Aerobic radical-cascade cycloaddition of isocyanides, selenium and imidamides: Facile access to 1,2,4-selenadiazoles under metal-free conditions

Article abstract of DOI:10.1039/c6gc03521c

A novel and facile metal-free method for the green synthesis of 1,2,4-selenadiazol-5-amine derivatives through the aerobic radical-cascade multi-component reactions of isocyanides, selenium powder and imidamides is reported herein. O₂ in the air was employed as the green oxidant to achieve the cycloaddition with the generation of H₂O as the sole by-product. It also features good functional group compatibility and broad substrate scope. In addition, this method was successfully applied to the functionalization of biologically active molecules.

Full text of DOI:10.1039/c6gc03521c

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Aerobic Radical-Cascade Cycloaddition of Isocyanides, Selenium
and Imidamides: Facile Access to 1,2,4-Selenadiazoles under
Metal-Free Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Yi Fang, Zheng-Lin Zhu, Pei Xu, Prof. Dr. Shun-Yi Wang,* and Prof. Dr. Shun-Jun Ji*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Kljnk (1963):
A novel and facile metal-free method for the green synthesis of
1,2,4-selenadiazol-5-amine derivatives through the aerobic
radical-cascade multi-component reactions of isocyanides,
selenium powder and imidamides is reported here. O2 in the air
was employed as the green oxidant to achieve the cycloaddition
with the generation of H2O as the sole by-product. It also features
good functional group compatibility and broad substrate scope. In
addition, this method was successfully applied to the
functionalization of biologically active molecules.
Oxidants
Se
N
N
-90 oC - rt
Se
(1)
(2)
(3)
R
3-87%
R
NH2
R
Oxidants : NBS, DMSO, m-CPBA or 30% H2O2
Takikawa (1991):
1) Br2
NH
N
N
2) KSeCN
Se
NH2
R
36-54%
R
NH2
This work (2016):
NH
R2NC, Se
250 mol% DIPEA
MeCN, 80 oC
under air, 4-8 h
up to 99% yield
N
Se
R1
Organoselenium compounds have shown great diversity and
wide applications in synthetic organic chemistry.1 What’s
more, they have been recognized as active reagents with
potent biological and medical activities.2-5 1,2,4-
Selenadiazoles, analogue of 1,2,4-thiadiazoles,6 are potential
important scaffolds for the construction of bioactive
R2
R1 NH2 HCl
N
N
H
Scheme 1. Synthetic approaches to 1,2,4-selenadiazoles.
compounds. However, the reported approaches to the facile and green approach for the synthesis of 1,2,4-
synthesis of 1,2,4-selenadiazoles are still
rare.7 selenadiazoles is still highly desirable.
Selenocarboxamides were employed as starting materials in
Diazenedicarboxylic acid (DEAD),8 Oxone,9 hypervalent
most of the groundbreaking explorations. In existing methods, iodine compounds10, copper(II) salt11 and element sulphur12
stoichiometric amounts of oxidants7a-e, palladium(II) salt7f or were employed to promote or catalyse the oxidative coupling
toxic liquid bromine7g-h should be used (Scheme 1, eq.1 and 2). of the N-S bond for the synthesis of 1,2,4-thiadiazoles. In
As a result, the yields of products were low and the substrate comparison, selenium shows greater metallic character than
scope was limited, besides, laborious manipulation was sulphur and thus selenium is more susceptible to oxidation. In
required. Noble transition metal catalysts or various view of this fact, we envisage that the synthesis of 1,2,4-
environmental unfriendly additives are required in most of the selenadiazole compounds could be achieved by utilization of
methods. Therefore, developing a novel,
milder oxidizing agent. Oxygen is an ideal oxidant, usually, its
reduction product is water instead of organic or metal wastes,
thus it can be called ‘green oxidant’. So, applying O2 in the
oxidative coupling process of N-Se bond is environmental
friendly.
Retrosynthetic analysis of 1,2,4-selenadiazol-5-amines
show that the assembly of 1,2,4-selenadiazol-5-amines can be
accomplished by using imidamides and isoselenocyanates
(Scheme 2). Imidamides are commercially available from a
wide variety of sources, or they can be easily synthesized from
nitriles13 or esters.14 Isoselenocyanates could be obtained in
situ by mixing selenium powder with isocyanides.15 Besides,
isocyanides are easy to prepare in large amounts with great
diversity.16,17 In addition, selenium powder is an ideal and
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5
TMG
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
50
50
50
50
50
50
80
80
80
80
80
80
80
17
trace
52
direct source to construct organoselenium compounds. In
contrast with inorganic selenium compounds (SeO2, SeCl2,
Na2SeO3, Na2SeO4, KSeCN, etc.), which are highly toxic and
unstable, the selenium powder is hypotoxic and easy to
handle. The ready availability and diversity of the three chunks
also ensure the broad substrate scope of 1,2,4-selenadiazol-5-
amines. As part of our interests in isocyanide chemistry,18,19
herein, we demonstrated a user-friendly and environmentally-
friendly strategy for preparing 1,2,4-selenadiazol-5-amines
through the aerobic radical-cascade multi-component
reactions of isocyanides, selenium powder and imidamides
under metal-free conditions (Scheme 1, eq. 3). The starting
materials are readily available and easy to handle, exploiting
oxygen as the green oxidant with the generation of water as
sole by-product.
6
7
K2CO3
Na2CO3
Cs2CO3
K3PO4
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
8
44
9
57
10
11
12
13
14
15
16
17
38
75
73
DMF
82
MeCN
THF
85
71
Dioxane
MeCN
72
92c
aReaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Se (0.24 mmol), base (0.4
mmol), solvent (2 mL), under air. bYields were determined by LC analysis using
biphenyl as an internal standard. c1a (0.2 mmol), 2a (0.3 mmol), selenium (0.3
mmol) and DIPEA (0.5 mmol).
Scheme 2. Retrosynthetic analysis of 1,2,4-selenadiazol-5-amines.
Results and discussion
With the optimized conditions in hand, we explored the
We initiated the studies by the reaction of benzamidine
hydrochloride (1a) with p-nitrophenyl isocyanide (2a) in the
presence of selenium powder. It was found that N, N-
diisopropylethylamine (DIPEA) served as an efficient base
(Table 1, entry 2), affording the desired product 3a in 73%
yield. Other organic bases (Table 1, entries 1, 3-6) or inorganic
bases (Table 1, entries 7-10) were also investigated, but lower
yields were obtained. Further screening of the reaction
temperatures and solvents showed that conducting the
substrate scope of various isocyanides 2. To our delight, an
array of aromatic isocyanides could participate in this three-
component reaction to give the 1,2,4-selenadiazol-5-amines in
65-95% yields (Table 2, top). Electron-withdrawing groups,
such as nitro (3a
moieties, are compatible with the reaction. Substrates bearing
electron-donating groups, such as methoxy (3e 3f) and methyl
3g) gave better results, leading to the expected products in
, 3b), trifluoromethyl (3c), and cyano (3d)
,
(
o
95%, 95% and 87% yields, respectively. In addition, the iodo
group (3h) was tolerated under current conditions. Moderate
to good yields could also be obtained when aliphatic
isocyanides were employed (Table 2, middle). Tertiary
isocyanides were proven to be suitable candidates for the one-
reaction in MeCN at 80 C gave better results (Table 1, entry
14). Finally, the highest yield (92%) was obtained by increasing
the amount of 2a and selenium powder to 1.5 equivalents and
the amount of DIPEA to 2.5 equivalents (Table 1, entry 17).
Table 1 Optimization of the reaction conditionsa
pot reaction, giving rise to the desired selenadiazoles (3i, 3j,
3k), albeit in moderate yields. In contrast, N-cyclohexyl
substituted isocyanide worked with improved efficiency to
deliver the product 3l in excellent yield. Besides, reactions
involving benzyl isocyanides and ethyl isocyanoacetate
produced 3n and 3o in 80% and 76% yields, respectively.
Disappointedly, we could not obtain products 3m and 3p
under the optimized conditions. Next, we investigated the
substrate scope with respect to the imidamides (Table 2,
bottom). A variety of aromatic imidamides are tolerated, with
the generation of selenadiazoles in high yields. Both substrates
Entry
Base
Et3N
Solvent
DMSO
DMSO
DMSO
DMSO
T [oC]
50
Yield [%]b
1
2
3
4
72
73
70
46
DIPEA
DABCO
pyridine
50
bearing electron-donating (3q
, 3r) and electron-withdrawing
50
groups (3s, 3u, 3v, 3w, 3x) could react smoothly. In addition,
the structure of 3u was unambiguously determined by X-ray
crystallography (see SI for details).20 Fortunately, hydroxyl
50
2 | J. Name., 2012, 00, 1-3
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group was also tolerated, giving 3t in 40% yield. Moreover,
In order to show the efficiency of our method, we
heterocycles, such as pyridine and furan, were compatible explored the scale-up reactions of 1a or 1g with cyclohexyl
with the mild reaction conditions as well, leading to 3y and 3z isocyanide 2l under the standard reaction conditions.
in 74% and 68% yields, respectively.
Gratifyingly, the desired products 3l and 3v were obtained in
90% and 99% yields, respectively. When the amount of 2n was
enlarged to 3 mmol, we were pleased to find that 3n could be
obtained in 78% yield after 6 hours, without compromising
reaction efficiency (Scheme 3). These results suggested that
this method had potential for industrial production.
Table 2 Substrate scope of reactiona,b
To illustrate the importance of the synthetic method, we
applied it to the late-stage modification of the bioactive
natural compound and saccharide compound (Scheme 4).
When we performed the reaction of tocopherol derivative 2o
with 1b under standard conditions, we were able to obtain
48% yield of the desired product 4a. In addition, when
galactose derivative 2p was employed under standard reaction
conditions, we could isolate 4b in 74% yield, providing a new
method for the synthesis of novel biologically and
pharmaceutically active compounds.
Aryl isocyanides
R = 4-NO2, 3a, 90%
3-NO2, 3b, 82%
4-CF3, 3c, 76%
4-CN, 3d, 79%
Se
N
R
R
NH
NH
Se
N
N
NH
I
N
R = 4-OMe, 3e, 95%
3,5-(OMe)2, 3f, 95%
2,6-(Me)2, 3g, 87%
3h, 65%
Se
N
N
Alkyl isocyanides
Se
H
N
Se
CN
NH
NH2
N
Se, DIPEA
Se
N
N
R
Se
N
N
+
O
HCl
R
NH
MeCN, 80 o
C
NH
NH
O
N
N
N
O
2o
1b
under air, 4 h
4a, 48%
3i, 69%
3j, 32%
3k, 45%
O
R =
O
Se
N
Se
N
Se
N
R
NH
NH
NH
N
N
N
D-alpha-Tocopherol
3l, 95%
3m, trace
R = Ph, 3n, 80%
CO2Et, 3o, 76% (6 h)
Ts, 3p, messy
H
CN
N
Se
N
O
O
N
O
NH
NH2
O
Imidamides
Se, DIPEA
O
O
MeO
+
HCl
NO2
O
O
MeCN, 80 o
under air, 4 h
C
O
O
O
OMe
Se
1a
2p
4b, 74%
O
O
R = 4-Me, 3q, 98% (6 h)
2-OEt, 3r, 82% (6 h)
4-F, 3s, 44%
N
Se
N
O
NH
NH
N
N
D-alpha-Galactose
derivative
R
4-OH, 3t, 40%
N
3y, 74%
Scheme 4. Late-stage functionalization of biologically active molecules.
R = 4-Cl, 3u, 94%
4-Br, 3v, 99% (8 h)
3-Br, 3w, 96% (8 h)
4-NO2, 3x, 88%
Se
N
Se
N
NH
NH
N
N
To gain a deep insight into the reaction mechanism, we
conducted several controlled experiments. Firstly, when
radical scavengers TEMPO and BHT were added to the reaction
mixture under standard conditions, 3l could be produced in up
to 87% yield. Although decrease of ca. 10% yield was
observed, the increase of equivalents of TEMPO had no
significant impact on the outcomes (Scheme 5, eq. 4). The
results of radical-inhibition experiments indicated that the
reactions were prone to undergo a non-radical process,
though we could not rule out the existence of radicals
rigorously. TEMPO could act as not only a radical inhibitor, but
also a radical initiator. It is known that two single electrons
exist in the oxygen molecule, thus we proposed that oxygen
might serve as an essential single-electron initiator in the
transformation. As a result, the same reaction under argon
was performed as well. As expected, the reaction could not
occur at all. However, a 81% yield of 3l could be isolated when
additional TEMPO (1.5 equiv.) was employed (Scheme 5, eq.
5). We believed that the single-electron oxidant TEMPO could
facilitate the radical-cascade cyclization reaction, which is also
consistent with the radical-inhibition experiments.
R
O
3z, 68% (5 h)
aReaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), Se (0.45 mmol), DIPEA (0.75
mmol), MeCN (3 mL), 80 oC, under air, 4 h. bIsolated yields.
Scheme 3. Scale-up synthesis of 1,2,4-selenadiazole-5-amines.
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Scheme 6. Plausible reaction mechanism.
second pathway for the formation of intermediate
undergoes deprotonation under the influence of DIPEA or
peroxide anion to yield (Scheme 6, route b). We believe that
TEMPO can trap intermediate to generate , which is
E, then E
3
E
G
unstable under the reaction conditions. As a result, a molecule
of TEMPOH will be eliminated by DIPEA or peroxide anion to
produce 3, which explains the aforementioned results why
TEMPO could not inhibit the reaction.22 The peroxide anion
and proton, which is formed in the reaction, will combine and
thermally decompose to H2O and O2 (Scheme 6, eq. 8). In
addition, TEMPO is regenerated from TEMPOH under the
action of peroxide anion (Scheme 6, eq. 9).23 At present,
neither of the plausible reaction routes could be ruled out.
More control experiments or theoretical calculation should be
conducted to further gain insights into the reaction
mechanism.
Scheme 5. Investigation of reaction mechanism.
Inspired by the above results, a SET (single electron
transfer) process was proposed to elucidate reaction
mechanism (Scheme 6). Firstly, the reaction of isocyanide
with selenium powder gives isoselenocyanate under the
action of DIPEA (Scheme 6, eq. 6). Next, reacts with
imidamide to produce the intermediate . Subsequently, is
oxidized by O2 or superoxide anion radical to give selenium
radical intermediate (Scheme 6, eq. 7). We propose that
may undergo two possible pathways to generate the desired
product . In the first pathway, diselenide intermediate is
generated by homocoupling of C 21
followed by deprotonation
under the action of DIPEA or peroxide anion, to afford product
(Scheme 6, route a). An intramolecular cyclization of is
2
A
A
1
B
B
Conclusions
C
C
In summary, we have developed a practical method to
synthesize
1,2,4-selenadiazole-5-amine
derivatives
in
3
D
moderate to excellent yields by multicomponent reaction of
isocyanides, selenium powder and imidamide compounds
under metal-free conditions. The reaction proceeds under mild
conditions with O2 as green oxidant and no extra catalysts or
oxidants are required. What’s more, this method can be used
for late-stage modification of biologically and pharmaceutically
active molecules, which featured the reaction in the discovery
and development of selenium-containing drugs. A detailed
mechanistic study and further potential applications of this
clean reaction in medicinal chemistry are currently undergoing
in our laboratory.
,
3
C
involved in the
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
China (21372174, 21542015, 21672157), PAPD, and Soochow
University for financial support, and State and Local Joint
Engineering Laboratory for Novel Functional Polymeric
Materials.
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Green Chemistry
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DOI: 10.1039/C6GC03521C
Aerobic Radical-Cascade Cycloaddition of Isocyanides, Selenium
and Imidamides: Facile Access to 1,2,4-Selenadiazoles under
Metal-Free Conditions
Yi Fang, Zheng-Lin Zhu, Pei Xu, Prof. Dr. Shun-Yi Wang,* and Prof. Dr. Shun-Jun Ji*
A facile and method for the synthesis of functionalized 1,2,4-selenadiazoles through aerobic
radical-cascade cyclization of isocyanides, selemium and imidamides is established. The reaction
proceeds smoothly under air atmosphere using O2 as the sole oxidant. This method features
good functional group compatibility, broad substrate scope, and easily available reagents. In
addition, the method was successfully applied to the late-stage functionalization of biologically
active molecules.