A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: A mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

Article abstract of DOI:10.3762/bjoc.15.155

A new multicomponent reaction has been developed between isocyanides, sulfur and alcohols or thiols under mild reaction conditions to afford O-thiocarbamates and dithiocarbamates in moderate to good yields. The one-pot reaction cascade involves the formation of an isothiocyanate intermediate, thus a catalyst-free synthesis of isothiocyanates, as valuable building blocks from isocyanides and sulfur is proposed, as well. The synthetic procedure suits the demand of a modern organic chemist, as it tolerates a wide range of functional groups, it is atom economic and easily scalable.

Full text of DOI:10.3762/bjoc.15.155

A novel three-component reaction between isocyanides,
alcohols or thiols and elemental sulfur: a mild, catalyst-free
approach towards O-thiocarbamates and dithiocarbamates
András György Németh, György Miklós Keserű and Péter Ábrányi-Balogh*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1523–1533.
Hungarian Academy of Sciences, Research Centre for Natural
Sciences, Institute of Organic Chemistry, Medicinal Chemistry
Research Group, 1519 Budapest, POB 286, Hungary
doi:10.3762/bjoc.15.155
Received: 19 March 2019
Accepted: 21 June 2019
Published: 10 July 2019
Email:
Péter Ábrányi-Balogh* - abranyi-balogh.peter@ttk.mta.hu
This article is part of the thematic issue "Multicomponent reactions III".
Guest Editor: T. J. J. Müller
* Corresponding author
Keywords:
ditihiocarbamate; elemental sulfur; multicomponent reaction; one-pot;
thiocarbamate
© 2019 Németh et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new multicomponent reaction has been developed between isocyanides, sulfur and alcohols or thiols under mild reaction condi-
tions to afford O-thiocarbamates and dithiocarbamates in moderate to good yields. The one-pot reaction cascade involves the for-
mation of an isothiocyanate intermediate, thus a catalyst-free synthesis of isothiocyanates, as valuable building blocks from
isocyanides and sulfur is proposed, as well. The synthetic procedure suits the demand of a modern organic chemist, as it tolerates a
wide range of functional groups, it is atom economic and easily scalable.
Introduction
O-Thiocarbamates belong to a class of important biologically moiety can be found in biologically active molecules widely
active molecules, used mainly as fungicides [1-3] in agricul- applied as fungicides, herbicides, pesticides [21-25] and in
tural and pharmaceutical fields. In particular, recently anti- some cases as enzyme inhibitors [26] or antitumor agents [27].
tumor [4], anesthetic [5] and enzyme inhibitory effects were These species are also used as valuable synthetic intermediates
discovered, including HIV-1 reverse transcriptase inhibition ac- [28] and chemosensors for mercury and silver [29,30].
tivity [6-11]. Moreover, their utilization as highly regio- and
stereoselective organocatalysts in specific types of chemical The general methods for the synthesis of O-thiocarbamates and
tranformations [12-17] was introduced, as well. More recently, dithiocarbamates traditionally rely on substitution reactions of
O-thiocarbamates have been used as H2S donors in biological the corresponding halogenated precursors, including thiophos-
systems [18] and as intermediates in pharmaceutically signifi- gene [31-33], thiocarbamoyl chlorides [34-37], chlorothionofor-
cant organic syntheses [19,20]. The dithiocarbamate structural mates or chlorodithioformates [38-41] providing the appro-
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Beilstein J. Org. Chem. 2019, 15, 1523–1533.
priate thiocarbamate analogues in good yields (Scheme 1).
However, these methods suffer from the formation of toxic,
malodorous and/or extremely corrosive byproducts generated
by the elimination of the halogen atoms. One should note that
the application of these halogenated thiocarbonic acid deriva-
tives might be dangerous and require thorough precaution.
Considering dithiocarbamates, a number of methods are based
on the reaction of amines and the readily available, but toxic
and volatile carbon disulfide [42-45]. Greener methods for the
synthesis of thiocarbamates and dithiocarbamates have been de-
veloped such as the addition of the amine component to potas-
sium thiocyanate [46,47] or isothiocyanate [48-52] showing
better atom economy. Nonetheless, only a few examples can be
found in the literature starting from thiocyanates, and regarding
the isothiocyanates the preparation of the reagent is required as
an additional reaction step before.
The synthesis of isothiocyanates generally relies on the reac-
tion between thiophosgene and amines, thus involves the use of
a highly toxic reagent with narrow functional group compati-
bility [53-56]. Various thiocarbonyl transfer reagents have been
developed in the last decades to overcome these drawbacks,
such as thiocarbonyl-diimidazole or di-2-pyridyl thionocar-
bonate [57,58]. Decomposition of dithiocarbamate salts or thio-
carbamates with various reagents offers a good alternative [59-
62] as well, however, this approach first requires the synthesis
of the appropriate precursor. Nitrile oxides react with thiourea
to afford isothiocyanate and harmless urea [63-65], but one
should note that the instability of the nitrile oxides leads to
many byproducts, turning this approach less attractive. The syn-
thesis of isothiocyanates starting from isonitriles involves
sulfur-containing reagents such as thallium thiocarboxylates or
thiols in the presence of radical initiators [66-68]. All the previ-
ously reported methods for the synthesis of O-thiocarbamates,
dithiocarbamates and isothiocyanates start from toxic and/or
unstable reagents, generate halogen waste or have narrow func-
tional group tolerance. The bench-stable, environmentally
benign, cheap and nontoxic elemental sulfur offers an alterna-
tive starting material to integrate sulfur into the product [69].
Scheme 1: Synthetic routes to O-thiocarbamates and dithiocarba-
mates.
For a single molecule, Tan and co-workers showed isothio- cogens and/or long reaction times. More recently, a novel three-
cyanate might be formed from an isocyanide by elemental component method has been published starting from readily
sulfur in the presence of a base in low yield [70]. In certain available amines and sodium bromodifluoracetate [84], but this
cases, sulfur can be trapped by in situ generated carbenes to synthetic route provides halogenated waste, as well. As a
afford O-thiocarbamates [71,72]. Thioureas and S-thiocarba- continuation of our interest in the development of multicompo-
mates are also accessible through multicomponent reactions nent reactions [85-87] and reactions involving sulfur [88],
starting from isocyanides and sulfur [73-75]. The cumbersome herein, we describe a novel synthesis of O-thiocarbamates and
synthesis of isothiocyanates from isocyanides and sulfur [76] dithiocarbamates via a three-component reaction of elemental
can be enhanced using various catalysts such as selenium, sulfur, isocyanides and alcohols or thiols (Scheme 1). More-
molybdenum, copper, rhodium [77-82] or tellurium [83] provid- over, during the investigation of the reaction mechanism, we
ing the isothiocyanates in excellent yields. These approaches on have identified and improved a catalyst-free method for the
the other hand suffer from the use of heavy metals, toxic chal- preparation of isothiocyanates.
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Results and Discussion
entry 5), and one can see that 2.5 equiv of sulfur and methanol
The model reaction of 2,6-dimethylphenyl isocyanide (1a), did not increase the yields either (Table 1, entry 6). A longer
elemental sulfur (S8) and methanol (2a) was employed to screen reaction time (2 h), however, enhanced the product yield from
for the optimal reaction conditions (Table 1). The reactions 72% (Table 1, entry 2) to 84% (Table 1, entry 7). Thus we have
were followed by TLC and HPLC–MS. Based on preliminary combined this reaction time with the elevated molar excess of
experiments in our laboratory, the reaction was performed in the reagents resulting in thiocarbamate 3a in 94% yield
tetrahydrofuran (THF) at 40 °C for 1 h using a 1.5 equiv excess (Table 1, entry 8). The advantageous effect of heating was sup-
of sodium hydride as the base, S8 and the alcohol component ported by the decreased yield (72%) obtained when performing
(Table 1, entry 1) resulting in the desired thiocarbamate 3a in the reaction at ambient temperature (Table 1, entry 9). Next, the
58% yield. During the purification procedure, the change of the effect of different solvents was investigated, showing that
stationary phase for the column chromatography from alumini- acetonitrile (MeCN) and 2-methyltetrahydrofuran (MeTHF)
um oxide to silica, resulted in an increased yield of 72% proved to be suitable alternatives to THF (Table 1, entries 13
(Table 1, entry 2). After the optimization of the purification and 15) that might be advantageous considering the wide appli-
process, the excess of the reagents and the role of the base were cation of these solvents in industrial production [89,90]. On the
studied. Increasing the molar excess of all reagents to 2 equiv contrary, the use of dioxane, methyl tert-butyl ether (MTBE),
provided 3a in 91% yield (Table 1, entry 3), however, the yield toluene or dichloromethane (DCM) was unfavorable, providing
was decreased by the use of a larger excess (Table 1, entry 4). the thiocarbamate in 67%, 29%, 12% and 30% yields, respec-
Reducing the amount of the reagents was not helpful (Table 1, tively (Table 1, entries 10, 11, 12, and 14). Notably, in the lack
Table 1: Optimization of the reaction conditions for the synthesis of O-thiocarbamates.
Entry
Solvent
Base
Time [h]
Molar excess
2a/S8/base
Yield [%]a,b
1
2
3
4
5
6
7
8
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
Cs2CO3
DIPEA
DBU
NaOEt
–
THF
THF
THF
THF
THF
THF
THF
THF
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1.5:1.5:1.5
1.5:1.5:1.5
2:2:2
2.5:2.5:2.5
1.5:1.5:2
2.5:2.5:2
1.5:1.5:1.5
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
58c
72
91
80d
61
88
84
94d
72e
67
9
THF
10
11
12
13
14
15
16
17
18
19
20
21
dioxane
MTBE
toluene
MeCN
DCM
MeTHF
THF
THF
THF
THF
THF
29
12d
92d
30
87d
72f
0 (26)g
0 (30)g
39
0 (53)g
n.r.
THF
2:2:2
aReaction conditions: 1a (1 mmol), S8, 2a, base, solvent (3 mL), time, under argon atmosphere at 40 °C. bIsolated yields. cFlash column chromatog-
raphy performed on aluminium oxide as stationary phase. dAverage of two runs. eRoom temperature. fLack of inert atmosphere. gYield of isothio-
cyanate intermediate. n.r. = no reaction.
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of inert atmosphere, the yield decreased to 72%, and unidenti- tively) that might be attributed either to steric hindrance or the
fied byproducts were detected that might be explained with the growing instability of the conjugate base of the secondary and
decomposition or side reactions of the isocyanide component tertiary alcohol, respectively. The present method provided the
under air. In the case of using other bases, such as caesium allylic derivative 3j in 72% yield, however, applying ethylene
carbonate (Cs2CO3), diisopropylethylamine (DIPEA) or sodi- glycol resulted in 3k in 34% yield only. In the latter case no
um ethoxide (NaOEt), only the isothiocyanate intermediate of dimeric product but several unidentified side products were
the reaction was isolated (Table 1, entries 17, 18, and 20). How- detected by TLC and HPLC–MS. Although the full conversion
ever, using diazabicycloundecene (DBU) as the base allowed of the isocyanide to the isothiocyanate intermediate was ob-
the formation of the desired product, but only in 39% yield served by TLC and HPLC–MS, phenol proved to be unreactive
(Table 1, entry 19). Without any basic additive, no reaction under the standard reaction conditions. Consequently, we have
occurred (Table 1, entry 21) and the starting compounds were turned our attention to different benzylic alcohols that could be
recovered.
utilized to further examine the functional group tolerance of the
reaction. Notably, chlorine, bromine and iodine substituents
With the optimized reaction conditions in hand, the generality were compatible with the transformation, providing 3m, 3n, 3r
and substrate scope of the reaction using different isocyanides and 3s in 81–89% yield. The nitrile derivative 3p was obtained
were investigated (Scheme 2). Considering the yield of various successfully in 62% yield, showing the reactivity difference be-
aromatic isonitriles, no significant difference was noticed be- tween the cyano and the isocyano groups. Interestingly, me-
tween electron-withdrawing and electron-donating substituents thoxy-substituted thiocarbamates 3o and 3t were obtained in
(3c and 3d, respectively). The ortho-iodo-substituted 3b was lower 53% and 56% yield, respectively, that decreased further
obtained in an excellent yield (94%) demonstrating that no to 34% in the case of the trimethoxy-substituted product 3u. As
steric hindrance occurs during the reaction. Taking into account the methoxy group is inert under the standard reaction condi-
aliphatic derivatives, O-methyl cyclohexylcarbamothioate (3e) tions, one might assume that the electron-donating ability
was formed in good yield (82%), however, O-methyl tert-butyl- reduces the stability of the in situ-generated anion, just as in the
carbamothioate (3f), partly due to the volatile nature of the case of the secondary and tertiary alcohols. The nitro derivative
isocyanide and the thiocarbamate as well, was obtained only in 3q was isolated in 30% yield along with multiple byproducts
54% yield.
detected that may be due to possible reductive side-reactions
caused by sulfur [91]. To the best of our knowledge, out of the
In order to further explore the scope of the reaction, different 21 synthesized O-thiocarbamate derivatives (Scheme 2 and
alcohols were tested (Scheme 3). Regarding the compounds Scheme 3), 18 compounds are new, and only 3d, 3e and 3f are
3g–i it can be noticed that the yield drops from the primary known in the literature [92-94]. The new derivatives have been
alcohol towards the tertiary one (85%, 52% and 45%, respec- characterized by 1H NMR, 13C NMR, HRMS and melting
Scheme 2: Substrate scope of isocyanides. aReaction conditions: 1 (1 mmol), S8 (2 mmol), 2a (2mmol), NaH (2 mmol), THF (3 mL), 2 h, under argon
atmosphere at 40 °C. Yields refer to isolated yields.
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Scheme 3: Substrate scope of alcohols. Reaction conditions: 1a (1 mmol), S8 (2 mmol), 2 (2mmol), NaH (2 mmol), THF (3 mL), 2 h, under argon at-
mosphere at 40 °C. Yields refer to isolated yields.
point. However, the thiocarbamate 3c happened to be unstable However, in this case only the isothiocyanate intermediate was
and started to decompose after work-up. Therefore, an obtained. Then, trimethylamine was applied in refluxing MeCN
HPLC–MS spectrum of the reaction mixture after completion of [95] or sodium hydroxide in dimethyl sulfoxide (DMSO) at
the reaction and an HRMS of the crude product are attached in 70 °C. In both cases only the isothiocyanate intermediate and
Supporting Information File 1.
phenol were observed by HPLC–MS but no formation of the
desired product.
Several experiments were performed to discover the reaction
conditions that enable the synthesis of O-aryl thiocarbamates. Then we turned to the synthesis of dithiocarbamate 5a under the
Initially, DBU was used in refluxing dioxane, as this base was standard reaction conditions, but only the isothiocyanate inter-
shown to provide the appropriate aliphatic O-thiocarbamate. mediate was obtained (Table 2, entry 1). Thus a new optimiza-
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Table 2: Optimization of the reaction conditions for the synthesis of dithiocarbamates.
Entry
Solvent
Base
Temp. [°C]
Molar excess
4a/S8/base
Yield [%]a,b
1
2
3
4
5
6
7
8
NaH
THF
40
40
70
100
70
70
70
70
70
70
70
2:2:2
2:2:2
2:2:2
2:2:2
3:3:3
2:2:2
2:2:2
2:2:2
2:2:2
2:2:2
2:1.2:2
0c
NaOH
NaOH
NaOH
NaOH
NaH
Cs2CO3
NaOH
NaOH
NaOH
NaOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMA
NMP
DMA
22
38
34
23
36
14
43
45
34
59
9
10
11
aReaction conditions: 1a (1 mmol), S8, 4a, base, solvent (3 mL), temperature, 3 h under argon atmosphere. bIsolated yield, unless noted otherwise.
cIsothiocyanate intermediate detected by HPLC–MS.
tion of the reaction conditions became necessary. Similarly to However, using N,N-dimethylformamide (DMF) or N,N-
the previous methodology, the base, the solvent, the tempera- dimethylacetamide (DMA) as the solvent provided 5a in 43%
ture and the molar excess of the reagents were changed using and 45% yield, respectively (Table 2, entries 8 and 9), while on
the model reaction of 2,6-dimethylphenyl isocyanide (1a), the other hand, N-methyl-2-pyrrolidone (NMP) was disadvanta-
sulfur and benzyl mercaptan (4a, Table 2). Initially, NaOH was geous for the reaction (Table 2, entry 10). It is well-known that
used in DMSO as shown in entry 2 (Table 2), providing the at elevated temperatures sulfur may act as an oxidant, which in
desired dithiocarbamate 5a in only 22% yield [96]. In order to this case may have compromised the reaction [97-99]. There-
improve the yield, firstly the temperature was elevated to 70 °C fore, the molar excess of sulfur was decreased, providing a pos-
and 100 °C to afford 5a in 38% and 34% yield, respectively itive effect on the reaction affording 5a in 59% yield.
(Table 2, entries 3 and 4). Larger excesses of the reagents and
the base cut back the yield to 23% (Table 2, entry 5). Using With the optimized reaction conditions in hand, a number of
NaH instead of NaOH did not improve the yield of the reaction dithiocarbamate derivatives were synthetized (Scheme 4). One
(Table 2, entry 6), nor did the use of Cs2CO3 (Table 2, entry 7). might notice the same trend as in the case of thiocarbamates
Scheme 4: Substrate scope of thiols. Reaction conditions: 1a (1 mmol), S8 (1.2 mmol), 4 (2 mmol), NaOH (2 mmol), DMAc (3 mL), time, under argon
atmosphere at 70 °C. Yields refer to isolated yields.
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3g–i, in particular, the primary mercaptans gave the highest We have envisaged that our multicomponent reaction could be
yields (5a and 5b), while in the case of secondary (5c and 5d) compatible with subsequent one-pot transformations. In order to
and tertiary thiols (5e) the products were isolated in lower demonstrate this capability, we performed the multicomponent
yields. Although a full conversion of the isocyanide to the iso- domino annulation between isocyanide 1a, sulfur and methyl
thiocyanate intermediate was observed by TLC and HPLC–MS, anthranilate (6) in DMSO in the presence of NaOH at 85 °C
thiophenol, likewise to phenol was unreactive under the stan- that provided 3-(2,6-dimethylphenyl)-2-thioxo-2,3-dihydro-
dard reaction conditions. The generally lower yields, harsher quinazolin-4(1H)-one (7), a new quinazolinone derivative in
reaction conditions and stronger negative effect of electron-do- 40% yield (Scheme 6). Notably, these heterocycles are known
nating groups might be explained with the softer nucleophilici- for their use as antitumor [101], anticonvulsant [102] or
ty of the thiols compared to the alcohols [100]. All five dithio- epidermal growth factor receptor tyrosine kinase inhibitory
carbamate derivatives synthesized are new and were character- agents [103], JNK inhibitors [104] or 5-HT3 antagonists [105].
ized by 1H NMR, 13C NMR, HRMS and melting point.
Earlier, a one-pot synthesis of an analogous compound was
accomplished by Sayahi et al. starting from isothiocyanates in
After the successful application of various nucleophiles, it was the presence of CuBr [106].
our intention to investigate the scalability of the procedure.
Thus, a twenty-fold scale-up of the reaction between the As aforementioned, in some cases only isothiocyanate 8 was
isocyanide 1a, sulfur and methanol (2a) was performed detected and/or isolated. Thus, in order to gain mechanistic
(Scheme 5). In this case, the experimental conditions were nec- insights on the generation of 3a, we performed a series of ex-
essarily slightly different, as in larger quantities the reaction be- periments (Scheme 7). As shown in Table 1, isocyanide 1a and
tween the alcohol and NaH needs to be kept under control. sulfur did not react in the absence of a base (Table 1, entry 21).
Therefore, the mixture of 1a, methanol and THF was added Therefore, the reaction was performed in the presence of NaH
dropwise to a mixture of NaH and sulfur in THF under ice-cool- under the standard reaction conditions, providing 8 in 85%
ing. After the work-up, no chromatography was necessary and yield (Scheme 7, reaction 1). Notably, the analogous reaction
the crude product was purified by recrystallization from hexane/ reported by Tan and co-workers using potassium tert-butylate
ethyl acetate. The three collected crops of crystals provided the in t-BuOH/dioxane at 55 °C for 6 h resulted in the desired iso-
thiocarbamate 3a in a total of 74% yield.
thiocyanate in only 34% yield [69]. In the next step, we investi-
Scheme 5: Scaled-up synthesis for 3a.
Scheme 6: Multicomponent domino synthesis of quinazolinone 7.
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Beilstein J. Org. Chem. 2019, 15, 1523–1533.
Scheme 7: Control experiments.
gated the acylation of the alcohol component by the isothio- 40 °C and 70 °C, and the same result was obtained when
cyanate (Scheme 7, reaction 2). In the absence of a base, no a solvent mixture of ethanol and THF was used (Scheme 7,
reaction occurred, and consequenctly the base was necessary for reaction 4).
both steps of the thiocarbamate formation. This also explains
why two equivalents of base were required. Sodium sulfide as Based on the above experimental results and previous reports
the base provided only traces of 3a suggesting that the activa- [74,107,108], a possible reaction mechanism has been pro-
tion of sulfur by NaH produces rather a polysulfide anion posed (Scheme 8). Initially, the reaction of elemental sulfur and
instead of sodium sulfide [74,107,108] (Scheme 7, reaction 3). NaH generates a polysulfide anion that is able to attack the
It caught our attention that only isothiocyanate was generated in carbenoid carbon atom of isocyanide 1a yielding the isothio-
the presence of NaOEt (Table 1, entry 20). We suspected that cyanate intermediate 8. Then, the present nucleophile (NuH,
THF might not be the best solvent for this base, hence the reac- alcohol or thiol) undergoes a nucleophilic addition on 8 provid-
tion was performed in MeCN providing exclusively 8 both at ing thiocarbamate 3a.
Scheme 8: Proposed mechanism.
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Conclusion
In summary, we have developed an efficient, convenient and
scalable multicomponent method for the synthesis of O-thiocar-
bamates and dithiocarbamates under mild reaction conditions.
This approach includes an improved catalyst-free synthesis of
isothiocyanates from elemental sulfur and isocyanides, and
shows good functional group tolerance to halogen, olefin and
nitrile groups among others. Moreover, this multicomponent
reaction is suitable for a one-pot cascade annulation providing a
thioxo dihydroquinazolinone derivative in a metal-free ap-
proach. Compared to other reported syntheses of thiocarba-
mates, this method is highlighted by its simplicity, atom eco-
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29 synthesized compounds, 18 new O-thiocarbamates, 5 new
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characterized.
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Supporting Information File 1
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of NMR spectra.
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Acknowledgements
The authors thank Renáta Szabó for her contribution, and
Krisztina Németh and Pál Szabó for the HRMS measurements.
P. Ábrányi-Balogh was supported by the Hungarian Science
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