Key words isothiocyanates - desulfuration - propane phosphonic acid anhydride (T3P
® ) - dithiocarbamates - amino acids - amines
Isothiocyanates (ITCs) belong to the group of heterocummulenes, 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 organocatalysts,[3a ]
[b ] chiral derivatizing auxiliaries,[3c ] and thiourea receptors,[4 ] whilst several natural ITCs exhibit chemopreventive and anticancer activity.[5 ] Natural ITCs are an element 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 present 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 ]
Scheme 1 Enzymatic formation of ITCs
All these facts have resulted in interest from the scientific 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 ]).
Scheme 2 Selected synthetic approaches to isothiocyanates
According to Scheme [2 ], azides, which can be considered as convenient amine precursors, are converted upon
reaction 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 reaction[8 ]). Alternatively, iminophosphoranes can be formed directly from amines and triphenylphosphine
dibromide[9 ] (Scheme [2 ]). The azide approach has been applied to the efficient synthesis of structurally
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-molecular-weight
organic azides makes their preparation dangerous. 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 Ratke[11a ] in 1872, are still currently extensively used as a direct and efficient route to
this class of compounds[4 ]
,
[11b ]
[c ]
[d ]
[e ] (Scheme [2 ]). The advantage of this approach is the straightforwardness 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, thiophosgene surrogates such as di(2-pyridyl) thionocarbonate,[12 ] 1,1′-thiocarbonyldiimidazole,[13 ] and 1,1′-thiocarbonyldi-2(1H )-pyridone[14 ] are used.
A particularly important route to ITCs is a two-step, and usually one-pot reaction
of primary amines with carbon disulfide 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 chloride,[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 chlorophosphate,[25 ] phenyl chlorothionoformate,[26 ] diacetoxyiodobenzene,[27 ] and 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide[28 ] have recently been employed as desulfurating agents. However, some of these protocols
suffer from difficulties 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 dehydrating 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 standpoint that water soluble side products are formed during reactions
involving T3P® , which should be easily removable during a standard work-up.
Figure 1 Propane phosphonic acid anhydride (T3P® ) (1 )
In this paper, we present the results of our investigation into the general synthesis
of structurally diverse isothiocyanates from their parent amines via a one-pot dithiocarbamate
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
dithiocarbamate 3a after one hour at room temperature, in dichloromethane as the solvent. Next, dithiocarbamate
3a was allowed to react in situ with T3P® (1.1 equiv) to give the target, (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 Et3 N is recommended to ensure optimal conditions for both steps. We also demonstrated
that increasing and decreasing the time for the desulfuration 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 isothiocyanate 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-diazabicyclo[5.4.0]undec-7-ene (DBU) were
tested. The reaction in the presence of NMM led to a yield comparable to that with
Et3 N (entry 4), whereas the reactions with DIPEA and DBU delivered lower yields when
compared to those of Et3 N and NMM (entries 1 and 4 vs entries 5 and 6). As the highest yield was obtained
in the presence of Et3 N, 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 observed 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 compatible with microwave (MW) conditions. After short
experimentation (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 isothiocyanate 4a and thiopyrophosphate 6 as a side product. Attempts to confirm the presence of 5a by 31 P NMR spectroscopy under the reaction conditions failed. However, a singlet at 96
ppm displayed in the 31 P NMR spectrum of the reaction mixture after quenching and subsequent hydrolysis of
intermediate 6 and unreacted T3P® (1 ), could be assigned to the propanephosphonothioic salt,[31 ] which confirms in part this mechanistic hypothesis.
Table 1 Optimization of the Reaction Conditionsa and a Plausible Mechanism
Entry
Base (B)
T3P® (equiv)
Time (h)
Yield (%)b
1
Et3 N
1.1
2c
77
2
Et3 N
1.1
24
71
3
Et3 N
1.1
0.25d
72
4
NMM
1.1
2
72
5
DIPEA
1.1
2
64
6
DBU
1.1
2
57
7
Et3 N
0.8
2
63
8
Et3 N
1.5
2
80
9
Et3 N
1.8e
2
85
10
Et3 N
1.8
5 minf
83
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.
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 conditions 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-isothiocyanatoethyl)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 possessing 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-fluorobenzene (4p ) were prepared in good yields from 4-methoxyaniline (2o ) and 4-fluoroaniline (2p ), respectively (entries 15 and 16). However, attempts to obtain 1-isothiocyanato-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 materials in this synthesis [entry
1 (see footnote c) and entries 8–13]. For ammonium salts, double the amount of Et3 N (10 equiv) had to be used to achieve good yields of isothiocyanates 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
conditions. Pure ITCs were easily obtained after flash chromatography through a short
pad of silica gel by simple elution of the products with hexane or pentane, followed
by careful evaporation of the eluate.
a Reaction conditions: 2a –p (2 mmol), CS2 (6 mmol, 3 equiv), Et3 N (10 mmol, 5 equiv) for 2a –g ,o –p or Et3 N (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.
b Yields of pure products after flash chromatography (hexane or pentane).
c Product 4a was obtained in 77% yield starting from 2-phenylethylammonium chloride.
d The following reaction conditions were applied: 2n (2 mmol), CS2 (8 mmol, 4 equiv), Et3 N (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.
e First step: 20 h at r.t., then T3P® was added at 4 °C, followed by 2 h at r.t.
To expand the synthetic utility of our protocol we focused on the preparation of bifunctional
isothiocyanates. The results demonstrate that the established conditions allowed the
reactions to proceed with a variety of bifunctional isothiocyanates and that the reaction
was compatible with a variety of functional groups. 1,6-Diisothiocyanatohexane (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 isothiocyanatoalkylphosphonates,[10a ]
[e ]
[16f ] diethyl aminoalkylphosphonate hydrochlorides were also examined as potential substrates.
We found that aminophosphonate hydrochlorides 2t –w afforded the corresponding products, diethyl (2-isothiocyanatoheptyl)phosphonate
(4t ), diethyl (3-cyclohexyl-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 protocol 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 Supporting Information,
Table S3) we found that to ensure the reaction was free of racemization the replacement
of Et3 N by a limited amount of NMM (3 equiv) was necessary. In addition, release of the
free amino esters from their hydrochlorides, the formation of the corresponding dithiocarbamates
in the first step, and also the addition of T3P® to the reaction mixture should be carried out at –5 °C. Thus modified, the protocol
allowed us to obtain enantiopure methyl (S )-2-isothiocyanato-3-phenylpropionate (4x ), methyl (S )-2-isothiocyanatopropionate (4y ), and methyl (R )-2-isothiocyanatopropionate (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 Et3 N or NMM under the standard reaction time/temperature (2 h, r.t.). Significant racemization
was observed only when Et3 N was used (52:48 er), while almost no racemization took place on exposure to NMM
(99:1 er).
Isothiocyanates derived from α-amino acids are valuable chiral building blocks, and
among numerous applications, they have recently been employed in the synthesis of
peptidomimetics[17d ]
[e ]
[33 ] and chiral carboxylate receptors.[4 ]
a Reaction conditions: 2q –z (2 mmol) [for 2q ,s –w Et3 N (20 mmol, 10 equiv) was used, for 2r Et3 N (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).
b Yields of pure products after flash chromatography.
c Double amounts of reagents were used: Et3 N (20 mmol, 10 equiv), CS2 (12 mmol, 6 equiv), T3P® (7.2 mmol, 3.6 equiv).
d CS2 , NMM and T3P® were added at –5 °C and the first step was continued for 2 h at r.t.
In order to compare the effectiveness of the proposed methodology with previously
reported methods, the conversion of the model amine 2a into isothiocyanate 4a was study using selected reagents. For this purpose, the dithiocarbamate was generated
in the reaction of 2a with carbon disulfide and then desulfurated to give 4a using either TsCl,[17b ] Boc2 O,[22 ] I2 ,[20 ] or H2 O2
[16f ]
[19 ] (Table [4 ], entries 2–5). Additionally, 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 highest 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 H2 O2 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 Boc2 O and I2 were slightly less effective (entries 3 and 4, 82% and 81%, respectively).
Table 4 A Comparative Study of the Reagents Used for the Synthesis of 4a from 2a
Entry
Reagents
Yield (%)
1a
CS2 , Et3 N, anhyd DCM, T3P®
85
2[17b ]
CS2 , Et3 N, THF, TsCl
85
3[22 ]
CS2 , Et3 N, EtOH, cat. DMAP, Boc2 O
82
4[20 ]
CS2 , Et3 N, MeCN, I2
81
5[16f ]
[19 ]
CS2 , Et3 N, THF, 30% H2 O2
77
6[4 ]
,
[11b ]
[c ]
[d ]
[e ]
NaHCO3 , CHCl3 /H2 O, CSCl2
90
a This work.
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.
Scheme 3 A gram-scale experiment
All the synthesized isothiocyanates, except for new compounds 4t and 4u , are described in the literature. However, 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 synthesis 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 compounds. 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 opinion, the established protocol makes a valuable contribution to those already
described for the synthesis of isothiocyanates.
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-diaminohexane were purchased from Sigma-Aldrich.
N -Boc-1,2-diaminoethane was prepared from 1,2-diaminoethane according to the procedure
described by Famulok et al.[34 ] 6-Bromohexylammoium bromide was prepared according to the procedure given by Obika
et al.[35 ] Aminophosphonate hydrochlorides 2t –w were obtained according 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 aluminum-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. Optical rotations were measured at 25 °C on a PolaAAr 3001
Polarimeter at λ = 589 nm, and are reported as follows: [α]D
25 (c = g/100 mL solvent). 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/H2 O 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/H2 O, 90%:10%; D: 0–1 min 20% MeCN, 5–15 min 70% MeCN, 20–30 min 80% MeCN. Samples were
prepared by dissolution of 0.5–1 mg in 1 mL of eluent (H2 O/MeCN, 80:20 or H2 O/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 Et3 N 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 Chiralpak 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
on an FT-IR Alpha Bruker (ATR) instrument and are reported in cm–1 . NMR spectra were measured on a Bruker Avance II Plus spectrometer (700 MHz for 1 H NMR, 176 MHz for 13 C NMR and 283 MHz for 31 P NMR) and a Bruker Avance DPX spectrometer (250.13 MHz for 1 H NMR) in CDCl3 solution. 1 H and 13 C NMR spectra are referenced according to the residual peak of the solvent based on
literature data. 31 P NMR chemical shifts are reported in ppm downfield from 85% H3 PO4 as an external standard. Chemical shifts (δ) are reported in ppm and coupling constants
(J ) in Hz. 31 P and 13 C NMR spectra are proton-decoupled. A Bruker MicrOTOF-Q II spectrometer (Bruker Daltonics,
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 Premier (Waters) spectrometer with a HP 7890 (Agilent) gas chromatograph
and an advanced autosampler was used for recording the high-resolution electron ionization
(MS-EI) spectra.
Isothiocyanates 4a–w; Method A
Isothiocyanates 4a–w; Method A
Et3 N (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 thermometer 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 allowed to
reach r.t. and was stirred for 2 h at this temperature. Next, the mixture was hydrolyzed
with H2 O (10 mL) for 30 min and diluted with DCM (50 mL). The organic layer was separated
and washed successively with H2 O (2 × 5 mL), 1 M HCl (2 × 5 mL), H2 O (2 × 5 mL), saturated NaHCO3 (2 × 5 mL), H2 O (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 eluents. Pure isothiocyanates 2a –w were isolated after careful evaporation of the solvent and removal of volatile residues
under reduced pressure.
Amino Acid Derived Isothiocyanates 4x–z; Method A
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 portions, 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 .
(2-Isothiocyanatoethyl)benzene (4a)
(2-Isothiocyanatoethyl)benzene (4a)
Colorless oil. Yield: 0.279 g, 1.7 mmol (85%) after flash chromatography (hexane).
Purity determined by HPLC was 98%, gradient A, t
R = 18.47 min.
IR (ATR): 2180 (NCS), 2079 (NCS), 1495, 1453, 1346, 748, 698 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.36–7.34 (m, 2 H, CH
Ar ), 7.30–7.27 (m, 1 H, CH
Ar ), 7.23–7.21 (m, 2 H, CH
Ar ), 3.73 (t, J
HH = 7.0 Hz, 2 H, CH
2 NCS), 3.00 (t, J
HH = 7.0 Hz, 2 H, CH
2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 137.0 (s, C
Ar ), 130.8 (s, NC S), 128.7 (s, C
Ar H), 128.6 (s, C
Ar H), 127.1 (s, C
Ar H), 46.3 (s, C H2 NCS), 36.4 (s, C H2 ).
The analytical data are in agreement with those reported previously in the literature.[37 ]
(R )-(1-Isothiocyanatoethyl)benzene (4b)
(R )-(1-Isothiocyanatoethyl)benzene (4b)
Colorless oil. Yield: 0.272 g, 1.68 mmol (84%) after flash chromatography (hexane).
Purity determined by HPLC was 99%, gradient A, t
R = 20.30 min.
The er was determined by HPLC using a Chiralpak ID column (hexane); t
major = 7.40 min, t
minor = 6.82 min (>99.9:0.1 er).
[α]D
25 –17.9 (c 1.0, CHCl3 ); [α]D
25 –5.7 (c 1.0, acetone) [Lit.[16e ] [α]D
20 –4.3 (c 1.0, acetone)].
IR (ATR): 2077 (NCS), 2039 (NCS), 1493, 1452, 1306, 1020, 756, 695 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.40–7.38 (m, 2 H, CH
Ar ), 7.34–7.32 (m, 3 H, CH
Ar ), 4.92 (q, J
HH = 6.8 Hz, 1 H, CH NCS), 1.68 (d, J
HH = 6.8 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 140.3 (s, C
Ar ), 132.5 (s, NC S), 129.0 (s, C
Ar H), 128.3 (s, C
Ar H), 125.5 (s, C
Ar H), 57.1 (s, C HNCS), 25.0 (s, C H3 ).
The analytical data are in agreement with those reported previously in the literature.[16e ]
[38 ]
(S )-(1-Isothiocyanatoethyl)benzene (4c)
(S )-(1-Isothiocyanatoethyl)benzene (4c)
Colorless oil. Yield: 0.270 g, 1.66 mmol (83%) after flash chromatography (hexane).
Purity determined by HPLC was 98%, gradient A, t
R = 20.41 min.
The er was determined by HPLC using a Chiralpak ID column (hexane); t
major = 6.82 min, t
minor = 7.40 min (>99.9:0.1 er).
[α]D
25 +5.4 (c 1.0, acetone); [α]D
25 +17.8 (c 1.0, CHCl3 ) [Lit.[32 ] [α]D
20 +16.6 (c 1.02, CHCl3 )].
IR (ATR): 2079 (NCS), 1495, 1450, 1306, 1019, 757, 696 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.40–7.38 (m, 2 H, CH
Ar ), 7.34–7.32 (m, 3 H, CH
Ar ), 4.91 (q, J
HH = 6.8 Hz, 1 H, CH NCS), 1.68 (d, J
HH = 6.8 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 140.3 (s, C
Ar ), 132.5 (s, NC S), 129.0 (s, C
Ar H), 128.3 (s, C
Ar H), 125.5 (s, C
Ar H), 57.1 (s, C HNCS), 25.0 (s, C H3 ).
The analytical data are in agreement with those reported previously in the literature.[32 ]
(Isothiocyanatomethyl)benzene (4d)
(Isothiocyanatomethyl)benzene (4d)
Colorless oil. Yield: 0.247 g, 1.66 mmol (83%) after flash chromatography (hexane).
Purity determined by HPLC was 99%, gradient A, t
R = 17.73 min.
IR (ATR): 2163 (NCS), 2068 (NCS), 1495, 1453, 1345, 694 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.41–7.39 (m, 2 H, CH
Ar ), 7.36–7.34 (m, 1 H, CH
Ar ), 7.33–7.31 (m, 2 H, CH
Ar ), 4.71 (s, 2 H, CH
2 NCS).
13 C NMR (176 MHz, CDCl3 ): δ = 134.3 (s, C
Ar ), 132.4 (s, NC S), 129.0 (s, C
Ar H), 128.5 (s, C
Ar H), 126.9 (s, C
Ar H), 48.8 (s, C H2 NCS).
The analytical data are in agreement with those reported previously in the literature.[17b ]
[39 ]
2-Isothiocyanatooctane (4e)[40 ]
2-Isothiocyanatooctane (4e)[40 ]
Colorless oil. Yield: 0.320 g, 1.87 mmol (94%) after flash chromatography (pentane).
Purity determined by HPLC was 98%, gradient B, t
R = 31.18 min.
IR (ATR): 2083 (NCS), 1456, 1378, 1334 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.77–3.72 (m, 1 H, CH NCS), 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, J
HH = 6.5 Hz, 3 H, CH
3 CH), 1.32–1.25 (m, 6 H, 3 × CH
2 ), 0.89 (t, J
HH = 7.0 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.9 (s, NC S), 54.1 (s, C HNCS), 37.6 (s, C H2 ), 31.6 (s, C H2 ), 28.8 (s, C H3 CH), 26.0 (s, C H2 ), 22.6 (s, C H2 ), 21.8 (s, C H2 ), 14.1 (s, C H3 ).
EI-MS: m /z [M• ]+ calcd for C9 H17 NS: 171.1082; found: 171.1078.
3-Isothiocyanatopentane (4f)
3-Isothiocyanatopentane (4f)
Colorless oil. Yield: 0.211 g, 1.63 mmol (82%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 20.76 min.
IR (ATR): 2137 (NCS), 2088 (NCS), 2049 (NCS), 1458, 1346, 821 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.53–3.49 (m, 1 H, CH NCS), 1.66–1.61 (m, 4 H, 2 × CH
2 ), 1.02 (t, J
HH = 7.4 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.9 (s, NC S), 61.9 (s, C HNCS), 28.6 (s, 2 × C H2 ), 10.6 (s, 2 × C H3 ).
The analytical data are in agreement with those reported previously in the literature.[41 ]
1-Isothiocyanato-2-methylpropane (4g)[42 ]
1-Isothiocyanato-2-methylpropane (4g)[42 ]
Colorless oil. Yield: 0.166 g, 1.44 mmol (72%) after flash chromatography (pentane).
Purity determined by HPLC was 99%, gradient A, t
R = 17.48 min.
IR (ATR): 2170 (NCS), 2074 (NCS), 1466, 1444, 1343, 690 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.33 (d, J
HH = 6.2 Hz, 2 H, CH
2 NCS), 1.99 (sept, J
HH = 6.3 Hz, 1 H, CH ), 1.00 (t, J
HH = 6.7 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.8 (s, NC S), 52.5 (s, C H2 NCS), 29.7 (s, C H), 19.9 (s, 2 × C H3 ).
EI-MS: m /z [M• ]+ calcd for C5 H9 NS: 115.0456; found: 115.0454.
(3-Isothiocyanatopropyl)benzene (4h)
(3-Isothiocyanatopropyl)benzene (4h)
Colorless oil. Yield: 0.266 g, 1.5 mmol (75%) after flash chromatography (hexane).
Purity determined by HPLC was 100%, gradient A, t
R = 21.60 min.
IR (ATR): 2181 (NCS), 2084 (NCS), 1495, 1451, 1344, 743, 697 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.33–7.31 (m, 2 H, CH
Ar ), 7.24–7.22 (m, 1 H, CH
Ar ), 7.20–7.19 (m, 2 H, CH
Ar ), 3.50 (t, J
HH = 6.5 Hz, 2 H, CH
2 NCS), 2.77 (t, J
HH = 7.4 Hz, 2 H, CH
2 ), 2.02 (quin, J
HH = 7.0 Hz, 2 H, CH
2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 140.0 (s, C
Ar ), 130.5 (s, NC S), 128.7 (s, C
Ar H), 128.6 (s, C
Ar H), 126.5 (s, C
Ar H), 44.3 (s, C H2 NCS), 32.6 (s, C H2 ), 31.5 (s, C H2 ).
The analytical data are in agreement with those reported previously in the literature.[17b ]
1-Isothiocyanato-3-methylbutane (4i)
1-Isothiocyanato-3-methylbutane (4i)
Colorless oil. Yield: 0.204 g, 1.58 mmol (79%) after flash chromatography (pentane).
Purity determined by HPLC was 99%, gradient A, t
R = 20.43 min.
IR (ATR): 2173 (NCS), 2090 (NCS), 2064 (NCS), 1468, 1351, 1329 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.53 (t, J
HH = 6.8 Hz, 2 H, CH
2 NCS), 1.75 (sept, J
HH = 7.0 Hz, 1 H, CH ), 1.59 (q, J
HH = 6.9 Hz, 2 H, CH
2 ), 0.93 (d, J
HH = 6.7 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.7 (s, NC S), 43.4 (s, C H2 NCS), 38.6 (s, C H2 ), 25.5 (s, C H), 22.1 (s, 2 × C H3 ).
The analytical data are in agreement with those reported previously in the literature.[43 ]
1-Isothiocyanatobutane (4j)
1-Isothiocyanatobutane (4j)
Colorless oil. Yield: 0.17 g, 1.48 mmol (74%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 17.72 min.
IR (ATR): 2173 (NCS), 2127 (NCS), 2089 (NCS), 1510, 1345, 771 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.51 (t, J
HH = 6.6 Hz, 2 H, CH
2 NCS), 1.67 (quin, J
HH = 7.7 Hz, 2 H, CH
2 ), 1.45 (sext, J
HH = 7.7 Hz, 2 H, CH
2 ), 0.94 (t, J
HH = 7.4 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.7 (s, NC S), 44.8 (s, C H2 NCS), 32.0 (s, C H2 ), 19.8 (s, C H2 ), 13.3 (s, C H3 ).
The analytical data are in agreement with those reported previously in the literature.[44 ]
1-Isothiocyanato-1-methylcyclohexane (4k)[45 ]
1-Isothiocyanato-1-methylcyclohexane (4k)[45 ]
Colorless oil. Yield: 0.169 g, 1.09 mmol (55%) after flash chromatography (pentane).
Purity determined by HPLC was 99%, gradient A, t
R = 25.27 min.
IR (ATR): 2077 (NCS), 2039 (NCS), 1447, 1258, 1165, 951, 771 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 1.89–1.86 (m, 2 H, CH
2 ), 1.70–1.66 (m, 1 H, H from CH2 ), 1.63–1.55 (m, 4 H, 2 × CH
2 ), 1.41–1.37 (m, 2 H, CH
2 ), 1.37 (s, 3 H, CH
3 ), 1.21–1.15 (m, 1 H, H from CH2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 130.0 (s, NC S), 61.8 (s, C NCS), 39.1 (s, 2 × C H2 ), 29.7 (s, C H3 ), 25.0 (s, C H2 ), 22.4 (s, 2 × C H2 ).
EI-MS: m /z [M• ]+ calcd for C8 H13 NS: 155.0769; found: 155.0776.
3-Isothiocyanato-3-methylpentane (4l)
3-Isothiocyanato-3-methylpentane (4l)
Colorless oil. Yield: 0.128 g, 0.89 mmol (45%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 23.68 min.
IR (ATR): 2075 (NCS), 1458, 1176, 819 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 1.71–1.66 (m, 2 H, CH
2 ), 1.61–1.56 (m, 2 H, CH
2 ), 1.31 (s, 3 H, CCH
3 ), 0.98 (t, J
HH = 7.4 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 129.8 (s, NC S), 65.2 (s, C ), 33.0 (s, 2 × C H2 ), 25.2 (s, C H3 ), 8.5 (s, 2 × C H3 ).
EI-MS: m /z [M• ]+ calcd for C7 H13 NS: 143.0769; found: 143.0770.
3-Isothiocyanatoprop-1-ene (4m)
3-Isothiocyanatoprop-1-ene (4m)
Colorless oil. Yield: 0.08 g, 0.81 mmol (41%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 14.55 min.
IR (ATR): 2164 (NCS), 2083 (NCS), 1435, 1416, 1341, 1324, 986, 920 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 5.84 (ddt, J
HaHc = 16.9 Hz, J
HaHb = 10.0 Hz, J
HaHde = 4.9 Hz, 1 H, CH
a ), 5.40 (dtd, J
HcHa = 16.9 Hz, J
HcHde = 1.8 Hz, J
HcHb = 0.5 Hz, 1 H, CH
c ), 5.28 (dtd, J
HbHa = 10.2 Hz, J
HbHde = 1.6 Hz, J
HbHc = 0.6 Hz, 1 H, CH
b ), 4.14 (dt, J
HdeHa = 4.9 Hz, J
HdeHa,Hb = 1.7 Hz, 2 H, CH
de NCS). For protons (a–e) labeling see Supporting Information.
13 C NMR (176 MHz, CDCl3 ): δ = 132.4 (s, NC S), 130.4 (s, C H), 117.7 (s, C H2 =CH), 47.2 (s, C H2 NCS).
The analytical data are in agreement with those reported previously in the literature.[46 ]
Isothiocyanatobenzene (4n)
Isothiocyanatobenzene (4n)
Colorless oil. Yield: 0.248 g, 1.83 mmol (92%) after flash chromatography (pentane).
Purity determined by HPLC was 99%, gradient A, t
R = 20.45 min.
IR (ATR): 2169 (NCS), 2030 (NCS), 2019 (NCS), 1589, 1451, 924, 745, 680 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.36–7.34 (m, 2 H, CH
Ar ), 7.29–7.27 (m, 1 H, CH
Ar ), 7.23–7.22 (m, 2 H, CH
Ar ).
13 C NMR (176 MHz, CDCl3 ): δ = 135.5 (s, NC S), 131.4 (s, C
Ar NCS), 129.6 (s, C
Ar H), 127.4 (s, C
Ar H), 125.8 (s, C
Ar H).
The analytical data are in agreement with those reported previously in the literature.[17b ]
1-Isothiocyanato-4-methoxybenzene (4o)
1-Isothiocyanato-4-methoxybenzene (4o)
Colorless oil. Yield: 0.270 g, 1.64 mmol (82%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 19.68 min
IR (ATR): 2174 (NCS), 2035 (NCS), 1580, 1499, 1459, 1243, 926, 826 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.16 (d, J
HH = 9.1 Hz, 2 H, CH
Ar ), 6.85 (d, J
HH = 9.1 Hz, 2 H, CH
Ar ), 3.80 (s, 3 H, CH
3 O).
13 C NMR (176 MHz, CDCl3 ): δ = 158.7 (s, C
Ar OCH3 ), 134.1 (s, NC S), 127.1 (s, C
Ar H), 123.7 (s, C
Ar NCS), 114.9 (s, C
Ar H), 55.6 (s, C H3 O).
The analytical data are in agreement with those reported previously in the literature.[17b ]
1-Fluoro-4-isothiocyanatobenzene (4p)
1-Fluoro-4-isothiocyanatobenzene (4p)
Colorless oil. Yield: 0.219 g, 1.43 mmol (72%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient A, t
R = 19.65 min.
IR (ATR): 2187 (NCS), 2029 (NCS), 1497, 1250, 930, 830 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.22–7.20 (m, 2 H, CH
Ar ), 7.05–7.03 (m, 2 H, CH
Ar ).
13 C NMR (176 MHz, CDCl3 ): δ = 161.3 (d, J
CF = 249.2 Hz, C
Ar F), 136.2 (s, NC S), 127.6 (s, C
Ar NCS), 127.5 (d, J
CF = 8.8 Hz, C
Ar H), 116.8 (d, J
CF = 23.3 Hz, C
Ar H).
The analytical data are in agreement with those reported previously in the literature.[17b ]
1,6-Diisothiocyanatohexane (4q)
1,6-Diisothiocyanatohexane (4q)
Colorless oil. Yield: 0.240 g, 1.2 mmol (60%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient B, t
R = 22.06 min.
IR (ATR): 2179 (NCS), 2071 (NCS), 1448, 1344 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.53 (t, J
HH = 6.5 Hz, 4 H, 2 × CH
2 NCS), 1.74–1.70 (m, 4 H, 2 × CH
2 ), 1.48–1.45 (m, 4 H, 2 × CH
2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 130.1 (s, NC S), 45.0 (s, 2 × C H2 NCS), 29.8 (s, 2 × C H2 ), 25.9 (s, 2 × C H2 ).
The analytical data are in agreement with those reported previously in the literature.[47 ]
tert -Butyl (2-Isothiocyanatoethyl)carbamate (4r)
tert -Butyl (2-Isothiocyanatoethyl)carbamate (4r)
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 determined by HPLC was 98%, gradient D, t
R = 4.91 min.
IR (ATR): 2193 (NCS), 2096 (NCS), 1688 (CO), 1528, 1436, 1278, 1165 cm–1 .
1 H NMR (250 MHz, CDCl3 ): δ = 4.88 (br s, 1 H, NH ), 3.64 (t, J
HH = 5.6 Hz, 2 H, CH
2 NCS), 3.37 (q, J
HH = 5.9 Hz, 2 H, CH
2 NH), 1.45 [s, 9 H, (CH
3 )3 ].
13 C NMR (176 MHz, CDCl3 ): δ = 155.7 (s, C O), 132.4 (s, NC S), 80.2 [s, C (CH3 )3 ], 45.5 (s, C H2 ), 40.7 (s, C H2 ), 28.4 [s, (C H3 )3 ].
The analytical data are in agreement with those reported previously in the literature.[48 ]
1-Bromo-6-isothiocyanatohexane (4s)[49 ]
1-Bromo-6-isothiocyanatohexane (4s)[49 ]
Colorless oil. Yield: 0.244 g, 1.1 mmol (55%) after flash chromatography (pentane).
Purity determined by HPLC was 100%, gradient B, t
R = 22.29 min.
IR (ATR): 2180 (NCS), 2082 (NCS), 1451, 1345 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 3.52 (t, J
HH = 6.6 Hz, 2 H, CH
2 NCS), 3.41 (t, J
HH = 6.7 Hz, 2 H, CH
2 Br), 1.90–1.86 (m, 2 H, CH
2 ), 1.73–1.69 (m, 2 H, CH
2 ), 1.51–1.43 (m, 4 H, 2 × CH
2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 130.1 (s, NC S), 45.1 (s, C H2 NCS), 33.6 (s, C H2 ), 32.5 (s, C H2 ), 29.9 (s, C H2 ), 27.4 (s, C H2 ), 25.8 (s, C H2 ).
EI-MS: m /z [M• ]+ calcd for C7 H12 BrNS: 220.9874; found: 220.9884.
Diethyl (2-Isothiocyanatoheptyl)phosphonate (4t)
Diethyl (2-Isothiocyanatoheptyl)phosphonate (4t)
Colorless oil. Yield: 0.366 g, 1.25 mmol (63%) after flash chromatography (hexane/EtOAc,
3:2). Purity determined by HPLC was 97%, gradient C, t
R = 5.11 min.
IR (ATR): 2078 (NCS), 1239, 1050, 1021 (P–O–C), 959 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 4.19–4.08 (m, 4 H, 2 × CH
2 O), 4.05–4.00 (m, 1 H, CH ), 2.15–2.09 (m, 1 H, H
α from PCH2 ), 2.01–1.96 (m, 1 H, H
β from PCH2 ), 1.74–1.70 (m, 2 H, CH
2 ), 1.52–1.46 (m, 1 H, H
α from CH2 ), 1.43–1.37 (m, 1 H, H
β from CH2 ), 1.35 (t, J
HH = 7.0 Hz, 3 H, CH
3 CH2 O), 1.34 (t, J
HH = 7.0 Hz, 3 H, CH
3 CH2 O), 1.33–1.26 (m, 4 H, 2 × CH
2 ), 0.89 (t, J
HH = 7.1 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 131.8 (s, NC S), 62.2 (d, J
CP = 6.5 Hz, C H2 O), 62.1 (d, J
CP = 6.5 Hz, C H2 O), 53.3 [s, C (2)H], 37.2 [d, J
CP = 11.2 Hz, C (3)H2 ], 35.5 [d, J
CP = 142.5 Hz, PC (1)H2 ], 31.1 (s, C H2 ), 25.4 (s, C H2 ), 22.4 (s, C H2 ), 16.5 (2 × d, J
CP = 5.5 Hz, 2 × C H3 CH2 O), 14.0 (s, C H3 ).
31 P NMR (283 MHz, CDCl3 ): δ = 25.64.
ESI–MS: m /z [M + Na]+ calcd for C12 H24 NNaO3 PS: 316.1107; found: 316.1111.
Diethyl (3-Cyclohexyl-2-isothiocyanatopropyl)phosphonate (4u)
Diethyl (3-Cyclohexyl-2-isothiocyanatopropyl)phosphonate (4u)
Yellow oil. Yield: 0.338 g, 1.06 mmol (53%) after flash chromatography (hexane/EtOAc,
3:2). Purity determined by HPLC was 97%, gradient C, t
R = 4.28 min.
IR (ATR): 2082 (NCS), 1248, 1051, 1021 (P–O–C), 960 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 4.18–4.07 (m, 5 H, 2 × CH
2 O, CH NCS), 2.13–2.08 (m, 1 H, H
α from PCH2 ), 1.99–1.94 (m, 1 H, H
β from PCH2 ), 1.80–1.75 (m, 1 H, H
α from CH2 ), 1.72–1.63 (m, 5 H, 5 × H
α from CH2 ), 1.52–1.45 (m, 2 H, H
β from CH2 , CH ), 1.35 (t, 3 H, J
HH = 6.9 Hz, CH
3 ), 1.34 (t, 3 H, J
HH = 6.9 Hz, CH
3 ), 1.30–1.22 (m, 2 H, 2 × H
β from CH2 ), 1.17–1.11 (m, 1 H, H
β from CH2 ), 0.98–0.93 (m, 1 H, H
β from CH2 ), 0.90–0.84 (m, 1 H, H
β from CH2 ).
13 C NMR (176 MHz, CDCl3 ): δ = 131.7 (s, NC S), 62.3 (d, J
CP = 6.7 Hz, C H2 O), 62.2 (d, J
CP = 6.4 Hz, C H2 O), 51.0 (s, C HNCS), 45.0 (d, J
CP = 10.8 Hz, C H2 ), 34.5 (s, C H), 33.6 (s, C H2 ), 33.1 (d, J
CP = 142.6 Hz, PC H2 ), 32.1 (s, C H2 ), 26.4 (s, C H2 ), 26.2 (s, C H2 ), 25.9 (s, C H2 ), 16.6 (d, J
CP = 6.1 Hz, C H3 ), 16.5 (d, J
CP = 6.1 Hz, C H3 ).
31 P NMR (283 MHz, CDCl3 ): δ = 25.59.
ESI-MS: m /z [M + Na]+ calcd for C14 H26 NNaO3 PS: 342.1263; found: 342.1269.
Diethyl [Isothiocyanato(4-methoxyphenyl)methyl]phosphonate (4v)
Diethyl [Isothiocyanato(4-methoxyphenyl)methyl]phosphonate (4v)
Yellow oil. Yield: 0.321 g, 1.02 mmol (51%) after flash chromatography (hexane/EtOAc,
7:4). Purity determined by HPLC was 97%, gradient C, t
R = 3.44 min.
IR (ATR): 2188 (NCS), 2044 (NCS), 1511, 1305, 1012 (P–O–C), 969 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.35 (dd, J
HH = 8.5 Hz, J
HP = 2.2 Hz, 2 H, 2 × CH
Ar ), 6.91 (d, J
HH = 8.5 Hz, 2 H, 2 × CH
Ar ), 4.93 (d, J
HP = 18.9 Hz, 1 H, PCH NCS), 4.14–3.99 (m, 4 H, 2 × CH
2 O), 3.81 (s, 3 H, CH
3 O), 1.28 (2 × td, J
HH = 7.1 Hz, J
HP = 3.1 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 160.1 (d, J
CP = 2.4 Hz, C
Ar OMe), 137.1 (s, NC S), 128.8 (d, J
CP = 5.2 Hz, 2 × C
Ar H), 123.8 (d, J
CP = 4.9 Hz, C
Ar ), 114.3 (d, J
CP = 2.1 Hz, 2 × C
Ar H), 64.3 (d, J
CP = 6.7 Hz, C H2 O), 63.9 (d, J
CP = 6.6 Hz, C H2 O), 57.5 (d, J
CP = 152.2 Hz, PC HNCS), 55.4 (d, J
CP = 2.0 Hz, C H3 O), 16.6 (d, J
CP = 5.2 Hz, C H3 ), 16.5 (d, J
CP = 5.2 Hz, C H3 ).
31 P NMR (283 MHz, CDCl3 ): δ = 15.62.
The analytical data are in agreement with those reported previously in the literature.[10a ]
Diethyl (Isothiocyanatomethyl)phosphonate (4w)
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, t
R = 2.19 min.
IR (ATR): 2224 (NCS), 2071 (NCS), 1243, 1014 (P–O–C), 971 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 4.25–4.21 (m, 4 H, 2 × CH
2 O), 3.78 (d, J
HP = 14.0 Hz, 2 H, PCH
2 NCS), 1.39 (t, J
HP = 7.1 Hz, 6 H, 2 × CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 135.8 (s, NC S), 63.5 (d, J
CP = 6.5 Hz, 2 × C H2 O), 40.5 (d, J
CP = 154.0 Hz, PC H2 NCS), 16.5 Hz (d, J
CP = 5.6 Hz, 2 × C H3 ).
31 P NMR (283 MHz, CDCl3 ): δ = 15.90.
The analytical data are in agreement with those reported previously in the literature.[10a ]
(S )-Methyl 2-Isothiocyanato-3-phenylpropanoate (4x)
(S )-Methyl 2-Isothiocyanato-3-phenylpropanoate (4x)
Colorless oil. Yield: 0.319 g, 1.44 mmol (72%) after flash chromatography (hexane/EtOAc,
20:1). Purity determined by HPLC was 98%, gradient D, t
R = 13.05 min.
The er was determined by HPLC using a Chiralpak IF column (hexane/i -PrOH, 99:1); t
major = 8.08 min, t
minor = 7.38 min (98.5:1.5 er).
[α]D
25 –62.2 (c 1.0, toluene) [Lit.[16d ] [α]D
20 –60.0 (c 1.0, toluene)].
IR (ATR): 2189 (NCS), 2088 (NCS), 1600 (CO), 1484, 1253, 1117, 964 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 7.35–7.33 (m, 2 H, CH
Ar ), 7.31–7.29 (m, 1 H, CH
Ar ), 7.23–7.22 (m, 2 H, CH
Ar ), 4.48 (dd, J
HaHb = 8.4 Hz, J
HaHc = 4.8 Hz, 1 H, CHa
NCS), 3.79 (s, 3 H, CH
3 O), 3.25 (dd, J
HcHb = 13.8 Hz, J
HcHa = 4.7 Hz, 1 H, CHc
Ph), 3.13 (dd, J
HbHc = 13.8 Hz, J
HbHa = 8.4 Hz, 1 H, CHb
Ph).
13 C NMR (176 MHz, CDCl3 ): δ = 168.4 (s, C O), 138.1 (s, NC S), 135.1 (s, C
Ar ), 129.4 (s, C
Ar H), 128.8 (s, C
Ar H), 127.7 (s, C
Ar H), 60.8 (s, C H3 O), 53.2 (s, C HNCS), 39.8 (s, C H2 ).
The analytical data are in agreement with those reported previously in the literature.[16d ]
(S )-Methyl 2-Isothiocyanatopropanoate (4y)
(S )-Methyl 2-Isothiocyanatopropanoate (4y)
Colorless oil. Yield: 0.185 g, 1.27 mmol (63%) after flash chromatography (hexane/EtOAc,
20:1). Purity determined by HPLC was 100%, gradient A, t
R = 13.25 min.
The er was determined by HPLC using a Chiralpak IC column (hexane/i -PrOH, 98:2); t
major = 7.02 min, t
minor = 6.77 min (>99.9:0.1 er).
[α]D
25 +25.8 (c 0.32, CHCl3 ) [Lit.[11c ] [α]D
20 +23.4 (c 0.32, CHCl3 )].
IR (ATR): 2042 (NCS), 1744 (CO), 1450, 1435, 1288, 1207, 1149, 1053 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 4.35 (q, J
HH = 7.1 Hz, 1 H, CH NCS), 3.81 (s, 3 H, CH
3 O), 1.60 (d, J
HH = 7.1 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 169.5 (s, C O), 137.5 (s, NC S), 54.9 (s, C H3 O), 53.3 (s, C HNCS), 19.6 (s, C H3 ).
The analytical data are in agreement with those reported previously in the literature.[11c ]
[50 ]
(R )-Methyl 2-Isothiocyanatopropanoate (4z)[11c ]
[33 ]
(R )-Methyl 2-Isothiocyanatopropanoate (4z)[11c ]
[33 ]
Colorless oil. Yield: 0.180 g, 1.24 mmol (62%) after flash chromatography (hexane/EtOAc,
20:1). Purity determined by HPLC was 100%, gradient D, t
R = 9.05 min.
The er was determined by HPLC using a Chiralpak IC column (hexane/i -PrOH, 98:2); t
major = 6.78 min, t
minor = 7.06 min (>99.9:0.1 er).
[α]D
25 –22.8 (c 0.32, CHCl3 ) [Lit.[11c ] [α]D
25 –23.9 (c 0.3, CHCl3 )].
IR (ATR): 2050 (NCS), 1745 (CO), 1455, 1436, 1288, 1208, 1150, 1053 cm–1 .
1 H NMR (700 MHz, CDCl3 ): δ = 4.35 (q, J
HH = 7.1 Hz, 1 H, CH NCS), 3.79 (s, 3 H, CH
3 O), 1.58 (d, J
HH = 7.1 Hz, 3 H, CH
3 ).
13 C NMR (176 MHz, CDCl3 ): δ = 169.5 (s, C O), 137.5 (s, NC S), 54.9 (s, C H3 O), 53.3 (s, C HNCS), 19.6 (s, C H3 ).
EI-MS: m /z [M• ]+ calcd for C5 H7 NO2 S: 145.0198: found: 145.0195.
(2-Isothiocyanatoethyl)benzene (4a); Method B
(2-Isothiocyanatoethyl)benzene (4a); Method B
Et3 N (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 procedure
described in Method A.
(2-Isothiocyanatoethyl)benzene (4a); Method C
(2-Isothiocyanatoethyl)benzene (4a); Method C
Et3 N (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 magnetic
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 colorless oil in 83% yield following the work-up procedure
described in Method A.
