Difunctionalization of the Isocyano Group: Atom-Economic Synthesis of Pyrimidinediones

Article abstract of DOI:10.1055/s-0037-1610348

The exploration of synthetic methods involving the formation of new chemical bonds at both the nitrogen and carbons atoms of the isocyano group would largely enrich the structural diversity of compounds. Herein, we disclosed a silver-catalyzed difunctiona

Full text of DOI:10.1055/s-0037-1610348

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
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J. Lang, Y. Wei
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Difunctionalization of the Isocyano Group: Atom-Economic
Synthesis of Pyrimidinediones
O
Jian Lang
O
R
N
Ye Wei*
0
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0
0-
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5
2
Ag
+
O18
CN R
C
O18
N
N
H
School of Chemistry and Chemical Engineering, Southwest University,
Chongqing 400715, P. R. of China
weiye712@swu.edu.cn
difunctionalization
of isocyano group
Dedicated to Professor Weiping Su
O
O18
isocyanide
insertion
Mumm-type
rearrangement
C
R
N
N
H
Received: 29.09.2018
Accepted after revision: 12.11.2018
Published online: 11.12.2018
DOI: 10.1055/s-0037-1610348; Art ID: st-2018-p0622-sp
Abstract The exploration of synthetic methods involving the forma-
tion of new chemical bonds at both the nitrogen and carbons atoms of
the isocyano group would largely enrich the structural diversity of com-
pounds. Herein, we disclosed a silver-catalyzed difunctionalization of
the isocyano group with cyclic oximes. This method can generate a
great array of structurally novel and interesting pyrimidinediones and
features excellent atom economy, good functional group compatibility,
and amenability to late-stage modifications.
Ye Wei was born in Sichuan province, China, in 1982. He earned his
BSc degree in 2005 from Huaqiao University and his PhD degree in
2010 from Fujian Institute of Research on the Structure of Matter,
Key words silver, isocyanides, oximes, insertion, N-heterocycles
Chinese Academy of Sciences, under the guidance of Prof. Weiping Su.
After a two-year postdoctoral appointment with Prof. Naohiko Yoshikai
at Nanyang Technological University, he went back to China to join the
College of Pharmacy at Third Military Medical University as an Associate
Professor. He was promoted to Professor in 2015. Recently, he moved
to the School of Chemistry and Chemical Engineering at Southwest
University. Wei’s research interests are primarily focused on atom- and
step-economic synthetic methods, with an emphasis on the transition-
metal-mediated novel organic transformations to construct hetero-
cyclic scaffolds.
Isocyanides can participate in numerous organic trans-
formations, such as Ugi and Passerini reactions, for the con-
struction of structurally interesting and useful organic mol-
ecules.1 Therefore, the exploration of the isocyanides as
useful building blocks has attracted considerable attention
from organic, medicinal, and material chemists. The power
of the isocyanides in the generation of chemical diversity
would be attributed to the unique reactivity of the isocyano
group. Both nitrogen and carbon atoms of the isocyano
group are potentially reactive sites toward new chemical-
bond formation. However, a vast amount of the known re-
actions merely involves the functionalization of the termi-
nal carbon atom, and the nitrogen atom remains intact
(monofunctionalization of the isocyano group, Scheme 1,
a). In order to exploit new reactivity profiles of the isocya-
nides and enrich the structural diversity of molecules, it is
highly desirable to develop new synthetic strategies, utiliz-
ing both the nitrogen and carbon atoms as the reactive
sites, to simultaneously construct new chemical bonds in
one step (difunctionalization of the isocyano group,
Scheme 1, b). In this regard, some important work has been
reported. For example, three-component reaction of isocya-
nides, allyl carbonate, and trimethylsilylazide has been uti-
lized to generate allyl cyanamides.2 In addition, cycloaddi-
tion reactions between isocyanides and propargylamines,
between isocyanides and enamides, and between two dif-
ferent isocyanides have been realized for the construction
of N-heterocycles.3–5 Despite these significant progress, the
reaction type and substrate scope remain limited.
It has been well-established that the isocyanides can
take part in various insertion reactions, such as the inser-
tion into heteroatom–hydrogen, carbon–hydrogen, carbon–
heteroatom, and carbon–metal bonds.6 These studies and
the carbene-like reactivity of the isocyano group prompted
us to expand the realm of the isocyanide insertion chemis-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
J. Lang, Y. Wei
Synpacts
Synlett
O
mono-
functionalization
O
C–C, C–N, or C–O
formed at C atom
Ag2O (5 mol%)
N
CO2Et
(a)
pyridine (1 equiv)
O
CN
CO2Et
+
N
1,4-dioxane
80 °C, 6 h
O
Ph
N
H
Ph
R
N
C
1
2
3, 92%
(b)
C–C or C–O and N–C or N–N
formed at C and N atoms
di-
Scheme 2 Reaction of 3-phenyl-5-isoxazolone with ethyl isocyano-
functionalization
acetate
Scheme 1 Functionalization of the isocyano group
try. Our recent work concerning oxime N–O bond transfor-
mations (NOT)7 let us raise a question: Can we realize the
isocyanide insertion into the oxime N–O bond and thereby
to develop new synthetic methods toward the construction
of valuable scaffolds, in particular N-heterocycles (Figure
1)?
O
O
R
Ag2O (5 mol%)
N
O
+
CN
R
pyridine (1 equiv)
N
N
H
O
1,4-dioxane, 80 °C, 6 h
oximes
O
O
O
4, R = 4-OMe, 79%
5, R = 4-NMe2, 87%
6, R = 4-CF3, 65%
7, R = 4-I, 91%
8, R = 3-Br, 82%
9, R = 2-Me, 91%
N
CO2Et
N
CO2Et
N
CO2Et
N
H
O
N
H
O
N
H
O
N
R
S
10, 75%
11, 86%
O
O
O
N
CO2Et
N
CO2Et
N
CO2Et
MeO2C
N
H
O
N
H
O
N
H
O
12, 83%
13, 97%
14, 79%
O
O
O
N
CO2Et
N
CO2Et
N
CO2Et
O
N
H
Me
N
H
O
Ph
N
H
O
15, 74%
16, 65%
17, 91%
isocyanides
O
O
O
O
N
Ts
N
PO(OEt)2
N
N
N
N
Ph
N
O
N
Ph
N
H
O
Ph
N
H
O
H
Ph
N
O
H
18, 78%
19, 82%
20, 78%
21, 45%
biologically active compounds
O
COOEt
O
O
N
N
COOEt
N
O
H
O
NH
N
N
H
H
H
MeO
22, 81%
Cl
23, 73%
Scheme 3 Substrate scope of the reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
J. Lang, Y. Wei
Synpacts
Synlett
nenolone- and cetirizine-derived cyclic oximes, and the
corresponding products were obtained in good yields (22
and 23).
heteroatom–H bond
C–H bond
C–M bond
The pyrimidinedione 25 prepared by our method can be
easily converted into compound 26, a precursor of autotax-
in inhibitor 27, through ester hydrolysis and amide-forma-
tion steps in 86% total yield (Scheme 4). This synthetic ap-
proach shows remarkable superiority over the reported
methods. The latter involves six synthetic steps including
N-protection/deprotection and Pd-catalyzed Suzuki cou-
pling reaction.9
isocyanide
insertion
N–O bond
C–heteroatom bond
Figure 1 Profiles for isocyanide insertions
With such an idea in mind, we initially investigated the
reactions of various acyclic ketoximes or aldoximes with
isocyanides. However, the insertion products were not ob-
served. We then turned our attention into isoxazol-5-ones,
a class of cyclic oximes. It has been known that the N–O
bond of such compounds can be cleaved by low-valent Pd
and Ir complexes.8 Thus, numerous experimentations have
been performed to study the reactions between isoxazol-5-
ones and isocyanides with Pd or Ir salts as the catalyst. Spe-
cifically, 3-phenyl-5-isoxazolone (1) and ethyl isocyanoace-
tate (2) were chosen as the substrates. Nonetheless, nega-
tive results were obtained. Interestingly, we serendipitously
found that the reaction of 1 with 2 gave rise to pyrimidine-
dione 3 with Ag2O as a catalyst. In terms of the product
structure, the terminal carbon atom of the isocyano group
formally inserted into the N–O bond, and two C–N bonds
and one C=O bond were newly generated at the isocyano
group. The survey of various reaction parameters revealed
that the model reaction delivered 3 in 92% yield in the pres-
ence of Ag2O (5 mol%) and pyridine (1 equiv) at 80 °C in 1,4-
dioxane within 6 h (Scheme 2).
This method exhibited good substrate scope and func-
tional group compatibility, a series of representative exam-
ples are shown in Scheme 3. Electron-donating and elec-
tron-withdrawing substituents on the aromatic ring did not
influence the reaction seriously (4–8). Oxime bearing an or-
tho-methyl group on the aryl ring also displayed good reac-
tivity (9). In addition, thiophene- and pyrrole-derived cyclic
oximes were suitable for the transformation (10 and 11).
Besides (hetero)aromatic functionalities, several other
groups including cyclopropyl (12), ester (14), and polyenic
(16) groups, can be introduced into the pyrimidinediones.
The isocyanides bearing acidic α-C–H bonds generally
showed good reactivity, such as p-tolylsulfonylmethyl iso-
cyanide (18), diethyl isocyanomethylphosphonate (19), and
benzotriazol-1-ylmethyl isocyanide (20). Yet, 1-isocy-
anonaphthalene displayed moderate reactivity in the reac-
tion (21). Unfortunately, tert-butyl isocyanide exhibited
significantly low reactivity (<10%) and cyclohexyl isocya-
nide and n-butyl isocyanide showed no reactivity in the
transformation. More significantly, our method was amena-
ble to the late-stage modification of the biologically active
molecules. For instance, the reaction was amenable to preg-
O
O
N
CO2Et
O
CN
CO2Et
N
N
H
O
standard conditions
Cl
Cl
24
25, 65%
(1) ester hydrolysis: 95%
(2) amide formation: 91%
O
N
H
N
COOH
Ph
N
O
H
O
ref 9
N
CO2Me
Ph
O
N
O
Cl
N
O
H
NC
Cl
27 (autotaxin inhibitor)
26
Scheme 4 Synthesis of an autotaxin inhibitor
Several experiments were conducted to gain insight into
the reaction mechanism (Scheme 5). O18-labeled substrate
1-O18 reacted with ethyl isocyanoacetate to deliver the tar-
get product, and the mass spectrometry result indicated
that the O18 atom was incorporated into the final product
O
O
O18
N
COOEt
CN
CO2Et
(a)
standard conditions
Ph
N
O
N
Ph
H
1-O18
3-O18, 90%
MS (ESI): m/z [M + Na]+
calcd.: 299.0894
found: 299.0896
O
N
O
HO
HO
COOEt
CN
CO2Et
(b)
(c)
O
standard conditions
N
H
O
N
H
28
29, 67%
O
O
CN
CO2Et
N
COOEt
O
standard conditions
N
Ph
N
H
O
Ph
1
BHT (2 equiv), 3 = 90%
Scheme 5 Mechanistic investigation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
J. Lang, Y. Wei
Synpacts
Synlett
(Scheme 5, a). Thus, all of the atoms in the two substrates
entered into the target product 3-O18. In addition, the reac-
tion of isoxazol-5(2H)-one derivative 28 with ethyl isocyano-
acetate also yielded the pyrimidinedione 29 in 67% yield
(Scheme 5, b), which suggested that the isoxazol-5(2H)-one
might be an intermediate in the reaction. Moreover, the
radical mechanism might be ruled out because the addition
of 2,6-di-tert-butyl-4-methylphenol (BHT) did not inhibit
the reaction (Scheme 5, c).
In conclusion, the difunctionalization of the isocyano
group has been achieved by means of the isocyanide inser-
tion into the oxime N–O bond, which can generate a great
majority of structurally new and interesting pyrimidinedi-
ones. It can be envisioned that with the strategy of difunc-
tionalization of the isocyano group, more useful and im-
portant N-heterocycles would be generated in the near fu-
ture.
The plausible reaction pathways for the Ag-catalyzed
pyrimidinedione synthesis are depicted in Scheme 6. The
cyclic oxime 30 might tautomerize to the isoxazol-5(2H)-
one 30′10 that then reacts with Ag(I) salt to generate a silver
complex 31 with pyridine as a base. Subsequent isocyanide
32 insertion produces a species 33, followed by ring open-
ing to deliver a silver-nitrene species 34.11 After intramolec-
ular nitrene insertion into the C–Ag bond,12 a species 35
could be formed, which then occurs protonation to furnish
an imidate 36. Such a compound could undergo ring open-
ing13 to produce a zwitterion 37, which is then converted
into the final product 38 through intramolecular C–N bond
formation. Another role of the pyridine might be to en-
hance the solubility of the silver salt due to its good coordi-
nation ability to the silver salt.14
Funding Information
This work was supported by the NSFC (No. 21772231, 21302220), the
Southwest University (No. SWU118129), the Natural Science Founda-
tion of Chongqing (No. cstc2016jcyjA0008), and Fundamental
Research Funds for the Central Universities.
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O
R2
O
N
R1
30
O
R2
O
N
R1
H
O
30'
R2
R1
O
R3
Ag(I)/pyridine
N
H
N
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pyH+
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O
R2
R2
R1
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R1
O
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R2
catalytic cycle
R3
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R1
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R3
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31 Ag
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H
Ag
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O
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CN R3
O
32
R2
O
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R2
R1
R3
O
O
O
R2
R1
R3
O
N
N
R1
R3
N
Ag
34
N
Ag
N
H
33
38
Scheme 6 Hypothesis for the reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
J. Lang, Y. Wei
Synpacts
Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E