Chemoselective isocyanide insertion into the N-H bond using iodine-DMSO: Metal-free access to substituted ureas

Article abstract of DOI:10.1039/c8cc05019h

Insertion of isocyanides into the N-H bond gives access to many medicinally important and structurally diverse complex nitrogen-containing heterocycles. Although the transition metal catalyzed isocyanide insertion into the N-H bond is very common, polymerization of isocyanides in the presence of a transition metal and their strong coordination with metals are the common drawbacks. On the other hand, the inertness of most of the isocyanides towards amines in the absence of a metal catalyst has stymied the growth of the metal-free approach for isocyanide insertion into amines. As a result, only a handful of metal catalysed methods with limited substrate scopes have been reported for the synthesis of ureas via isocyanide insertion into amines and no metal-free version has been reported yet. Interestingly, chemoselective isocyanide insertion into amines has not been reported in the literature. We employed the I₂-DMSO reagent system for the chemoselective synthesis of ureas, where isocyanides react with aliphatic amines only, while aromatic amines need a nucleophilic activator (DABCO) to facilitate the formation of ureas. This method gave direct and chemoselective access to ureas by evading the commonly used yet toxic isocyanates.

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Chemoselective isocyanide insertion into N-H bond using iodine-DMSO:
A metal-free access to substituted ureas
Porag Bora,a and Ghanashyam Bez*a
Received (in XXX, XXX), Accepted (in XXX, XXX)
First published
DOI: 10.1039/b000000x
50 electron-withdrawing groups.2 Only recently, a couple of
5
Insertion of isocyanide into N-H bond gives entry to many
methods have been reported for metal-free isocyanides
insertion into amines; (i) synthesis of perfluoroalkyl substituted
amidines via somophilic isocyanide insertion using
medicinally important and structurally diverse complex nitrogen-
containing heterocycles. Although the transition metal catalyzed
isocyanide insertion to N-H bond is very common, polymerization
of isocyanide in the presence of a transition metal and its strong
triethylamine at 100 oC3 and (ii)
55 carbodiimide synthesis.4
I2/CHP catalyzed
10 coordination with metals are the common drawbacks. On the
other hand, inertness of most of the isocyanides towards amines in
the absence of a metal catalyst has stymied the growth of the
metal-free approach for isocyanide insertion into amine. As a
result, only a handful of metal catalysed methods with limited
15 substrate scope are reported for synthesis of ureas via isocyanide
insertion into amine and no metal-free version is reported yet.
Interestingly, no report on chemoselective isocyanide insertion
into amine is reported in the literature. We have employed I2-
DMSO reagent system for chemoselective synthesis of ureas,
20 where the isocyanides react with aliphatic amines only while the
aromatic amines need a nucleophilic activator (DABCO) to
facilitate the formation of ureas. This method gave direct and
chemoselective entry to the ureas by evading the commonly used
yet toxic isocyanates.
The interest on ureas has recently been tremendously
reinvigorated due to their applications in the field of
stereoselective organocatalysis,5 supramolecular chemistry,6
and drug discovery. The presence of urea scaffold in various
60 natural products,7 agrochemicals8 and pharmaceuticals that
work as antimalarial,9 HIV protease inhibitors,10 p38-MAP
kinase inhibitors,11 raf kinase inhibitor,12 antitumor,13
antinociceptive,14
antiglycation,15
CCK-B
receptor
antagonists,16 endothelin antagonists,17 acyl-CoA cholesterol
65 acyltransferase (ACAT) inhibiting activity,18 L-8 Receptor
antagonsts,19 neuropeptide Y Y5 receptor antagonists,20 and
glucokinase activators21 have contributed enormously to the
recent developments of new synthetic methodologies. Majority
of the reported methods for the synthesis of urea proceed
70 through isocyanate intermediate,22 albeit other interesting
methods have also been reported.23 Some of these methods
have not found desired applications due to their toxicity, poor
stability, low yields, long reaction time, multi-step synthetic
design, high cost and challenging reaction conditions.
75 However, no method has addressed chemoselective synthesis
of ureas starting from aliphatic and aromatic amines.
25
The chemistry of the isocyanides is profoundly different from
the rest of organic chemistry because of both divalent and
tetravalent nature of carbon of the isocyanide group that can
exist as electrophilic carbene and nucleophilic zwitterion. Ever
30 since the synthetic applications of this dual philicity of
isocyanide in the Passerini and Ugi reactions, isocyanides have
been proven as a versatile C1 building block for synthesis of
numerous biologically relevant heterocycles via C−C, C−N,
and C−O bond formation reactions. Specially the application of
35 isocyanide insertion to amine has taken unprecedented stride
for the synthesis of huge libraries of heterocycles having
tremendous structural and medicinal significance. Yet, most of
the reported achievements mainly focus on the metal catalyzed
insertion of isocyanides into amines for the synthesis of
40 nitrogen-containing compounds.
Scheme 1 Synthesis of urea via isocyanide insertion into N-H bond
Although most of the synthesis involving isocyanide insertion
into amines are catalyzed by electrophilic metal catalysts to
activate the weakly nucleophilic isocyanides, the use of
45 isocyanide is handicapped by polymerization in the presence of
a transition metal,1 and strong coordination with metals leading
to reduction of catalytic activity. Its metal-free version also
experiences significant challenges due to the inertness of
amines towards isocyanides, except those activated by
Interestingly, the synthesis of ureas via isocyanide insertion
80 into N-H bond is hardly explored. Only a few metal catalysts
26
viz. bulk gold,24 cobalt(II) acetylacetonate,25 and Cu(OAc)2
have recently been reported for the synthesis of ureas via
insertion of isocyanide into N-H bond. But these methods are
plagued by limited substrate scope,24-26 formation of
85 byproducts24 and poor reactivity with amines.24 Despite the
limitations of metal catalyzed methods, a metal-free approach
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to synthesize ureas via isocyanide insertion into N-H bond has
not been explored due to poor reactivity of isocyanide with
amines in the absence of a metal catalyst (Scheme 1).
between aliphatic and aromatic amines for chemoselective
synthesis of urea derivatives.
25 As a starting point, we chose the reaction of cyclohexyl
isocyanide with cyclohexylamine as the model reaction for the
said synthesis. A series of model reactions were conducted in
DMSO by varying the amount of the iodine and the temperature
(Table 1S in the ESI). Although the reaction was complete with
30 20 mol% of the iodine within 20 h at 100 oC, the optimum
conditions required 1 equiv. of iodine to complete the reaction
Table 1 Synthesis of symmetrical and unsymmetrical ureas from aliphatic
aminesa,b
o
within 1h at 100 C. With the optimized conditions in place, a
few alkyl isocyanides were reacted with various alkyl amines
to study the scope of the reaction (Table 1). Our protocol gave
35 both symmetrical and unsymmetrical ureas with consumate
ease. There was practically no difference in yield of urea
derivatives for the reaction of alkyl isocyanides with 1o and 2o
amines. The electron rich aryl isocyanides (entries 2a-i), which
are less prone to undergo insertion into N-H bond, also gave
40 excellent yield of both di-and trisubstituted urea derivatives
with 1o and 2o amines.
In order to see if this protocol can be applied for synthesis of
chiral ureas, we carried out the reaction of phenylalanine
45 methyl ester with benzyl isocyanide and also cyclohexyl
isocyanide to achieve excellent yields (Scheme 2). Chiral
HPLC analyses revealed complete retention of configuration
without any racemization. At the same time, the methyl ester
functionality was found to be compatible to our reaction
50 conditions.
Scheme 2 Synthesis of chiral ureas
The scope of our method was tested for the synthesis of
carbamates. Surprisingly, when the reaction of cyclohexyl
55 isocyanide with benzyl alcohol was carried out under similar
reaction conditions (Scheme 3), the formation a symmetrical urea
was detected instead of the desired carbamate product. In the
absence of amine, CyNC might have formed isocyanate in the
absence of an amine30 which subsequently formed
5
aReactions are carried out at 1 mmol scale; bIsolated yields are reported.
Given its low cost, ready availability, ease of handling, 60 dicyclohexylurea via moisture-curing process for isocyanates,
nontoxic, and nonmetallic nature, the I2-DMSO reagent system
is finding interesting applications in organic synthesis because
presumably involving adventitious water.31
10 hydroiodic acid generated from iodine in the catalytic process
is oxidised by DMSO to regenerate iodine.27 In continuation of
our interest on development of iodine mediated chemical
transformations,28 we envisioned that highly reversible nature
of binding between isocyanide and iodine29 in forming
15 isocyanide diiodide adduct may be put into use for activation
of weakly nucleophilic isocyanide group. The isocyanide
diiodide can, in principle, facilitate double nucleophilic
addition in the presence of an amine and DMSO to form urea
via insertion of isocyanide into N-H bond. Our investigations
20 led to a hitherto unknown chemoselective isocyanide insertion
into amine that could exploit the difference of nucleophilicity
Scheme 3 Reaction of isocyanide with alcohol
65 Interestingly, the cyclohexyl isocyanide did not react with aniline
also under our reaction conditions, instead N,N′-dicyclohexyl urea
was formed (Scheme 4[a]). This observation suggests that the
electrophilicity of cyclohexyl isocyanide diiodide might not be
enough to react with aromatic amines under our optimized reaction
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conditions. Notably, when yet less electrophilic phenyl isocyanide
was treated with aniline under similar reaction conditions, the
desired product did not form at all after prolong exposure (Scheme
4[b]). It might be due to poor philicity of both phenyl isocyanide
diiodide and aniline under the given reaction conditions.
conditions gave only N-Benzyl-N'-cyclohexylurea in 88% yield
(Scheme 7[a]). The reaction of 2-(4-aminophenyl)ethylamine with
40 cyclohexyl isocyanide (1 equiv.) led to formation of urea
derivative with aliphatic amine and the protection of aromatic
amine was not detected (Scheme 7[b]). The reaction of cyclohexyl
isocyanide (2 equiv.) with 2-amino-1-phenylethanol under the
optimized conditions gave the urea derivative in 85% yield leaving
45 the hydroxy group unaffected (Scheme 7[c]).
5
Scheme 4 Reaction of isocyanides with aniline
10 The fact that N,N′-dicyclohexylurea was formed rather than
formation of the desired unsymmetrical olefin, we performed the
reaction in the absence of aromatic amine to achieve complete
conversion of the starting isocyanide with 47% isolated yield.
Since, no literature report is available for synthesis of symmetrical
15 ureas from isocyanide without employing amine, we explored the
substrate scope for synthesis of symmetrical ureas directly from
the alkyl isocyanides. Our findings on synthesis of symmetrical
ureas from the reaction of alkyl isocyanide with iodine and DMSO
50 Scheme 7 Reaction of isocyanides with aniline
The fact that the reaction of isocyanides under Johnson and
Daughhetee30 conditions takes 24 h to give very low yield of
isocyanate, while the same reaction under our reaction conditions
takes only 4 h with no trace of isocyanate, we propose that the
55 reaction might follow altogether a different route (Scheme 6).
Initially, upon treatment with I2, isocyanides form its diiodide
derivative. The diiodide derivative reacts with amine to form
highly electrophilic hydroiodide salt of N,N'-disubstituted
carbamimidic iodide which then react with DMSO to form the
60 complex A that leads to generation of urea derivative along with
dimethyl sulphide and iodine. The less nucleophilic aromatic
amines might not have reacted with isocyanide diiodide under our
reaction conditions. The addition of highly nucleophilic DABCO
might have activated the isocyanide diiodide by forming a complex
65 B which facilitated the reaction of aromatic amines to form similar
hydroiodide derivative of N,N'-disubstituted carbamimidic iodide.
The source of oxygen was confirmed by 18O isotopic study, where
it was observed that the reaction of benzyl isocyanide with benzyl
amine in the presence of iodine and Me2SO18 under the optimized
70 reaction conditions led to the formation of 18O labelled N,N'-
dibenzyl urea (m/z 243.1425 for M+H peak).
o
at 100 C are shown at Scheme 5. We propose that the reaction
20 might follow the same mechanism (Scheme S1 in the ESI) as
explained in case of Scheme 3.
Scheme 5 Synthesis of symmetrical urea from isocyanide without
using amine
Given the fact that isocyanide dichloride, despite being more
25 electrophilic, reacts with aromatic amine only at very high
temperature,32 we assumed that the reaction between less
electrophilic isocyanide diiodide and aromatic amine is not
favorable. Therefore, we proposed to add a highly nucleophilic
amine to activate the isocyanide diiodide. After screening various
30 amines (Table 2S in the ESI), it was observed that addition of a one
equivalent of DABCO facilitated the formation of diarylureas
(Scheme 6).
Scheme 6 Synthesis of symmetrical urea from isocyanide without
using amine
35 Both intra- and intermolecular chemoselectivity were studied
(Scheme 7). Reaction of cyclohexyl isocyanide (2 equiv.) with an
equimolar mixture of benzylamine and aniline under the optimized
Scheme 9 Plausible mechanism
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a
Department of Chemistry, North Eastern Hill University, Shillong-
793022, Meghalaya, India.. Fax: 91 364 255 8014; Tel: 91 364 272 2624;
20 E-mail: ghanashyambez@yahoo.com
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
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