Click Reaction of Selenols with Isocyanates: Rapid Access to Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-Peroxidase-Like Catalysts

Article abstract of DOI:10.1002/adsc.202100611

Selenols react with isocyanates under mild catalyst-free conditions to generate selenocarbamates in good yield and with high selectivity over potentially competing nucleophilic additions. The methodology enables the incorporation of a wide variety of functional groups providing access to a broad array of densely functionalised selenocarbamates. In the presence of competing heteroatom-centered nucleophiles, isocyanates selectively couple with selenols. Selenocarbamates exhibited thiol-peroxidase-like properties, enabling the reduction of hydrogen peroxide at the expense of thiols, which are converted into the corresponding disulfides. A series of control experiments suggested that the catalytic mechanism proceeds through a pathway, involving a H₂O₂-promoted transcarbamoylation reaction leading to a thiocarbamate with concomitant releasing of catalytically active selenolate anions. By undergoing peroxide-driven thiol-selenol exchange, selenocarbamates behave as equivalents of selenolate anions with thiol-peroxidase-like activity. (Figure presented.).

Full text of DOI:10.1002/adsc.202100611

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100611
Click Reaction of Selenols with Isocyanates: Rapid Access to
Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-
peroxidase-Like Catalysts
Antonella Capperucci,a Alessandra Petrucci,a Cristina Faggi,a and
Damiano Taninia,*
a
University of Florence, Department of Chemistry “Ugo Schiff”, Via della Lastruccia 3–13, I-50019 Sesto Fiorentino, Italy
Phone: +39 05545735–50/-52; fax +39055 4574913
E-mail: damiano.tanini@unifi.it
Manuscript received: May 19, 2021; Revised manuscript received: July 5, 2021;
Version of record online: July 14, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100611
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Abstract: Selenols react with isocyanates under mild catalyst-free conditions to generate selenocarbamates in
good yield and with high selectivity over potentially competing nucleophilic additions. The methodology
enables the incorporation of a wide variety of functional groups providing access to a broad array of densely
functionalised selenocarbamates. In the presence of competing heteroatom-centered nucleophiles, isocyanates
selectively couple with selenols. Selenocarbamates exhibited thiol-peroxidase-like properties, enabling the
reduction of hydrogen peroxide at the expense of thiols, which are converted into the corresponding disulfides.
A series of control experiments suggested that the catalytic mechanism proceeds through a pathway, involving
a H2O2-promoted transcarbamoylation reaction leading to a thiocarbamate with concomitant releasing of
catalytically active selenolate anions. By undergoing peroxide-driven thiol-selenol exchange, selenocarbamates
behave as equivalents of selenolate anions with thiol-peroxidase-like activity.
Keywords: Selenocarbamates; Selenols; Isocyanates; Antioxidants; Glutathione peroxidase-like catalysts
Introduction
palladium-catalysed reaction of selenocarbamates with
alkynes was exploited for the regio- and stereo-
Selenocarbamates have considerable synthetic potential selective synthesis of β-selenoacrylamides. An intra-
because of the facile homolytic cleavage of their weak molecular version of such selenocarbamoylation was
carbon-selenium bond. In this regard, selenocarba- efficiently extended to N-alkynyl-substituted selenocar-
mates have recently emerged as unconventional alter- bamates to access conjugated α-alkylidene lactams.[6]
native reagents for the generation of N-acyl radicals. A related Pd(0)-catalysed selenocarbamoylation of
As such, radical cleavage of selenocarbamates has allenes enabled the regioselective formation of func-
been exploited as
a
versatile tool in organic tionalised allyl selenides[7] and allylseleno-substituted
synthesis.[1–3] For example, Ishihara and co-workers α,β-unsaturated lactams.[8] N-Allenyl selenocarbamates
constructed the azabicyclo[3.3.1]nonane core of also undergo palladium-catalysed decarbonylative re-
(À )-haliclonin A through an elegant stereoselective arrangement providing access to 3-seleno-1-
tandem radical reaction of a key selenocarbamate azadienes.[9]
precursor with allyltributylstannane.[4]
On the other hand, the unique biological properties
Selenocarbamates undergo palladium-catalysed in- of selenium-containing organic compounds continue to
sertion of isocyanides into the carbon-selenium bond attract the interest of medicinal chemists and has led to
providing amino-2-oxoethanimidoselenoates.[5] The disclose a wide array of biologically active selenium-
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based derivatives. For example, Ebselen, which argu- makes selenocarbamates a new class of highly
ably represents one of the most deeply investigated effective peroxides-switchable antioxidants.
selenium-containing heterocycles, have been very
recently found to exhibit a promising biological
Results and Discussion
activity against the main protease Mpro of SARS-CoV-
2.[10] In this context, selenocarbamates also exhibited We commenced our investigations by studying the
interesting antiviral activity.[11]
reaction of benzeneselenol 1a with 3,5-dimeth-
However, in spite of their wide application, only a ylphenylisocyanate 2a in different solvents. Results of
few methodologies have been reported for the prepara- this screening are reported in the Table 1.
tion of selenocarbamates. These approaches generally
Pleasingly, the coupling of 1a with 2a occurred
rely on the reactivity of isocyanates with selenium- smoothly, enabling the formation of the corresponding
centered nucleophiles such as selenocarboxylic acids[12] selenocarbamate 3a with moderate to good conversion
or selenolates, generated by means of reductive values in most of the evaluated solvents. Interestingly,
cleavage of diselenides with Zn/AlCl3.[13] N-Alkyl-Se- higher conversions were generally achieved upon using
alkylselenocarbamates can be prepared from isocya- polar non protic solvents such as acetonitrile and
nates and haloalkanes by using LiAlHSeH as the DMSO (Table 1, entries 5 and 6). Particularly, using
selenating reagent.[14] Other methods involve the acetonitrile as the solvent, the selenol-isocyanate
reaction of amines and carbon monoxide with elemen- coupling was found to be fast and highly selective,
tal selenium, followed by treatment with alkyl leading to 3a with excellent yield. On the other hand,
halides,[15] the reduction of diselenides with lithium dichloromethane and methanol (Table 1, entries 2 and
triethylborohydride followed by the reaction with 7) proved to be poor solvents in promoting the desired
diethyl carbamoyl chloride,[16] as well as the reductive transformation. Intriguingly, no reaction was observed
cleavage and subsequent alkylation of bis(N,N-dimeth- in dichloromethane and unreacted 2a was almost
ylcarbamoyl)diselenide.[17] The reaction of N-tosyl- quantitatively recovered. Conversely, as expected,
amines with triphosgene and benzeneselenol in the methanol reacted with isocyanate 2a leading to the
presence of pyridine have also been exploited for the corresponding methyl-substituted carbamate, which
synthesis of selenocarbamates.[18] Recently, a synthetic was isolated as the main product alongside with a
route relying on the oxidative CÀ Se coupling of N,N- minor amount of 3a (ca. 10%). Notably, excellent
disubstituted formamides and diselenides under tert- conversion was also observed under solvent-free
butyl hydroperoxide conditions has also been conditions, although a longer time was required in
developed.[19]
order to achieve complete consumption of the starting
Most of the reported methodologies rely on multi- material (Table 1, entry 8). The effect of catalysts was
step procedures which often employ unstable selenylat- also evaluated. Both aluminium trioxide and triethyl-
ing reagents and require strictly controlled reaction amine, employed in toluene and dichloromethane
conditions. The use of strong reducing agents, acids or respectively, led to improved conversion values and
bases significantly limits the functional group tolerance
and the scope of the existing procedures. In order to
Table 1. Optimisation of the synthesis of selenocarbamates.
address these limitations, we envisaged the possibility
to employ selenols and isocyanates as convenient
starting materials to develop a mild protocol for the
synthesis of selenocarbamates. We recently reported a
convenient approach towards stable aliphatic and
aromatic selenols,[20] which reacted efficiently with a
wide number of eletrophiles providing access to a
plethora
of
functionalised
organoselenium
compounds.[21] Owing to their exquisite electrophilic
character,[22] isocyanates would couple with selenols
under mild conditions. Hereby, we report the synthesis
of a diverse range of selenocarbamates with remark-
able thiol-peroxidase-like properties through the cata-
lyst-free click coupling of selenols with isocyanates.
To our knowledge, these systems exhibited higher
catalytic activity than most of the reported Se-
containing catalysts, including ebselen and diphenyl
diselenide. Our studies elucidated that catalytic mech-
anism proceeds through an unprecedented path involv-
ing a peroxide-driven transcarbamoylation which
[a] Determined by 1H NMR spectroscopy.
[b] According Snyder.[23]
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enhanced selenocarbamate formation rates with respect selenocarbamates bearing fluoro (3e,f), chloro (3g),
to reactions performed in the same solvents under bromo (3h), and trifluoromethyl (3i) moieties were
catalyst-free conditions (Table 1, entries 9 and 10 vs smoothly achieved from the corresponding isocya-
entries 1 and 2).
nates. Additionally, carbamoselenoate 3j, bearing the
Having established two set of optimal conditions furan moiety, was prepared in 81% yield upon reaction
for the successful selenol-isocyanate coupling, we next of furfuryl isocyanate with benzeneselenol. The reac-
turned our attention to evaluating the scope of the two tion was also amenable to aliphatic isocyanates and
reaction partners. Employing benzeneselenol 1a as a could be successfully applied to the synthesis of N-
standard substrate, the scope of isocyanates was butyl-selenocarbamate 3k. Notably, N-trimethylsilyl
explored and found to be wide, encompassing a variety isocyanate 2l was also effective and led to the
of electron-rich and electron-deficient aromatic deriva- corresponding 1-(phenylselanyl)formamide 3l upon
tives (Scheme 1). Electron-rich aryl isocyanates bear- coupling with 1a and protodesilylation reaction occur-
ing alkyl and alkoxy substituents worked well, provid- ring at the nitrogen atom; to our knowledge, this is the
ing access to N-aryl-selenocarbamates 3a,c,d in good first example of selenocarbamate bearing the unsub-
yields. In the case of electron-poor aryl substrates, stituted carbamoyl moiety.
Next, we set out to investigate the scope of the
reaction with respect to the selenol partner. Thus,
different selenols were used in the reaction with
isocyanates 2 under the optimised conditions. Both p-
tolueneselenol 1b and o-tolueneselenol 1c reacted
efficiently with 2h (R1 =4-BrÀ C6H4) providing seleno-
carbamates 3m and 3n in good yield. The Se-o-tolyl
carbamoselenoate 3o, bearing the unsubstituted carba-
moyl group, was also easily achieved from o-
tolueneselenol and N-trimethylsilyl isocyanate 2l.
Furthermore, selenylation reaction of 2a with 4-
fluorobenzeneselenol 1d provided 3p, albeit in rather
low yield (Scheme 1).
The reaction was also found to be amenable to
alkyl- and benzyl-selenols, enabling the synthesis of a
variety of Se-alkyl and Se-benzyl-substituted carbamo-
selenoates. Dodecaneselenol 1e was successfully
employed, giving the corresponding N-aryl- and N-
unsubstituted selenocarbamates 3q,r. Benzyl selenol
1f was reacted with a variety of N-substituted
isocyanates which were readily converted into Se-
benzyl carbamoselenoates 3s–v (Scheme 1). To further
demonstrate the utility of this catalyst-free click
methodology, alkyl selenols bearing valuable func-
tional groups were also employed. Through our simple
approach, primary (1g,h) and secondary (1i) β-
hydroxy-selenols could be easily and selectively
functionalised at the selenol moiety, enabling the
synthesis of β-hydroxy-selenocarbamates 3w–z, bear-
ing the 3,5-dimethylphenyl substituent, the furan
group, and the sterically demanding adamantyl moiety,
in good yield. N-tosyl β-amino-selenol 1k was also
efficiently used, providing access to the corresponding
L-alanine-derived selenocarbamate 3aa (Scheme 1).[24]
The structure of selenocarbamate 3h was confirmed
by single-crystal X-ray crystallography (Figure 1). A
strong intermolecular H-bond involving the oxygen
and the hydrogen of the carbamoyl group is evident in
PARST analysis. Furthermore, the C(O)···Se intermo-
lecular distance (3.374 A) is suggestive of intermolec-
ular chalcogen bonding interactions (Figure S5).[25]
Scheme 1. The scope of the coupling of selenols 1 with
isocyanates 2 under catalyst-free conditions. All yields refer to
[a]
isolated pure material. Yields in parenthesis refer to reactions
[b]
performed under neat conditions. 10% of diphenyl diselenide
was detected. [c] Racemic.
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possibility to employ such compounds as unconven-
tional glutathione peroxidase (GPx)-like catalytic anti-
oxidants. Indeed, the thiol-mediated ionic cleavage of
the carbon-selenium bond of selenocarbamates would
release a selenolate anion which, similarly to the
selenocysteine-derived selenolate involved in the cata-
lytic cycle of GPx, is expected to catalyse the reduction
of hydroperoxides at the expense of a thiol cofactor.
In order to verify this hypothesis, N-3,5-dimeth-
ylphenyl-substituted selenocarbamate 3a was used as
catalyst in the oxidation of dithiothreitol (DTTred) with
hydrogen peroxide according to Iwaoka’s method.[26]
Figure 1. Molecular structure of 3h and selected distances:
C4À Se1=1.915(3) A; Se1À C3=1.959(3) A; C3À O1=1.211(4)
A; N1À C3=1.345(4) A; N1À C11=1.412(5) A.
Given the fast and selective coupling of isocyanates The progress of the reaction, performed in CD3OD,
1
with selenols here described, we were intrigued by the was followed by H NMR spectroscopy. Pleasingly,
investigation of the reactivity of selenols in the complete oxidation of DTTred was observed within 2
presence of competing chalcogen-centered nucleo- minutes from the addition of H2O2. Such a short time,
philes. Thus, an equimolar mixture of benzeneselenol generally unusual for organoselenium-based thiol-
and benzenethiol in acetonitrile was treated with peroxidase-like catalysts, highlights the excellent activ-
isocyanate 2a (1.0 equiv.). Surprisingly, the selenocar- ity of compound 3a. On the basis of these results, the
bamate 3a was selectively formed while benzenethiol catalytic properties of a series of differently Se- and N-
remained unreacted and no traces of thiocarbamate substituted selenocarbamates was investigated. Results
were detected (Table 2, entry 1). The exquisite seleno- of this study are reported in Table S1 and in Figure 2
philicity of isocyanates in addition reactions was (see ESI for details). Compounds 3a and 3c, bearing a
confirmed upon using different thiols (p-thiocresol and phenylseleno moiety and electron-rich N-aryl substitu-
1-pentanethiol: Table 2, entries 2, 3) as competing ents, were showed to be the most effective catalysts
nucleophiles. Similar results in terms of selectivity within the studied series (T50 <60 sec). On the other
were also observed in the presence of related O- and hand, the presence of an electron-poor N-4-fluorophen-
N-centered nucleophiles such as phenol and aniline yl substituent brought about a significant reduction of
(Table 2, entries 4, 5). These results suggest that the the thiol-peroxidase-like properties (3f, T50 =2845�
specificity of the selenol-isocyanate coupling could be 126 sec). Selenocarbamate 3h, bearing a 4-bromo-
exploited for the development of isocyanate-based phenyl group onto the nitrogen atom, exhibited a
probes for the selective detection or the sensoring of higher catalytic activity with respect to the related
selenols.
fluoro-substituted analogue and led to complete DTTred
Owing to the high reactivity of the selenium-carbon oxidation within 20 minutes from the addition of H2O2
bond of selenocarbamates, which can be easily cleaved (T50 =368�21 sec). Intriguingly, the N-unsubstituted
both via radical and ionic pathway, we envisaged the carbamoyl derivative 3l behaved as a poor catalyst
with respect to its N-aryl-substituted analogues (T50 >
3600 sec).
Table 2. Competition experiments: reaction of benzeneselenol
1a with isocyanate 2a in the presence of competing nucleophi-
les.[a]
Figure 2. Oxidation of DTTred with H2O2 in the presence of
catalytic amounts of selenocarbamates 3 or selenolesters 10
[a] Reaction conditions: 2a (0.73 mmol), PhSeH (0.80 mmol),
RXH (0.80 mmol), acetonitrile (1 mL), r.t., 10 min.
[b] c.a.p.: competitive addition product.
(10 mol%). Reaction conditions: [DTTred]0 =0.14 M, [H2O2]0 =
0.16 M, [catalyst]=0.014 M, CD3OD (1.1 mL). In the control
experiment the reaction was run with no catalyst. The mean �
SD values of three separate experiments are reported.
[c] Determined by 1H NMR spectroscopy.
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The nature of the group bond to the selenium atom of 4a and 4b were detected after 12 h. The H2O2-
also affected significantly the thiol-peroxidase-like mediated oxidation of the selenol or selenolate reason-
catalytic properties of 3.
ably represents the driving force of the transcarbamoy-
Compounds 3m and 3n, bearing an electron- lation reaction. Indeed, in the presence of H2O2,
donating substituent respectively at the para- and at diphenyl disulfide or DTTox and diphenyl diselenide
the ortho- position of the Se-aryl ring, exhibited lower were the sole reaction products formed along with
catalytic activity (T50 >3600 sec) with respect to the 4a,b. The formation of both 4a,b and diphenyl
related Se-phenyl-substituted analogue 3h (T50 =368� diselenide is suggestive of a thiol-selenol exchange
21 sec). Notably, steric effects were demonstrated to occurring at the carbamoyl carbon. Such a reaction
play only a marginal role on the catalytic performances would lead to a selenol or a selenolate anion. Both
of 3m and 3n, which displayed comparable thiol- theoretical and experimental data suggest that seleno-
peroxidase-like properties. On the other hand, the late anions undergo oxidation faster than the parent
presence of the electron-poor Se-4-fluorophenyl sub- selenols.[28]
stituent (3p) led to an improved catalytic activity with
respect to the related derivative 3a, bearing the Se- bond of 3 as the rate-determining step of the process,
phenyl substituent.[27]
and considering the excellent catalytic performances of
Envisaging the cleavage of the carbon-selenium
The catalytic activity of Se-alkyl-substituted carba- the selenocarbamate 3a, we postulated that a seleno-
mates 3q,w resulted dramatically decreased when late, instead of a selenol, should be involved in the
compared with that of related Se-phenyl-substituted oxidation mechanism. To confirm this hypothesis, the
derivatives. This behaviour might be ascribed to the catalytic properties of benzeneselenol and sodium
higher basicity – and therefore poor leaving group benzeneselenolate, easily generated upon treatment of
ability – of alkylselenolates with respect to arylseleno- benzeneselenol with a stoichiometric amount of
lates. The presence of a rather poor leaving group NaOH, were investigated and compared. Surprisingly,
engenders Se-alkyl-carbamoselenoates less sensitive to benzeneselenol exhibited poor catalytic activity and
the trans-carbamoylation reaction with thiols (vide only 30% of DTTred was converted into DTTox after 30
infra).[24]
minutes from the addition of H2O2. On the other hand,
To glean insights into the catalytic mechanism of complete DTTred oxidation was achieved within 2
the selenocarbamate-mediated oxidation of thiols, a minutes when sodium benzeneselenolate was em-
series of control experiments and NMR investigations ployed as the catalyst (Figure 3). To the best of our
were carried out. We postulated that the first step of knowledge, this is the first study where the thiol-
the mechanism involves the thiol-mediated cleavage of peroxidase-like activity of a selenol and a related
the carbon-selenium bond of 3 releasing a thiocarba- selenolate anion is experimentally compared. Notice-
mate and a selenol or a selenolate anion. These latter ably, when a slight excess of hydrogen peroxide
entities are expected to react with H2O2 providing the (1.2 equiv. with respect to DTT) was used, sodium
active selenium-based oxidant species involved in the
thiol-disulfide conversion. Our hypothesis was con-
firmed by the isolation of thiocarbamates 4a and 4b
arising from the reaction of 3a with thiophenol and
dithiothreitol, respectively, in the presence of H2O2
(Scheme 2). Notably, when a solution of 3a in
methanol or acetonitrile was treated with PhSH or
DTT in absence of H2O2, the thiol-selenol exchange
occurred very slowly and only trace amounts (<10%)
1
Figure 3. Series of H NMR spectra obtained in the oxidation
of DTTred (0.15 mmol) with H2O2 (0.18 mmol) in the presence
of 10% of sodium benzeneselenolate. I) 1H NMR spectrum
1
Scheme 2. Reaction of 3a with thiols in the presence of H2O2
affording thiocarbamates 4, disulfides, and diphenyl diselenide.
Reaction time: 10 min. In control experiments performed in
absence of H2O2, c.a. 90% of 3a remained unreacted.
acquired before the addition of H2O2; II) H NMR spectrum
1
acquired after 90 seconds from the addition of H2O2. III) H
NMR spectrum acquired after 120 seconds from the addition of
H2O2.
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benzeneselenolate was converted into diphenyl disele- yield the corresponding diselenide 9 (Scheme 3 and
nide at the end of the catalytic cycle (Figure 3, spectra Figure 3, vide infra).
I and II vs spectrum III).
Having disclosed that reactivity of the SeÀ C(O)
On the basis of results of our experiments and bond is key for the thiol-peroxidase-like activity of
literature-reported data, we propose the catalytic selenocarbamates, we sought to compare their activity
mechanism outlined in Scheme 3. The first step with those of selected related selenolesters. Com-
reasonably involves a thiol-selenol exchange reaction pounds 10a,b, structurally similar to 3a and 3f, easily
occurring at the carbamoyl carbon and leading to a prepared from the corresponding acyl chlorides and
thiocarbamate 4 and a selenolate anion 5, which benzeneselenol,[29] were chosen as model compounds
readily undergoes oxidation to provide the correspond- (Scheme 4).
ing selenenic acid 6. The oxidation of the leaving
Remarkedly, while 10a catalysed efficiently the
selenolate reasonably drives the equilibrium of the oxidation of DTTred to DTTox (T50 =90 � 18 sec), the
transcarbamoylation reaction towards 4. The selenenic 4-fluorophenyl-substituted derivative 10b exhibited a
acid 6 is then converted into the selenenyl sulfide 7 significantly lower catalytic activity (T50 >3600 sec).
upon reaction with a thiol. Compound 7 can also be These results are in line with the activity of seleno-
formed through an alternative pathway foreseeing the carbamates 3a and 3f, bearing respectively the 3,5-
conversion of the selenenic acid into the anhydride 8, dimethylphenyl- and the 4-fluorophenyl- group, and
which undergoes nucleophilic reaction with a thiol to suggest a catalytic mechanism that plausibly proceeds
give 7 and selenenic acid 6. The thiophilic attack of a through a transesterification key step.
thiol onto the sulfur atom of 7 affords a disulfide and
converts the selenenyl sulfide into the selenol 1, whose
deprotonation provides the selelenolate 5 to restart the
Conclusion
catalytic cycle.
In summary, we have reported a direct approach to
After complete consumption of the thiol substrate, selenocarbamates through the catalyst-free coupling of
the selenenic acid 6 reacts rapidly with selenol 1 to selenols with isocyanates. Given the mild reaction
conditions, the broad functional group tolerance and
the readily availability of selenols and isocyanates, the
protocol here described can be applied to the synthesis
of a wide range of functionalised selenocarbamates.
Owing to the high selenophilicity of isocyanates,
selenocarbamates were also selectively formed in the
presence of different heteroatom-centered competing
nucleophiles.
The thiol-peroxidase-like catalytic properties of the
so obtained selenocarbamates were investigated. The
results of our study suggest that the catalytic mecha-
nism proceeds through a peroxide-driven transcarba-
moylation reaction engendering thiocarbamates and
selenolate anions. The latter, readily released in the
presence of the oxidant, catalyse the thiol-disulfide
conversion with the concomitant reduction of hydrogen
peroxide to water. Thus, owing to the reactivity of the
selenium-carbon bond, selenocarbamates behave as
equivalents of selenolate anions and can be considered
as precatalysts capable of generating the catalytic
Scheme 3. Proposed catalytic mechanism for the thiol-
peroxidase-like activity of selenocarbamates.
species upon peroxide-mediated activation. Consider-
ing the broad scope of the methodology and the
reactivity of selenocarbamates here described, we
believe that the results of this study could find
application for the preparation and the development of
selenocarbamate-based synthetically and biologically
valuable molecules.
Scheme 4. Synthesis of selenolesters 10a,b.
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Detailed experimental procedures, products characterization,
crystallographic details, and copy of NMR spectra of new
products are reported in the Supplementary Material.
Experimental Section
General Information
All commercial materials were purchased from Merck - Sigma-
Aldrich and used as received, without further purification.
Solvents were dried using a solvent purification system (Pure-
Solv™). Flash column chromatography purifications were
performed with Silica gel 60 (230–400 mesh). Thin layer
chromatography was performed with TLC plates Silica gel 60
F254, which was visualised under UV light, or by staining with
an ethanolic acid solution of p-anisaldehyde followed by
heating. High resolution mass spectra (HRMS) were recorded
by Electrospray Ionization (ESI). GC-MS was performed on a
Varian CP 3800/Saturn 2200 instrument. 1H and 13C NMR
spectra were recorded in CDCl3 using Varian Mercury 400 and
Bruker 400 Ultrashield spectrometers operating at 400 MHz for
1H and 100 MHz for 13C. 77Se NMR spectra were recorded using
a Bruker 400 Ultrashield spectrometer, operating at 76 MHz.
NMR signals were referenced to nondeuterated residual solvent
signals (7.26 ppm for 1H, 77.0 ppm for 13C). Diphenyl
diselenide (PhSe)2 was used as an external reference for 77Se
NMR (δ=461 ppm). Chemical shifts (δ) are given in parts per
million (ppm), and coupling constants (J) are given in Hertz
Acknowledgements
We thank MIUR-Italy (“Progetto Dipartimenti di Eccellenza
2018–2022” allocated to Department of Chemistry “Ugo
Schiff”).
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1
by H NMR spectroscopy. CD3OD was used as the solvent.
Hydrogen peroxide was freshly standardized prior to use.
Synthesis of Selenocarbamates 3
General Procedure. To a stirred solution of selenol 1a–j
(1.0 mmol, 1.1 equiv.) in anhydrous acetonitrile (1 mL) at room
temperature under a nitrogen atmosphere, isocyanate 2a–m
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tography (petroleum ether/Ethyl acetate) to afford selenocarba-
mates 3a–aa.
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Adv. Synth. Catal. 2021, 363, 1–9
8
© 2021 The Authors. Advanced Synthesis & Catalysis
published by Wiley-VCH GmbH
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These are not the final page numbers!

RESEARCH ARTICLE
Click Reaction of Selenols with Isocyanates: Rapid Access to
Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-
peroxidase-Like Catalysts
Adv. Synth. Catal. 2021, 363, 1–9
A. Capperucci, A. Petrucci, C. Faggi, D. Tanini*