Direct, Microwave-Assisted Synthesis of Isothiocyanates

Article abstract of DOI:10.1002/ejoc.201900105

A microwave-assisted desulfuration of readily available dithiocarbamates, formed in situ from primary amines, leading to target isothiocyanates has been developed. This efficient protocol provides a rapid, environmentally benign route to aliphatic and aromatic isothiocyanates.

Full text of DOI:10.1002/ejoc.201900105

A Journal of
Accepted Article
Title: Direct, microwave-assisted synthesis of isothiocyanates.
Authors: Łukasz Janczewski, Anna Gajda, and Tadeusz Gajda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900105
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10.1002/ejoc.201900105
European Journal of Organic Chemistry
COMMUNICATION
Direct, microwave-assisted synthesis of isothiocyanates
Łukasz Janczewski, Anna Gajda, and Tadeusz Gajda*[a]
Abstract: A microwave-assisted desulfuration of readily available
dithiocarbamates, formed in situ from primary amines, leading to
target isothiocyanates has been developed. This efficient protocol
provides a rapid, environmentally benign route to aliphatic and
aromatic isothiocyanates.
conditions in the presence of CS2 are known,[14] the practical
potential of such transformation has never been exploited, not to
mention the assistance of MW irradiation for this purpose. Up to
now, the only exception is KOH-promoted transformation of
anilines to aryl ITCs by using the mechanochemical ball-milling
technique.[15] Herein, we report on direct, microwave-assisted
synthesis of ITCs from the corresponding amines. In the
presence of an organic base, the reaction proceeds via
intermediate dithiocarbamate without an extra desulfurating
agent. The method is general, broad in scope, and makes
possible preparation of a wide array of aliphatic and aromatic
ITCs (Scheme 1, Eq. 5).
Introduction
Over the past few decades, isothiocyanates (ITCs) have
become the focus of medicinal chemistry and chemical biology
gaining attention as many of these natural (e.g., BITC or SFN)
and synthetic heteroanulenes have chemopreventive and
antiproliferative[1] as well as antibacterial[2,3] activity. In flow
cytometry[4] and in proteomics studies, ITCs are also exploited
as probes[5] (see Scheme 1 for selected examples); they are
also useful building blocks in the synthesis of sulfur-containing
heterocycles[6] and thiourea-derived organocatalysts.[7]
There are two basic strategies for synthesizing ITCs: the first
uses organic azides as reactants, which in the tandem
Staudinger/aza-Wittig reaction with triphenylphosphine and
carbon disulfide are converted into target ITCs;[8] the second,
which is most exploited due to the large availability of starting
materials, achieves the goal through the direct reaction of
primary amines with highly toxic thiophosgene,[9] or its more
expensive surrogates such as di(2-pyridyl) thionocarbamate,[10a]
1,1′-thiocarbonyldiimidazole,[10b] and 1,1′-thiocarbonyldi-2-(1H)-
pyridone.[10c] In an alternative two-step protocol, amines are
converted
by reactions
with carbon disulfide
into
dithiocarbamates followed by their decomposition to the desired
ITCs under the action of the desulfurating agent. There is a wide
choice of desulfurating agents and their selection depends on
the implementation of a specific objective.[11] In 2018, Xu et al.11j
developed a route for the efficient synthesis of ITCs from amines
and carbon disulfide in water using sodium persulfate as a
desulfurating reagent (Scheme 1, Eq. 1). Recently, fluorine-
containing reagents such as the Langlois reagent
-
(F3CSO2Na),[12a]
(PDFA)/S8
(Me4N)SCF3,[12b]
and
Ph3P+CF3CO2
[12c]
were disclosed as effective alternatives to
Scheme 1. Examples of biologically related isothiocyanates and
recent approaches to their synthesis.
thiophosgene and CS2 in the traditional amine pathway to ITCs
(Scheme 1, Eq. 2–4).
Most recently, we have reported on the transformation of amines
to ITCs via dithiocarbamate approach using propane phosphonic
acid anhydride (T3P®) as an efficient desulfurating agent.[13a] We
have also demonstrated on a model amine,[13a] that the
abovementioned reaction is strongly accelerated by microwave
(MW) irradiation.[13b] Developing this idea, we hypothesized
whether T3P®, and, in general, any desulfurating agents, is
necessary for decomposition of dithiocarbamates when
microwave irradiation is applied. Despite the fact that isolated
cases of conversion of amines to ITCs under the strong alkaline
Results and Discussion
Optimization studies were performed using phenethylamine (1f)
as a model reactant (Table 1). The reaction of 1f with 3 equiv. of
carbon disulfide in the presence of 5 equiv. of triethylamine
leading to the intermediate dithiocarbamate 2f was performed in
DCM for 5 min at rt. Next, the reaction mixture was irradiated in
a pressure vial with MW (initial 150 W power) at 50 °C for 20 min.
The target 3f was formed under these conditions; however, the
reaction yield had to be improved (entry 1). Increasing the
temperature to 90 °C, with other parameters remaining the same,
provided 3f in 76% yield (entry 2). Further increase in
temperature did not result in a higher yield of reaction (not
shown). Next, the amount of Et3N was optimized. To ensure
[a]
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University
of Technology, 116 Żeromski Str., 90-924 Lodz, Poland;
E-mail: tadeusz.gajda@p.lodz.pl
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900105
European Journal of Organic Chemistry
COMMUNICATION
optimal conditions for both steps of transformation, the use of 4
equiv. of Et3N and MW with an initial 150 W power at 90 °C is
recommended (entry 3). A gradual reduction of Et3N amount,
from 4 to 2 equivalents, resulted in the loss of reaction efficiency
(entries 3 vs. 4 and 5). DCM is a solvent of choice, and as for
the reaction carried out in toluene, no 3f was formed (entry 3,
footnote c). Finally, in the series of experiments performed under
base (see Table 1 for details), DCM (2 mL), first step: 5 min at rt and
then MW irradiation at standard mode (with initial 150 W power) for the
time and temperature given in Table 1; bYields of isolated 3f after flash
chromatography (hexane); cNo 3f was formed in toluene; dTwo-phase
f
system in H2O; eConventional heating at reflux in DCM; MW heating in
an open vessel in refluxing DCM; gConventional heating in a sealed
tube (20 min at 90 °C in DCM)
optimal
conditions,
other
bases
such
as
N,N-
diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane
(DABCO), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), N-
methylmorpholine (NMM), and potassium carbonate were tested.
The reaction in the presence of DIPEA led to yield comparable
to that with Et3N (entry 6 vs. 3), whereas with DABCO and DBU,
transformations were less efficient when compared to those of
Et3N (entries 7 and 8). To our surprise, the reaction with NMM
provided 3f in 6% yield only (entry 9), whereas with K2CO3 as a
base, in a two-phase system (DCM/H2O), no product was
obtained (entry 10). In order to evaluate the benefit of the MW-
assisted desulfurization over the conventional heating,
comparative studies were accomplished for model 1f. Thus, the
reaction performed in DCM, under reflux in an open vessel with
MW assistance afforded ITC 3f in 39% yield (entry 12). On the
contrary, no target 3f was formed under conventional heating in
boiling DCM (entry 11). However, 3f was formed when a
stronger base such as DBU in boiling DCM was applied, albeit in
considerably lower 59% yield (entry 14). We found that the
prolongation of reaction time under the abovementioned
conditions did not improve the yield of 3f. On the other hand, the
independent synthesis of 3f carried out in DCM in a sealed tube,
under conventional heating at 90 °C provided 3f in 60% yield
(entry 13). Taken together, the aforementioned results support
the MW assistance in desulfuration step (entries 12 vs. 11, and
13 vs. 3).
With the optimized conditions in hand (Table 1, entry 3), the
scope of amines was evaluated. A series of structurally diverse
aliphatic ITCs 3a–p were isolated in moderate to high yields
from the corresponding amines precursors’ 1a–p under the
conditions shown in Table 2. Isolation of pure ITCs was easy.
Simple elution of crude product with hexane through a short pad
of silica gel was followed by evaporation of the solvent. Benzyl
and phenethyl ITCs (3a, 3d, 3e, 3f, and 3g) were prepared in
53–83% yields using this protocol. Alkyl ITCs 3i, 3j, and 3l were
isolated in 50–83% yields. More sterically demanding ITCs 3h
and 3k–o with secondary and tertiary group adjacent to -NCS
moiety were also obtained in moderate to high yields (48–82%).
The reaction was applicable to amino alcohol 1p; ITC 3p was
isolated in 75% yield. The protocol was also compatible with
enantiopure 1-phenylethanamines 1b and 1c, respectively. The
corresponding (R)- and (S)-(2-isothiocyanatoethyl)benzenes 3b
and 3c were formed with retention of configuration and without
racemization in yields over 80% (Table 2). However, amino
acids esters more susceptible for racemization underwent
racemization under the abovementioned conditions (not shown).
Table 2. The scope of alkyl isothiocyanatesa
Table 1. Optimization for alkyl isothiocyanatesa
MW conditions
Entry
B: (equiv)
Yield (%)b
t (min)
20
T (°C)
50
1
2
Et3N (5)
Et3N (5)
Et3N (4)
Et3N (3)
Et3N (2)
DIPEA (4)
DABCO (4)
DBU (4)
NMM (4)
K2CO3 (2)
Et3N (4)
Et3N (4)
Et3N (4)
DBU (4)
28
76
87c
82
75
82
77
72
6
20
90
3
20
90
4
20
90
5
20
90
6
20
90
7
20
90
aConditions: amines 1a
–p (2 mmol), Et3N (8 mmol), CS2 (6 mmol), DCM
8
20
90
9
20
90
(2 mL), first step: 5 min at rt and then MW irradiation at standard mode
for 20 min at 90 °C. Isolated yields after flash chromatography (hexane);
bScale-up experiment in a 35 mL pressure vial: 1a (1.21 g, 10 mmol).
10
11
12
13
14
20
90d
refluxe
refluxf
90g
refluxe
0
20
0
20
39
60
59
20
To demonstrate the scale-up applicability of the protocol, we
synthesized 3a on a 10 mmol scale. Reaction accomplished in a
35 mL pressure vial, under the optimal condition established for
20
aConditions: 10 mL pressure vials; 1f (2 mmol), CS2 (6 mmol, 3 equiv.),
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10.1002/ejoc.201900105
European Journal of Organic Chemistry
COMMUNICATION
the small-scale experiment, afforded 1.485 g of 3a in higher
yield compared with small-scale reaction (91% vs. 83%, Table 2,
footnote b).
electron-deficient fluoroanilines 6h and 6k were also well
tolerated. On the contrary, the reaction of very strongly electron-
deficient 3,5-di(trifluoromethyl)aniline 4o resulted in 25% yield of
6o only. Moreover, using this protocol, diisothiocyanate 6n and
heterocyclic ITC 6p could be accomplished in good yields (57%
and 72%) from their parent amines. Finally, we synthesized 6a
on a 10 mmol scale (0.99 g) in 73% yield (Table 3, footnote b).
Additional experiments were performed to shed some light on
the probable course of the reaction (see ESI Scheme S1). Thus,
MW irradiation of pure triethylammonium dithiocarbamate 2a at
90 °C afforded thiourea derivative 7 only, confirming reversibility
of dithiocarbamate formation.[14,16] On the contrary, MW-assisted
reactions of 2a in the presence of an extra amount of Et3N or
CS2 resulted in the formation of target ITC 3a, albeit in low 33%
and 26% yields, respectively. Contrary to the abovementioned
outcomes, MW-promoted reaction of 2a with an extra amount of
Et3N/CS2 mixture led to 3a in 80% yield, suggesting that the
Next, we focused on the synthesis of aryl ITCs from the
corresponding aryl amines. Unfortunately, the model reaction of
aniline (4a), CS2, and Et3N under the condition optimized for
aliphatic ITCs afforded target isothiocyanatobenzene 6a in 24%
yield only (see ESI, Table S1). After short experimentation, we
found that the use of a considerably stronger base such as DBU
and MW assistance at 100 °C was essential to ensure the
optimal condition of conversion, provided 6a in 77% yield.
Table 3. The scope of aryl isothiocyanatesa
-
zwitterionic adduct (Et3N+-CS2 ) can be formed that plays a vital
role in the acceleration, improving the efficiency of this reaction.
The potential of such tertiary amine-CS2 adduct has been
demonstrated in the synthesis of 2-mercaptobenzimidazole.[17]
Jessop et al.[18] have also assumed the formation of the
analogous adduct in the reaction of DBU and CS2. Unfortunately,
our attempts to show the presence of this species using 13C or
15N NMR failed. Based on the present results and previous
reports concerning the chemistry of dithiocarbamates,[14,16,17] two
plausible reaction pathways shown in Scheme 2 have been
proposed.
aConditions: amine 4a
–p (2 mmol), DBU (8 mmol), CS2 (6 mmol), DCM
(2 mL), first step: 5 min at rt, MW conditions: 100 °C, 20 min. Yields of
products after flash chromatography; bScale-up experiment in a 35 mL
pressure vial: 4a (0.93 g, 10 mmol).
Using optimized conditions, we next explored the scope of
aromatic amines (Table 3). The procedure proved to be
compatible with a wide array of ortho-, meta-, or para-substituted,
electron-rich and electron-deficient aromatic amines, yielding the
corresponding ITCs in moderate to high yields (Table 3).
Efficient synthesis of p- and m-methoxy derivatives 6e and 6f
could be taken as examples. Steric effects had no impact on the
efficiency of transformation, as o-methyl-, 2,6-dimethyl-, 2,4,6-
trimethyl-, and o-methoxy-substituted ITCs 6b–d and 6g,
respectively, were achieved in high (87–98%) yields. 4-
Aminophenol, with an unprotected hydroxy group, was also
compatible with this protocol, giving the target product 6m in
72% yield. The procedure was adaptable to halogenoanilines,
providing 6h–l in yields of 54–95%, and among them, strongly
Scheme 2. A plausible mechanism for the MW-assisted reaction of amines
with CS2 in the presence of Et3N (triethylammonium cation was omitted for
better clarity).
-
Thus, Et3N+-CS2 adduct, formed reversibly from Et3N and CS2,
reacts with benzylamine 1a to give tetrahedral intermediate 9a.
This, after the elimination of Et3N, undergoes conversion to
dithiocarbamate 2a, which in turn equilibrates under the alkaline
conditions with dianion[14] 10a. Finally, MW-assisted elimination
of the sulfide anion from 10a affords the target ITC 3a.
Nevertheless, direct conversion of 9a to final 3a cannot be
excluded (pathway a). Alternatively, as shown in pathway b, the
reaction of benzylamine 1a and CS2 affords dithiocarbamate 2a,
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accomplishes the target product 3a.
Conclusions
In summary, using the microwave technique, a practical and
general synthesis of ITCs from primary amines and carbon
disulfide has been reported. This protocol provides a facile and
efficient route to aliphatic and aromatic ITCs with a broad
substrate scope. The use of MW assistance, in place of extra
added desulfurating agents, for the decomposition of the
intermediate dithiocarbamates into ITCs provides an
operationally simple, safe, and environmentally benign synthetic
route to the target compounds.
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Experimental Section
CS2 (0.36 mL, 6 mmol) was added to a solution of aliphatic amines 1a−p
or aromatic amines 4a−p (2 mmol), Et3N (1.11 mL, 8 mmol) for aliphatic
amines 1a−p, or DBU (1.2 mL, 8 mmol) for aromatic amines 4a−p in dry
DCM (2 mL), and placed in pressure vial, equipped with a magnetic bar.
The mixture was stirred for 5 min at rt. After that MW-irradiation (with
initial 150 W power) was applied. The following conditions were used: 20
min at 90 °C for aliphatic amines 1a−p, and 20 min at 100 °C, for
aromatic amines 4a−p. Thereafter, the reaction mixture was diluted with
DCM (50 mL), and successively washed with H2O (5 mL), 1M HCl (5 mL),
H2O (5 mL) and then dried over anhydrous MgSO4. The crude product
was purified by flash chromatography on silica gel (7 g) using hexane as
eluent. Pure ITCs 3a−p and 6a−p were obtained after careful
evaporation of the solvent and removal of volatile residues under
reduced pressure. All the synthesized isothiocyanates, except compound
3h, are described in the literature.
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Acknowledgments
Authors are thankful to the Lodz University of Technology for its
support (Statutory Funds no 501/13/18/1/6228).
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Keywords: isothiocyanates • desulfuration • dithiocarbamates •
amines • microwave chemistry
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European Journal of Organic Chemistry
COMMUNICATION
Layout 2:
COMMUNICATION
Isothiocyanates
Łukasz Janczewski, Anna Gajda,
Tadeusz Gajda*
Page No. – Page No.
Direct, microwave-assisted synthesis
of isothiocyanates
Application of microwave technique allowed to accomplish novel, general and
“greener” one-pot protocol for the synthesis of isothiocyanates from amines.
Reactions are easily scalable and take place without racemization of chiral
amines. Decomposition of the intermediate dithiocarbamates into isothiocyanates
proceeds without any additional desulfurating agent under these conditions.
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