A more sustainable isothiocyanate synthesis by amine catalyzed sulfurization of isocyanides with elemental sulfur

Article abstract of DOI:10.1039/d0ra10436a

Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its derivatives, or CS2. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides, elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was optimized in terms of sustainability, especially considering benign solvents such as Cyrene or γ-butyrolactone (GBL) under moderate heating (40 °C). Purification by column chromatography was further optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989 were achieved and the versatility of this straightforward procedure was shown by converting 20 different isocyanides under catalytic conditions, while obtaining moderate to high yields (34-95%). This journal is

Full text of DOI:10.1039/d0ra10436a

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A more sustainable isothiocyanate synthesis by
amine catalyzed sulfurization of isocyanides with
elemental sulfur†
Cite this: RSC Adv., 2021, 11, 3134
a
a
ab
P. Conen,a S. M. Gabrielsen
and M. A. R. Meier
*
R. Nickisch,
Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its
derivatives, or CS2. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides,
elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and
catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was
optimized in terms of sustainability, especially considering benign solvents such as Cyrene™ or g-
butyrolactone (GBL) under moderate heating (40 ꢀC). Purification by column chromatography was further
optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989
were achieved and the versatility of this straightforward procedure was shown by converting 20 different
isocyanides under catalytic conditions, while obtaining moderate to high yields (34–95%).
Received 11th December 2020
Accepted 7th January 2021
DOI: 10.1039/d0ra10436a
rsc.li/rsc-advances
As chemists, we should avoid such problematic functional
groups and their synthesis whenever possible, but we cannot
stop using these important functional groups completely. Thus,
Introduction
Isothiocyanates (ITCs) are widely used in heterocycle1–10 and
thiourea synthesis11–13 as well as for medicinal and biochemistry
applications (e.g. in the Edman degradation14,15 for amino acid
sequencing of peptides or as electrophiles in bioconjugates).16–23
Several representatives of this group are known to exhibit bio-
logical activity,24 e.g. anti-cancer,25–33 anti-inammatory,34–38 anti-
microbial,39 antibiotic,39 antibacterial,40 fungicidal41 or insecti-
cidal activity.42,43 Commonly, they are synthesized by using thi-
onyl transfer agents (thiophosgene, its derivatives,2,44–48 or, more
recently, uorinated agents)49–54 or via the formation of dithio-
carbamate salts with carbon disulde under basic conditions,
followed by desulfurization (Scheme 1a).44,55–57 These approaches
are usually chosen due to the easy access of the respective
amines, which can be transferred quickly to the ITC in one or two
steps. However, these reagents are highly toxic (thiophosgene
and carbon disulde, the latter additionally being volatile) and
their synthesis typically involves noxious compounds (i.e.
considering the synthesis of thiophosgene, perchloromethyl
mercaptan,58 chlorine and carbon disulde are used).59 Moreover,
ITCs are in general noxious compounds (GHS05 and GHS08) and
must be handled with care.
applying in situ approaches to minimize their risks is a typical
aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Straße
am Forum 7, 76131 Karlsruhe, Germany. E-mail: m.a.r.meier@kit.edu; Web: http://
www.meier-michael.com
bInstitute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-
FMS), Karlsruhe Institute of Technology (KIT), Straße am Forum 7, 76131
Karlsruhe, Germany
Scheme
1 Overview of reported synthesis protocols towards
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra10436a
isothiocyanates.
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Scheme 2 Possible mechanistic pathway of the MCR between isocyanide (black), elemental sulfur (purple) and an amine (blue), whereby the
amine acts as reactant as well as catalyst to form polysulfur chains A. Applying primary or secondary amines leads to thioureas, while tertiary
amines lead to isothiocyanates B.
strategy, but only applicable if such compounds can be used as required reagents and a waste product of the industrial
intermediates. Here, we focused our work on a more sustain- saccharin synthesis.79,80 With this in hand, we had all tools we
able synthesis route toward ITCs by considerably reducing the need to pursue the synthesis of ITCs via isocyanides in a more
toxicological impact of the used synthesis reagents as well as sustainable fashion (Scheme 1c).
´
´
In 2019, Abranyi-Balogh and co-workers reported on
minimizing the amount of waste (E-factor), two very important
aspects in terms of overall sustainability. The above described a mechanistic investigation of a MCR between isocyanides,
inherent toxicity of the ITC functional group does of course elemental sulfur and alcohols or thiols under basic conditions
remain unchanged and thus, these compounds have to be (sodium hydride, 2.00 eq.), obtaining (di)thio carbamates. They
handled with caution. Besides the aforementioned synthesis showed that ITCs are intermediates in this reaction, which
starting from amines, several other functional groups2,44,45,60–62 could be isolated in excellent yields for one compound (2,6-
can be converted to ITCs, of which isocyanides, commonly used dimethylphenyl isothiocyanate).81 In an earlier work from Al-
in multicomponent reactions (MCRs),63–65 are particularly Mourabit and co-workers, a similar MCR was reported82 using
interesting as they are generally less toxic.63 The sulfurization of primary or secondary amines instead of alcohols, leading to
isocyanides with elemental sulfur was previously reported in thioureas.
literature for a few compounds,66,67 however this reaction was
This strategy was later on applied for the synthesis of orga-
reported to proceed only at high temperatures (80 C and 130 nocatalysts.83 In this previous work, ITCs were not conrmed as
ꢀC)66,67 and thus, several catalysts have since been reported to intermediates, but hypothesized as one possibility of three
allow milder reaction conditions (Scheme 1b). Most commonly, postulated pathways. In this reaction, no external base was
selenium68–70 (or tellurium)71,72 in the presence of an amine base required, as an excess of amine (1.20 eq.) was suggested to
efficiently catalyzes the formation of ITCs even at room catalyze the reaction sufficiently. The then postulated mecha-
temperature. Employing several metal catalysts (i.e. molyb- nistic pathway, involving the ITC intermediate for this MCR
denum and rhodium based) led to excellent yields as well.73,74 (Scheme 2), entails the nucleophilic attack of an amine to the
However, selenium and tellurium are highly toxic, and thus we sulfur ring, thus forming polysulfur chains, which then attack
sought to investigate the use of sulfur as suitable sulfurization the isocyanide to yield an ITCs aer eliminating a Sxꢁ1 sulfur
agent and simultaneously avoiding the use of toxic metal cata- chain. Since primary or secondary amines were used, the
lyst in this approach. The use of elemental sulfur is highly possibly present ITC intermediate was immediately converted
desired considering the current storage issues of millions of to the respective thiourea. Thus, we hypothesized that the use of
tons of sulfur produced as waste product from the petroleum tertiary amines would prevent further reaction of the ITC and
industry (almost 80 million metric tons in 2019)75 due to safety thus allow a catalytic synthesis of ITCs.
ꢀ
reasons76 as well as acidication of soil and water.77 Further-
We thus started investigating the use of tertiary amines as
more of importance for the herein described new approach, we organocatalysts for the sulfurization of isocyanides to yield ITCs
recently reported a more sustainable synthesis of non-sterically in a more sustainable fashion. We further optimized the reac-
demanding aliphatic isocyanides,78 avoiding toxic compounds tion conditions (temperature, solvent, stoichiometry) as well as
such as phosgene, its derivatives or POCl3. This reaction relies the purication (normally ash column chromatography) to
on p-toluenesulfonyl chloride, which is less toxic than otherwise minimize the resulting E-factor by maintaining high purity.
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present is doubled compared to the other bases, which might
lead to higher conversions in this case. These results show that
not only basicity denes the reactivity of the applied amine
base, albeit a certain degree of basicity is certainly crucial to
activate elemental sulfur.
In a second step, we sought to apply the two best performing
amines, i.e. DBU and TBD, in a sub-stoichiometric/catalytic
amount, as no side products were detected, while monitoring
the reaction with GC (Table 1, entries 7–10). As a highly
remarkable result, 10 mol% of DBU or TBD were able to convert
isocyanide 1a aer 22 hours at room temperature with high
conversion (67% or 69%, respectively) and the corresponding
ITC 3a was obtained. DBU showed better results, i.e. 57%
conversion aer only two hours, compared to 36% conversion
for TBD aer the same time.
Results and discussion
Mechanistic investigation of sulfur activation
We initially evaluated the reactivity of various amines in the
reaction of a model isocyanide (n-dodecyl isocyanide 1a) with
elemental sulfur by reacting them in stoichiometric amounts in
a suspension of DMSO, while monitoring the formation of the
respective ITC 3a (Table 1, entries 1–6). In every case, the instant
formation of the polysulfur chains was visible, since the reac-
tion mixture turned dark brown (same color change was
observed in literature)84,85 as soon as the base was added. As the
reaction proceeded, the consumption of the suspended sulfur
was also visually observed. GC monitoring of the test reactions
revealed that equimolar amounts 1,8-diazabicyclo[5.4.0]undec-
7-en (DBU) or 1,5,7-triazabicyclo[4.4.0]dec-5-en (TBD) led to
quantitative conversion aer 2 hours of reaction time (Table 1,
entries 3 and 6, respectively). Nucleophilic aromatic amines,
like N,N-dimethylamino pyridine (DMAP) and N-methyl imid-
azole (NMI), were less efficient, both resulting in 38% of
conversion, which was attributed to their lower basicity. In
general, steric hindrance was deemed less important for the
formation of the polysulfur chains, since the conversion of
isocyanide 1a observed using the sterically hindered triethyl-
amine (TEA) and 1,4-diazabicyclo[2.2.2]octane (DABCO) were
also high, 76% and 84%, respectively.
Optimization of the reaction conditions
Having identied two amine bases (TBD and DBU) that can be
applied in substoichiometric amounts, we optimized the reac-
tion conditions addressing as many of the Twelve Principles of
Green Chemistry90 as possible and further minimized the E-
factor91 (not yet taking the purication steps into account).
Initially, when screening the reaction temperature, higher
conversions were obtained at higher temperatures, but in the
context of sustainability a less energy-consuming procedure is
desired and we thus considered moderate temperatures (40 ꢀC)
for further experiments. Next, we altered the solvents focusing
on greener alternatives for commonly used solvents according
to solvent selection guides92–94 (for the complete screening,
please see the ESI†). A clear trend was observed, i.e. polar
aprotic solvents like DMSO, GBL and Cyrene™ (dihy-
drolevoglucosenone) favored product formation, probably due
to their ability to dissolve and stabilize polysulfur chains.
Taking into account the basicity of the evaluated amines
(Table 1, entries 1–6), it was noted that the most basic amine
(TBD) led to the highest conversion, which is consistent with
previous reports in which elemental sulfur was activated by
strong bases like NaH81 or K2CO3.85 However, DABCO, exhibit-
ing the second lowest pKa-value, also showed good perfor-
mance. Assuming both tertiary amine groups of DABCO are able
to activate sulfur in this reaction, the amount of active groups
Table 1 GC-screening of various amine bases (bold) for the activation of elemental sulfur, leading to the formation of n-dodecylisothiocyanate
3a
Entry
Amine (pKa-value in H2O)
Eq. of amine base
Reaction time/h
Conversiona/%
1
2
3
4
5
6
7
8
9
10
DMAP (9.2)86
NMI (7.1)87
DBU (11.5)86
DABCO (8.9)86
TEA (10.7)88
TBD (14.5)89
DBU
DBU
TBD
TBD
1.00
1.00
1.00
1.00
1.00
1.00
0.10
0.10
0.10
0.10
2
2
2
2
2
2
2
22
2
22
38
38
99
84
76
100
57
67
36
69
a
1 mmol of n-dodecyl isocyanide 1a was reacted with elemental sulfur (2.00 eq. of sulfur atoms) and the respective amount of amine in 1 mL of
DMSO at room temperature (r.t.). GC samples were taken aer the respective time and conversions were calculated using biphenyl (0.25 eq.) as
internal standard (IS).
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Table 2 Optimization of reaction conditions (concentration) for the
sulfurization of isocyanide 1a via GC-screening to decrease the E-
factor
To decrease both reaction time and waste, we increased the
concentration of isocyanide 1a up to 6 M in Cyrene™ (Table 2,
entries 2–4), which was the upper limit due to practical reasons
(since elemental sulfur was only partially dissolved at the
beginning of the reaction, a certain amount of solvent was
needed to facilitate stirring). Thus, the E-factor could be
reduced to 1.12 maintaining full conversion aer 30 minutes
(Table 2, entry 4). Furthermore, we decreased the excess of
elemental sulfur to 1.12 eq. of sulfur atoms, while maintaining
high conversion (98% aer 30 minutes). Since 10 mol% of
catalyst performed excellent under the optimized conditions,
we then evaluated lower catalyst loadings of DBU (Table 3),
since (i) higher conversions in less amount of time were ob-
tained in prior tests and (ii) the stirring of the reaction is
facilitated by DBU being a liquid.
Entry
Solvent
Concentrationa/M
Conversionb/%
E-Factorc
1
2
3
3
4
—
—
6.7
85
99
100
100
16.9
5.71
2.95
1.58
1.12
Cyrene™
Cyrene™
Cyrene™
Cyrene™
1.0
2.0
4.0
6.0
a
b
Concentration of isocyanide 1a in the solvent. 1.00 mmol of n-
dodecylisocyanide 1 was reacted with elemental sulfur (2.00 eq. of
We note however that the toxicity of DBU is higher compared
sulfur atoms) and TBD (10 mol%) in the Cyrene™ at 40 ꢀC. GC- to TBD (DBU is labeled with GHS05, while TBD is labelled as
samples were taken aer 30 minutes of reaction time and conversions
were calculated using biphenyl (0.25 eq.) as IS. E-Factor was
GHS07). As a result of the high concentration of isocyanide 1a in
the solvent (6 M), the catalyst loading of DBU could be further
c
calculated assuming conversion equals the yield, as no side-reaction
were observed, not taking the purication steps into account.
reduced to 1 mol% while still achieving nearly quantitative
conversion aer prolonged reaction times of 20 hours. Using
2 mol% of DBU at the same concentration of 1a resulted in
complete conversion aer only four hours. For more diluted
reaction mixtures (c(isocyanide) ¼ 2 M), the amount of DBU had
to be increased to 5 mol% to obtain full conversion aer four
hours, which is still a low catalyst-loading. The nal optimized
reaction conditions are depicted in Scheme 3. We note that
when a liquid isocyanide was used, the conditions were 2 mol%
of DBU in 6 M Cyrene™ solution, while for solid isocyanides
5 mol% of DBU in 2 M Cyrene™ was used, predominantly to
facilitate stirring.
Amongst them, Cyrene™ allowed full conversion of isocyanide
1a aer two hours reaction time, while GBL and DMSO also led
to high conversions (92 and 85%, respectively). Both GBL and
Cyrene™ are greener alternatives if compared to DMSO and are
synthesized from renewable resources (butane-1,4-diol95 and
cellulose,96 respectively), thus decreasing the overall environ-
mental impact. However, more volatile compounds would allow
an easier removal and recycling of the solvent. Among the more
volatile and sustainable solvents, only acetone was able to
achieve good, yet lower conversions (69%). The contribution of
the solvent for the proceeding of this reaction was further
underpinned by testing the reaction in absence of any solvent,
resulting in a low conversion of ꢂ8% aer 30 minutes (Table 2,
entry 1).
Evaluating the scope of the sulfurization of isocyanides
Having the optimized reaction conditions in hand, we synthe-
sized several mono- and diisothiocyanates to evaluate the
substrate scope of our new procedure (Scheme 3). Aliphatic,
Table 3 Optimization of reaction conditions (catalyst loading of DBU, bold) for the sulfurization of isocyanide 1a via GC-screening
Entry
Catalysts loading/mol%
Concentrationa/M
Reaction time/h
Conversionb/%
1
2
3
4
5
6
7
5
5
2
2
2
1
1
2.0
2.0
2.0
2.0
6.0
6.0
6.0
0.5
4
0.5
20
4
59
100
29
99
100
78
4
20
96
a
Concentration of isocyanide 1a in Cyrene™. b 1.00 mmol of n-dodecylisocyanide 1 was reacted with elemental sulfur (1.12 eq. of sulfur atoms) and
DBU (respective amount) in Cyrene™ at 40 ꢀC. GC-samples were taken aer the respective time and conversions were calculated using biphenyl
(0.25 eq.) as IS.
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Scheme 3 Herein synthesized ITCs 3a–3t using the new procedure in a 2.5 mmol scale using elemental sulfur (1.12 eq. of sulfur atoms). If the
isocyanide was a liquid at 40 ꢀC, 2 mol% DBU and 417 mL solvent was used, if it was a solid, 5 mol% DBU and 1.25 mL solvent were used. For each
compound, the yield and the reaction time are displayed. The first line corresponds to the reaction using Cyrene™ as solvent, the second line
using GBL. The third line displays the reaction in Cyrene™ in a 15.5 mmol scale. GC-purities were in general >95% (see ESI†). (a) GC-purity was not
determined (n.d.); (b) pressure vial was used; (c) GC-purity of the starting material 1i was 80% and of ITC 3i 83%; (d) 2.31 mmol isocyanide 1k was
used; (e) 5 mol% DBU was used; (f) 2.00 mmol isocyanide 1t was used; (g) starting material was not/less soluble.
benzylic as well as aromatic isocyanides were successfully con- aromatic isothiocyanates, electron-rich and decient as well as
verted to the respective isothiocyanates. Comparing aliphatic condensed aromatic isocyanides were successfully converted
isothiocyanates, steric hindrance was found to have minor obtaining yields from 45 to 95%, whereby no trend related to
impact on the yield, which varied from 34 to 94%. In the case of electron density was observed. In addition, the reaction had
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Scheme 4 Synthesis of polythioureas P1–3 with 1,5-diaminopentane 4 (green) and herein synthesized ITCs 3c, 3d and 3h (black).
Table 4 Comparison of sulfurization approaches of isocyanide 3q considering E-factors, energy consumption and purification methods
Catalyst/reactant
Conditions
Yield/%
E-Factora (syn.)
E-Factorb
Purication
Ref.
5 mol% DBU
5 mol% DBU
2.00 eq. NaH
40 ꢀC, 4 h
95
80
85
0.129
0.349
0.982
3.84
5.30
20.2
(1) Optimized ash cc
(1) Optimized ash cc
(1) Dilution with EA, (2)
ltration, (3) ash cc
(1) Flash cc
This workc
This workd
81
40 ꢀC, 4 h
40 ꢀC, 2 h, Ar-atm
1 mol% RhH(Ph3)4
56 ꢀC, 2.5 h, Ar-atm
56 ꢀC, 2.5 h, Ar-atm
56 ꢀC, 72 h, Ar-atm
96e
91e
91
0.353
0.412
0.342
10.4
11.0
2.10
74
74
73
1 mol% Rh(acac)(CH2 ¼ CH2)2
(1) Flash cc
(1) Dilution with
1 mol% Mo(O)(S2CNEt2)2
petroleum ether, (2) ltration,
(3) distillation
(1) Filtration, (2) distillation
5 mol% Se, 2.40 eq. TEA
66 ꢀC, 1 h
74
2.28
17.0
70
a
Synthetic E-factor involving reactants, catalysts and remaining starting material. b E-Factor taking the used reaction solvent into account. c GBL
d
e
was used as solvent. Cyrene™ was used as solvent. Reference mentioned that high purity of isocyanide was very important. cc ¼ column
chromatography.
a high degree of chemoselectivity, since several functional These results showed that GBL can be superior to Cyrene™ in
groups (double bond (internal), ether (aliphatic and aromatic), some cases, depending on the applied substrate.
thioether (aliphatic), tertiary amine, p-toluenesulfonyl, ester)
Purication of all herein reported compounds was per-
were tolerated. However, the carboxylic acid salt 3u (85% purity) formed by a modied ash column chromatography to reduce
could not be converted, probably due to solubility issues. waste (vide infra). Furthermore, multigram scale reactions (15.5
Considering the tertiary amine of 2-morpholinoethyl isocyanide mmol) were easily performed, generally resulting in similar or
3j, an (auto-)catalytic effect might be anticipated, however it was higher yields (i.e. 3a, 3g, 3m and 3p in Scheme 3). This increased
ruled out by performing the reaction in absence of DBU (no yield was likely due to small amounts of sulfur sticking to the
yield aer 3 hours). Since some isocyanide compounds are wall of the reaction ask, which is a negligible effect for larger
volatile (3e), a pressure tube was crucial to obtain the respective scale reactions. All herein newly synthesized compounds were
product. Besides Cyrene™, GBL performed very similar as fully characterized by proton and carbon NMR-spectroscopy, IR-
solvent in this reaction, converting isocyanide 1a to ITC 3a and spectroscopy and high-resolution mass spectrometry. Purities
thus, we hypothesized that GBL could be a more suitable solvent of all synthesized ITCs were determined by gas chromatography
for some ITCs. Therefore, we tested six substrates and as and, for several substrates, elemental analysis (vide infra).
a result, better yields were obtained for aromatic ITCs 3p and 3r, Furthermore, E-factors were calculated for every ITC (see the
while the yield of ITC 3g was lower. Synthesis of ITC 3b in GBL ESI† for characterization, purity and E-factor data).
only resulted in minor traces of the product. Nevertheless, in
the case of 3o and 3t, Cyrene™ exhibited similar retention time
on silica gel and thus GBL was found to be more feasible for this
reaction in the light of fast and more sustainable purication.
Improving sustainability of purication
Purication of ITCs is commonly performed by (ash) column
chromatography, thus adding a considerable amount of waste
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and resulting in poor E-factors. Therefore, we sought to opti- a molybdenum catalyst resulted in a lower E-factor of 2.10 due
mize the purication procedure as well. Initial attempts to avoid to the use of acetone. Nevertheless, even lower E-factors, down
column chromatography by applying several washing steps of to 0.989 (for 3m), were achieved with our method converting
the organic layers led to lower purities. Furthermore, excessive liquid isocyanides (for an overview of all E-factors see ESI†). In
washing with aqueous layers was needed and thus, column addition, this new procedure does not require inert atmo-
chromatography was the purication method of choice, sphere, while only moderate energy consumption is needed
resulting in high purity and less waste (GC-purities in general (40 ꢀC for ca. 4 hours). Comparing the purication methods, we
over 95%, see ESI†). Ultimately, a dry loaded small column (5– minimized the amount of waste produced by purication using
8 cm, see Fig. S1 in ESI†), similar to a silica plug, was applied as an optimized ash column chromatography step as sole puri-
sole purication step directly at the end of the reaction. The cation step. Furthermore, this procedure is metal-free and the
amount of used silica, solvent and time was therefore mini- overall toxicity of the reaction is minimized by using catalytic
mized. Residual elemental sulfur was thus also removed, as amounts of DBU. Nevertheless, the reader has to be reminded
conrmed by elemental analysis (elemental analysis was per- that ITCs intrinsically bear a certain degree of toxicity, which
formed for several non-volatile ITCs, see ESI†).
must be addressed by applying adequate safety measures.
To further underpin the high purity of this less waste
producing purication, we performed a polyaddition reaction of
diisothiocyanates 3c, 3d and 3h with renewable 1,5-diamino
pentane (98% purity) in an equimolar stoichiometry. Since high
purities of the monomers, here of the ITCs, are crucial to obtain
high molecular weights via step-growth polymerization,
a successfully polymerization is a good indication of the suit-
ability of this more sustainable purication (Scheme 4). In all
three cases, high molecular weights (Mn of P1–3 were 18.6 kDa,
55.1 kDa and 58.1 kDa, respectively, for SEC-graphs see ESI†)
were obtained, proving that this optimized purication step
resulted in excellent purities. However, for compounds 3o and
3t, applying a classic common column chromatography could
not be avoided, since the retention time of the substrate and the
solvent were similar to the solvent (vide supra).
Conclusion
Mechanistic investigations of a MCR between isocyanide,
amines and elemental sulfur, leading to thioureas, conrmed
isothiocyanates as intermediates, which could be trapped
herein by using tertiary amines. As a result, a more sustainable
synthesis protocol for the sulfurization of isocyanides towards
isothiocyanates was established using DBU as greener catalyst
in low loading down to 2 mol% and the green solvents Cyrene™
and GBL. E-Factors down to 0.989 were achieved while toxicity,
energy and time consumption of the reaction was minimized
obtaining moderate to excellent yields. The sulfurization
method tolerates several functional groups and is easily appli-
cable yielding the desired product in high purity. We hope that
this procedure can pave the way for greener syntheses of iso-
thiocyanates starting from the respective isocyanides and
further the formamides and amines.
Overall sustainability
Combining the herein reported DBU catalyzed sulfurization of
isocyanides with elemental sulfur and the optimized purica-
tion step, very low E-factors were obtained and the toxicity of the
overall reaction was minimized by avoiding highly toxic starting
materials. This is underpinned by comparison of the synthesis
of compound 3q starting from the respective isocyanide 1q with
several literature known procedures (Table 4). For a better
comparison of the synthesis protocols, we calculated the E-
factor with and without the amount of solvent used (E-factor
calculated without respect to solvent was herein called synthetic
E-factor), since some of these procedures would decrease their
E-factors drastically by conducting the reaction in higher
concentrations. Obviously, the use of a catalyzed reaction,
compared to reactions using stoichiometric amounts of
reagents, resulted in lower E-factors. Using the herein reported
protocol with Cyrene™ resulted in the lowest yield of 80%, for
which the synthetic E-factor was comparable to that of proce-
Experimental
General synthesis of isothiocyanates (solid isocyanide)
ꢀ
The corresponding solid isocyanide (1.00 eq., mp >40 C) was
dissolved in dihydrolevoglucosenone (Cyrene™; c(isocyanide)
¼ 2 M) and elemental sulfur (1.12 eq. of sulfur atoms) was
added. Aer addition of 5 mol% of 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) the reaction mixture was stirred for 4 hours
ꢀ
at 40 C. Aer completion of the reaction, purication by opti-
mized ash column chromatography applying a dry loaded
small column (typically height of silica loading around 5–8 cm,
width was 3 cm, see Fig. S1 in ESI†) and a mixture of cyclo-
hexane and ethyl acetate yielded the pure product.
General synthesis of isothiocyanates (liquid isocyanide)
dures using transition metal catalysts offering higher yields The corresponding liquid isocyanide (1.00 eq., mp #40 ꢀC) was
(RhH(Ph3)4 and Mo(O)(S2CNEt2)2 obtaining 96 and 91%, dissolved in dihydrolevoglucosenone (Cyrene™; c(isocyanide)
respectively). On the other hand, the lowest synthetic E-factor of ¼ 6 M) and elemental sulfur (1.12 eq. of sulfur atoms) was
0.129 was obtained using our procedure with GBL as solvent, added. Aer addition of 2 mol% of 1,8-diazabicyclo[5.4.0]
obtaining an excellent yield as well. Taking the solvent into undec-7-ene (DBU), the reaction mixture was stirred for 4
account, the E-factor of our new protocol for the synthesis of 3q hours at 40 ꢀC. Aer completion of the reaction, purication by
remained very low with 3.84 and 5.30 for GBL and Cyrene™, optimized ash column chromatography applying a dry loaded
respectively. Only the procedure reported by Bargon using small column (typically height of silica loading around 5–8 cm
3140 | RSC Adv., 2021, 11, 3134–3142
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width was 3 cm, see Fig. S1 in ESI†) and a mixture of cyclo- 27 A. P. Lawson, M. J. C. Long, R. T. Coffey, Y. Qian,
hexane and ethyl acetate yielded the pure product.
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Conflicts of interest
There are no conicts of interest to declare.
30 IARC Handbooks of Cancer Prevention, Cruciferous Vegetables,
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