1050, 1021 (P–O–C), 959 cm–1
Diethyl (Isothiocyanatomethyl)phosphonate (4w)
Yellow oil. Yield: 0.209 g, 1 mmol (50%) after flash chromatography
(hexane/acetone, 3:1). Purity determined by HPLC was 97%, gradient
C, tR = 2.19 min.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
Ł. Janczewski et al.
Paper
Synthesis
IR (ATR): 2224 (NCS), 2071 (NCS), 1243, 1014 (P–O–C), 971 cm–1
1H NMR (700 MHz, CDCl3): δ = 4.25–4.21 (m, 4 H, 2 × CH2O), 3.78 (d,
JHP = 14.0 Hz, 2 H, PCH2NCS), 1.39 (t, JHP = 7.1 Hz, 6 H, 2 × CH3).
13C NMR (176 MHz, CDCl3): δ = 135.8 (s, NCS), 63.5 (d, JCP = 6.5 Hz, 2 ×
CH2O), 40.5 (d, JCP = 154.0 Hz, PCH2NCS), 16.5 Hz (d, JCP = 5.6 Hz, 2 ×
CH3).
.
1H NMR (700 MHz, CDCl3): δ = 4.35 (q, JHH = 7.1 Hz, 1 H, CHNCS), 3.79
(s, 3 H, CH3O), 1.58 (d, JHH = 7.1 Hz, 3 H, CH3).
13C NMR (176 MHz, CDCl3): δ = 169.5 (s, CO), 137.5 (s, NCS), 54.9 (s,
CH3O), 53.3 (s, CHNCS), 19.6 (s, CH3).
EI-MS: m/z [M•]+ calcd for C5H7NO2S: 145.0198: found: 145.0195.
31P NMR (283 MHz, CDCl3): δ = 15.90.
(2-Isothiocyanatoethyl)benzene (4a); Method B
Et3N (1.4 mL, 10 mmol, 5 equiv) and CS2 (0.36 mL, 6 mmol, 3 equiv)
were added in one portion to a solution of amine 2a (0.242 g, 2 mmol)
in anhyd DCM (10 mL). Next, the solution was stirred for 1 h at r.t.
Thereafter, the mixture was cooled to 4 °C in an ice bath, T3P® (1.3
mL, 2.2 mmol, 1.1 equiv) was added over 5 min in three portions and
the solution was stirred for 15 min at reflux. Pure 4a (0.235 g) was
isolated as a colorless oil in 72% yield following the work-up proce-
dure described in Method A.
The analytical data are in agreement with those reported previously
in the literature.10a
(S)-Methyl 2-Isothiocyanato-3-phenylpropanoate (4x)
Colorless oil. Yield: 0.319 g, 1.44 mmol (72%) after flash chromatogra-
phy (hexane/EtOAc, 20:1). Purity determined by HPLC was 98%, gradi-
ent D, tR = 13.05 min.
The er was determined by HPLC using a Chiralpak IF column (hex-
ane/i-PrOH, 99:1); tmajor = 8.08 min, tminor = 7.38 min (98.5:1.5 er).
[α]D25 –62.2 (c 1.0, toluene) [Lit.16d [α]D20 –60.0 (c 1.0, toluene)].
(2-Isothiocyanatoethyl)benzene (4a); Method C
Et3N (1.4 mL, 10 mmol, 5 equiv) and CS2 (0.36 mL, 6 mmol, 3 equiv)
were added in one portion to a solution of amine 2a (0.242 g, 2 mmol)
in anhyd DCM (2 mL) in a 10 mL pressure vial equipped with a mag-
netic stir bar. Next, the solution was stirred for 1 h at r.t. Thereafter,
the mixture was cooled to 4 °C and T3P® (2.12 mL, 3.6 mmol, 1.8
equiv) was added over 5 min in three portions. The reaction mixture
was subjected to microwave (MW) irradiation (standard procedure,
pressure vial, 5 min at 80 °C). Pure 4a (0.270 g) was isolated as a color-
less oil in 83% yield following the work-up procedure described in
Method A.
IR (ATR): 2189 (NCS), 2088 (NCS), 1600 (CO), 1484, 1253, 1117, 964
cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.35–7.33 (m, 2 H, CHAr), 7.31–7.29 (m,
1 H, CHAr), 7.23–7.22 (m, 2 H, CHAr), 4.48 (dd, JHaHb = 8.4 Hz, JHaHc = 4.8
Hz, 1 H, CHaNCS), 3.79 (s, 3 H, CH3O), 3.25 (dd, JHcHb = 13.8 Hz, JHcHa
=
4.7 Hz, 1 H, CHcPh), 3.13 (dd, JHbHc = 13.8 Hz, JHbHa = 8.4 Hz, 1 H, CHbPh).
13C NMR (176 MHz, CDCl3): δ = 168.4 (s, CO), 138.1 (s, NCS), 135.1 (s,
CAr), 129.4 (s, CArH), 128.8 (s, CArH), 127.7 (s, CArH), 60.8 (s, CH3O), 53.2
(s, CHNCS), 39.8 (s, CH2).
The analytical data are in agreement with those reported previously
in the literature.16d
Funding Information
The authors gratefully acknowledge financial support from the Polish
(S)-Methyl 2-Isothiocyanatopropanoate (4y)
National Science Centre (grant no. DEC 2011/03/B/ST5/01058).Psoih
l
N
oaitn
a
l
S
ecin
c
e
C
e
nrte
D(
E
C
2
0
1
1
0/
3
B/S/
T
5
0/
1
0
5
8)
Colorless oil. Yield: 0.185 g, 1.27 mmol (63%) after flash chromatogra-
phy (hexane/EtOAc, 20:1). Purity determined by HPLC was 100%, gra-
dient A, tR = 13.25 min.
Acknowledgment
The er was determined by HPLC using a Chiralpak IC column (hex-
ane/i-PrOH, 98:2); tmajor = 7.02 min, tminor = 6.77 min (>99.9:0.1 er).
We express our gratitude to Prof. Łukasz Albrecht for access to chiral
[α]D25 +25.8 (c 0.32, CHCl3) [Lit.11c [α]D20 +23.4 (c 0.32, CHCl3)].
stationary phase HPLC.
IR (ATR): 2042 (NCS), 1744 (CO), 1450, 1435, 1288, 1207, 1149, 1053
cm–1
.
Supporting Information
1H NMR (700 MHz, CDCl3): δ = 4.35 (q, JHH = 7.1 Hz, 1 H, CHNCS), 3.81
(s, 3 H, CH3O), 1.60 (d, JHH = 7.1 Hz, 3 H, CH3).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591842.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
13C NMR (176 MHz, CDCl3): δ = 169.5 (s, CO), 137.5 (s, NCS), 54.9 (s,
CH3O), 53.3 (s, CHNCS), 19.6 (s, CH3).
The analytical data are in agreement with those reported previously
in the literature.11c,50
References
(1) Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1.
(2) Pace, V.; Monticelli, S.; de la Vega-Hernández, K.; Castoldi, L.
Org. Biomol. Chem. 2016, 14, 7848.
(3) (a) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593.
(b) Koutoulogenis, G.; Kaplaneris, N.; Kokotos, C. G. Beilstein J.
Org. Chem. 2016, 12, 462. (c) Sabot, C.; Mosser, M.; Antheaume,
C.; Mioskowski, C.; Rachid Baati, R.; Wagner, A. Chem. Commun.
2009, 3409.
(4) Ulatowski, F.; Jurczak, J. J. Org. Chem. 2015, 80, 4235.
(5) (a) Fimognari, C.; Lenzi, M.; Hrelia, P. Curr. Med. Chem. 2008, 15,
440. (b) Nakamura, Y.; Miyoshi, N. Biosci. Biotechnol. Biochem.
2010, 74, 242. (c) Singh, S. V.; Singh, K. Carcinogenesis 2012, 33,
1833.
(R)-Methyl 2-Isothiocyanatopropanoate (4z)11c,33
Colorless oil. Yield: 0.180 g, 1.24 mmol (62%) after flash chromatogra-
phy (hexane/EtOAc, 20:1). Purity determined by HPLC was 100%, gra-
dient D, tR = 9.05 min.
The er was determined by HPLC using a Chiralpak IC column (hex-
ane/i-PrOH, 98:2); tmajor = 6.78 min, tminor = 7.06 min (>99.9:0.1 er).
[α]D25 –22.8 (c 0.32, CHCl3) [Lit.11c [α]D25 –23.9 (c 0.3, CHCl3)].
IR (ATR): 2050 (NCS), 1745 (CO), 1455, 1436, 1288, 1208, 1150, 1053
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

K
Ł. Janczewski et al.
Paper
Synthesis
(6) (a) Brown, K. K.; Hampton, M. B. Biochim. Biophys. Acta 2011,
1810, 888. (b) Hanschen, F. S.; Lamy, E.; Schreiner, M.; Rohn, S.
Angew. Chem. Int. Ed. 2014, 53, 11430.
(20) (a) Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org. Chem.
2009, 1849. (b) Guin, S.; Rout, S. K.; Khatun, N.; Patel, B. K. RSC
Adv. 2012, 2, 3180.
(7) (a) Shapiro, T. A.; Fahey, J. W.; Wade, K. L.; Stephenson, K. K.;
Talalay, P. Cancer Epidemiol. Biomark. Prev. 1998, 7, 1091.
(b) Shapiro, T. A.; Fahey, J. W.; Wade, K. L.; Stephenson, K. K.;
Talalay, P. Cancer Epidemiol. Biomark. Prev. 2001, 10, 501.
(8) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(b) Staudinger, H.; Hauser, E. Helv. Chim. Acta 1921, 4, 861.
(c) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437. (d) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron
1992, 48, 1353. (e) Isoda, T.; Hayashi, K.; Tamai, S.; Kumagai, T.;
Nagao, Y. Chem. Pharm. Bull. 2006, 54, 1616. (f) Palacios, F.;
Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J. M. Tetra-
hedron 2007, 63, 523.
(9) Molina, P.; Alajarin, M.; Arques, A. Synthesis 1982, 596.
(10) For recent papers, see: (a) Psurski, M.; Błażewska, K.; Gajda, A.;
Gajda, T.; Wietrzyk, J.; Oleksyszyn, J. Bioorg. Med. Chem. Lett.
2011, 21, 4572. (b) Elhalem, E.; Recio, R.; Werner, S.; Lieder, F.;
Calderón-Montaño, J. M.; López-Lázaro, M.; Fernández, I.; Khiar,
N. Eur. J. Med. Chem. 2014, 87, 552. (c) Gosling, S.; El Amri, C.;
Tatibouët, A. Synthesis 2014, 46, 1079. (d) Shelnut, E. L.; Nikas, S.
P.; Finnegan, D. F.; Chiang, N.; Serhan, C. N.; Makriyannis, A. Tet-
rahedron Lett. 2015, 56, 1411. (e) Psurski, M.; Janczewski, Ł.;
Świtalska, M.; Gajda, A.; Goszczyński, T.; Oleksyszyn, J.;
Wietrzyk, J.; Gajda, T. Eur. J. Med. Chem. 2017, 132, 63.
(21) Hodgkins, J. E.; Ettlinger, M. G. J. Org. Chem. 1956, 21, 404.
(22) Munch, H.; Hansen, J. S.; Pittelkow, M.; Christensen, J. B.; Boas,
U. Tetrahedron Lett. 2008, 49, 3117.
(23) Sun, N.; Li, B.; Shao, J. P.; Mo, W. M.; Hu, B. X.; Shen, Z. L.; Hu, X.
Q. Beilstein J. Org. Chem. 2012, 8, 61.
(24) Liu, P.; Li, C.; Zhang, J.; Xu, X. Synth. Commun. 2013, 43, 3342.
(25) Kaboudin, B.; Ehsan, J. Synthesis 2008, 2683.
(26) Li, Z.-Y.; Ma, H.-Z.; Han, C.; Xi, H.-T.; Meng, Q.; Chen, X.; Sun, X.-Q.
Synthesis 2013, 45, 1667.
(27) Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org. Chem. 2008,
6189.
(28) Yella, R.; Ghosh, H.; Murru, S.; Sahoo, S. K.; Patel, B. K. Synth.
Commun. 2010, 40, 2083.
(29) Pizova, H.; Bobal, P. Tetrahedron Lett. 2015, 56, 2014.
(30) Basavaprabhu; Vishwanatha, T. M.; Panguluri, N. R.;
Sureshbabu, V. V. Synthesis 2013, 45, 1569.
(31) Swierczek, K.; Peters, J. W.; Hengge, A. C. Tetrahedron 2003, 59,
595.
(32) Foreiter, M. B.; Nimal Gunaratne, H. Q.; Nockemann, P.; Seddon,
K. R.; Stevenson, P. J.; Wassell, D. F. New J. Chem. 2013, 37, 515.
(33) Lamani, R. S.; Nagendra, G.; Sureshbabu, V. V. Tetrahedron Lett.
2010, 51, 4705.
(34) Eisenführ, A.; Arora, P. S.; Sengle, G.; Takaoka, L. R.; Nowick, J. S.;
Famulok, M. Bioorg. Med. Chem. 2003, 11, 235.
(35) Abdur Rahman, S. M.; Baba, T.; Kodama, T.; Ariful Isla, M.;
Obika, S. Bioorg. Med. Chem. 2012, 20, 4098.
(36) (a) Gajda, T.; Nowalińska, M.; Zawadzki, S.; Zwierzak, A. Phos-
phorus, Sulfur Silicon Relat. Elem. 1995, 105, 45. (b) Bernacka, E.;
Klepacz, A.; Zwierzak, A. Tetrahedron Lett. 2011, 42, 5093.
(37) Kim, T.; Kim, Y.-J.; Han, I.-H.; Lee, D.; Ham, J.; Kang, K. S.; Lee, J.
W. Bioorg. Med. Chem. Lett. 2015, 25, 62.
(11) (a) Ratke, A. Ber. Dtsch. Chem. Ges. 1872, 5, 799. (b) Nowick, J.
S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen, T. M.;
Huang, S.-L. J. Org. Chem. 1996, 61, 3929. (c) Michalski, O.;
Cież, D. J. Mol. Struct. 2013, 1037, 225. (d) Kiełbasiński, P.;
Łuczak, J.; Cierpiał, T.; Błaszczyk, J.; Sieroń, L.; Wiktorska, K.;
Lubelska, K.; Milczarek, M.; Chilmończyk, Z. Eur. J. Med. Chem.
2014, 76, 332. (e) Gondela, A.; Tomczyk, M. D.; Przypis, Ł.;
Walczak, K. Z. Tetrahedron 2016, 72, 5626.
(12) Barone, M.; Carol, A.; Graziano, E.; Marrazzo, A.; Gemmellaro, P.;
Santagati, A.; Cardi, V. Mol. Diversity 2013, 17, 445.
(38) Shubina, T. E.; Freund, M.; Schenker, S.; Clark, T.; Tsogoeva, S. B.
Beilstein J. Org. Chem. 2012, 8, 1485.
(13) Larsen, C.; Harpp, D. N. J. Org. Chem. 1981, 46, 2465.
(14) Kim, S.; Yi, K. Y. J. Org. Chem. 1986, 56, 2613.
(39) Ang, M. T. C.; Phan, L.; Alshamrani, A. K.; Harjani, J. R.; Wang, R.;
Schatte, G.; Mosey, N. J.; Jessop, P. G. Eur. J. Org. Chem. 2015,
7334.
(40) Hiegel, G. A.; Nguyen, J.; Zhou, Y. Synth. Commun. 2004, 34,
2507.
(15) Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1868, 1, 170.
(16) (a) Boas, U.; Jakobsen, M. H. J. Chem. Soc., Chem. Commun. 1995,
1995. (b) Boas, U.; Pedersen, B.; Christensen, J. B. Synth.
Commun. 1998, 28, 1223. (c) Boas, U.; Pedersen, H. G.;
Christensen, J. B.; Heegaard, P. M. H. Tetrahedron Lett. 2004, 45,
269. (d) Tsogoeva, S. B.; Hateley, M. J.; Yalalov, D. A.; Meindl, K.;
Weckbecker, C.; Huthmacher, K. Bioorg. Med. Chem. 2005, 13,
5680. (e) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.;
Weckbecker, C.; Huthmacher, K. Eur. J. Org. Chem. 2005, 4995.
(f) Psurski, M.; Piguła, M.; Ciekot, J.; Winiarski, Ł.; Wietrzyk, J.;
Oleksyszyn, J. Tetrahedron Lett. 2012, 53, 5845.
(17) (a) Stephensen, H.; Zaragoza, F. J. Org. Chem. 1997, 62, 6096.
(b) Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969.
(c) Sureshbabu, V. V.; Naik, S. A.; Hemantha, H. P.; Narendra, N.;
Das, U.; Guru Row, T. N. J. Org. Chem. 2009, 74, 5260. (d) Fu, Z.;
He, J.; Tong, A.; Xie, Y.; Wei, Y. Synthesis 2013, 45, 2843. (e)
Basavaprabhu; Sharanabai, K. M.; Prabhu, G.; Panduranga, V.;
Sureshbabu, V. V. Synthesis 2015, 47, 801.
(41) Ferreira, R. B.; Tormena, C. F.; Almeida, W. P. J. Mol. Struct. 2013,
1037, 186.
(42) Rajski, S.; Mays, J. R. US Patent 2013/116203 A1, 2013.
(43) Dolles, D.; Nimczick, M.; Scheiner, M.; Ramler, J.; Stadtmüller,
P.; Sawatzky, E.; Drakopoulos, A.; Sotriffer, C.; Wittmann, H.-J.;
Strasser, A.; Decker, M. ChemMedChem 2016, 11, 1270.
(44) Grzywa, R.; Winiarski, Ł.; Psurski, M.; Rudnicka, A.; Wietrzyk, J.;
Gajda, T.; Oleksyszyn, J. Bioorg. Med. Chem. Lett. 2016, 26, 667.
(45) Iwasawa, N.; Funahashi, M.; Mayakawa, S.; Ikeno, T.; Narasaka,
K. Bull. Chem. Soc. Jpn. 1999, 72, 85.
(46) Glaser, R.; Hillebrand, R.; Wycoff, W.; Camasta, C.; Gates, K. S.
J. Org. Chem. 2015, 80, 4360.
(47) Kumar, S.; Newby Spano, M.; Arya, D. P. Bioorg. Med. Chem.
2015, 23, 3105.
(48) Gondela, A.; Tomczyk, M. D.; Przypis, Ł.; Walczak, K. Z. Tetra-
hedron 2016, 72, 5626.
(49) Garmaise, D. L.; Paris, G. Y.; Efthymiadis, G. Can. J. Chem. 1971,
49, 971.
(50) Kunze, U.; Burghardt, R. Phosphorus, Sulfur Silicon Relat. Elem.
1987, 29, 373.
(18) Hu, K.; Qi, Y.; Zhao, J.; Jiang, H.; Chen, X.; Ren, J. Eur. J. Med.
Chem. 2013, 64, 529.
(19) (a) Li, G.; Tajima, H.; Ohtani, T. J. Org. Chem. 1997, 62, 4539.
(b) Tajimia, H.; Li, G. Synlett 1997, 773.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K