Silver-Assisted Oxidative Isocyanide Insertion of Ethers: A Direct Approach to β-Carbonyl α-Iminonitriles

Article abstract of DOI:10.1021/acs.orglett.9b03590

An efficient silver-assisted oxidative coupling of simple ethers with tert-butyl isocyanide was realized in the presence of DDQ. The direct synthesis of high density functional β-carbonyl α-iminonitriles was achieved in a single step with high yields through the synergetic cascade isocyanide insertion into C(sp³)-H bond, where the isocyanide was used as crucial "CN" and "C=N" sources and the tert-butoxyl group acted as the carbonyl source. Diverse reactivity of β-carbonyl α-iminonitriles has been demonstrated.

Full text of DOI:10.1021/acs.orglett.9b03590

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Assisted Oxidative Isocyanide Insertion of Ethers: A Direct
Approach to β‑Carbonyl α‑Iminonitriles
Leiyang Zhao,† Bingxin Liu,† Qitao Tan,† Chang-Hua Ding,*,† and Bin Xu*,†,‡
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient silver-assisted oxidative coupling of simple ethers with tert-butyl isocyanide was realized in the
presence of DDQ. The direct synthesis of high density functional β-carbonyl α-iminonitriles was achieved in a single step with
high yields through the synergetic cascade isocyanide insertion into C(sp3)−H bond, where the isocyanide was used as crucial
“CN” and “CN” sources and the tert-butoxyl group acted as the carbonyl source. Diverse reactivity of β-carbonyl α-
iminonitriles has been demonstrated.
Scheme 1. Synthesis of β-Carbonyl α-Iminonitriles
socyanides have shown a wide variety of applications as
Iversatile building blocks in organic synthesis, medicinal
chemistry, and materials science.1 Over the past few decades,
extensive effects have been devoted to the development of
multicomponent reactions involving isocyanides for the
synthesis of nitrogen-containing heterocycles.1a In contrast,
isocyanide insertion under Lewis acid and transitional-metal
catalysis received less attention although it represented an
efficient approach to construct complicated molecules.1c The
documented isocyanide insertions are mainly focused on
exploring the insertion into heteroatom−hydrogen bonds,2
carbon−halogen bonds,3 C(sp2)−H and C(sp)−H bonds,4
and metal carbenes.5 However, the direct insertion of
isocyanides into C(sp3)−H bonds was scarce1f,6 and remained
challenging because of the high energy barrier for cleaving the
chemically inert C(sp3)−H bonds.
The direct synthesis of highly functionalized compounds
from simple and readily available starting materials is an
appealing but formidable strategy in organic chemistry.
Particularly, direct functionalization of C(sp3)−H bond has
proved to be a challenging task.7 α-Iminonitriles are important
intermediates for the synthesis of functional compounds such
as N-alkyl ketene−imines,8a cyanoenamides,8b amidines,8c and
nitrogen-containing heterocycles,8d which are normally re-
quired multisteps to these moieties. The β-carbonyl α-
iminonitriles, bearing an additional carbonyl group compared
with α-iminonitriles, may demonstrate a rich array of
chemistry.9 Previous methods for their synthesis have been
barely reported, mainly concentrated on using prefunctional-
ized substrates, such as α-amino carbonyl compounds9a,c or β-
carbonyl nitriles,9b as the starting materials and required the
utility of toxic sodium cyanide9a or trimethylsilyl cyanide9c
(Scheme 1). Also, the reactivity of β-carbonyl α-iminonitriles
remains to be further explored. Therefore, the development of
new approaches for their direct access and synthetic
application are extremely attractive, but challenging issues.
During our researches on isocyanide insertion reactions,10
we realized a silver-assisted oxidative coupling of readily
available ethers and tert-butyl isocyanide, affording β-carbonyl
α-iminonitriles in high yields (Scheme 1). The distinct features
of the given chemistry included: (1) direct synthesis of high
density functional β-carbonyl α-iminonitriles was achieved in a
single step through the synergetic cascade isocyanide insertion
into C(sp3)−H bond; (2) both the crucial “CN” and “CN”
sources originated from isocyanide, while the tert-butoxyl
Received: October 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
group acted as the carbonyl source; (3) subtle and diverse
reactivity of produced β-carbonyl α-iminonitriles was revealed.
At the outset of this study, we started our investigation by
exploring the reaction of 1a with tert-butyl isocyanide at 80 °C
in the presence of DDQ11 in chlorobenzene under a nitrogen
atmosphere. Intriguingly, different from the assumed C(sp3)−
H bond amidation product12 or gem-α-iminonitriles,10e the
unexpected β-carbonyl α-iminonitrile product 2a was obtained
in 69% yield (entry 1, Table 1). Encouraged by this initial
the amounts of isocyanide (entry 27) and DDQ (entry 28), we
confirmed that the reaction performed best at 80 °C under a
nitrogen atmosphere using DDQ as the oxidant (entry 10).
Notably, replacing the tert-butoxyl group of 1a with methoxyl
or iso-propoxyl group led to a complicated reaction mixture,
indicating the use of tert-butyl ether is essential for this
reaction.
With the optimized reaction conditions in hand, we next
examined the substrate scope of tert-butyl ethers. As illustrated
in Scheme 2, a wide variety of substitution patterns and
a
Table 1. Optimization of Reaction Conditions
a
Scheme 2. Substrate Scope of tert-Butyl Ethers
temp
(°C)
yield
b
entry
solvent
oxidant
DDQ
additive
atmos
(%)
1
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DMSO
NMP
CH3CN
DCE
toluene
CF3Ph
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
-
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
air
O2
N2
N2
N2
N2
N2
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
80
69
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
BQ
Ti(OiPr)4
FeCl3
AlCl3
CuCl
65
52
66
61
55
61
64
59
82
73
75
74
N.R.
N.R.
34
20
78
AgNO3
AgOAc
Ag2CO3
Ag2O
AgOTf
Cu(OTf)2
Yb(OTf)3
LiOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
71
62
67
78
80
N.R.
N.R.
N.R.
68
36
PIFA
p-chloranil
DDQ
DDQ
c
d
a
t
Reaction conditions: 1a (0.3 mmol), oxidant (0.6 mmol), BuNC
(1.2 mmol), additive (10 mol %), solvent (3.0 mL), 80 °C, 3 h. BQ =
1,4-Benzoquinone. DDQ = 2,3-Dicyano-5,6-dichlorobenzoquinone.
PIFA = [Bis(trifluoroacetoxy)iodo]benzene. DCE = Dichloroethane.
a
t
Reaction conditions: 1 (0.3 mmol), DDQ (0.6 mmol), BuNC (1.2
mmol), AgOTf (10 mol %), and PhCl (3.0 mL), 80 °C, 3 h, under a
b
NMP = N-Methyl pyrrolidone. N.R. = No reaction. Isolated yield.
nitrogen atmosphere. Yields shown are of the isolated products.
c
d
t
0.9 mmo of BuNC was used. 0.3 mmol of DDQ was used.
b
c
t
t
DDQ (0.9 mmol), BuNC (1.5 mmol). DDQ (1.2 mmol), BuNC
(2.4 mmol), AgOTf (20 mol %).
result, various additives were next tested including Ti(OiPr)4,
FeCl3, AlCl3, CuCl, and silver salts (entries 2−10). The yield
of product 2a was improved to 82% when AgOTf was applied
as the additive (entry 10). Other salts bearing triflate anion
were then tested, and AgOTf stood out as the superior choice
due to its higher yield (entries 11−13 vs entry 10).
Optimization of solvents such as DMSO, NMP, acetonitrile,
DCE, toluene, and (trifluoromethyl)benzene indicated chlor-
obenzene was the best choice (entries 14−19 vs entry 10).
After further screening of temperature (entries 20 and 21),
atmosphere (entries 22 and 23), oxidant (entries 24−26), and
functional groups were well tolerated. Aryl tert-butyl ethers
bearing either electron-withdrawing or electron-donating
substituents at the para-position of the aryl ring were smoothly
converted into the corresponding products (2a−2j) in
moderate to good yields (69−92%). The structure of 2i was
further determined by X-ray crystallographic analysis.13
Substrates containing different groups, such as alkynyl (2k),
alkenyl (2l), alkyls (2m and 2n), halides (2o, 2q−2r), and
alkoxy (2s) were compatible with this reaction as well,
B
DOI: 10.1021/acs.orglett.9b03590
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Organic Letters
Letter
regardless of their different electronic properties and meta- or
ortho-positions. The newly established protocol was not
limited to a simple monosubstituted benzene ring since
substrates containing a naphthyl (2t) or thienyl (2u) group
could also be transformed into the corresponding products in
good yields. As indicated in Scheme 2, the reaction efficiency
was not affected substantially by the substituents of substrates,
and the corresponding arylacetimidoyl cyanides were provided
in high yields. Notably, substrate 1m with two potential
reactive sites, gave only mono-β-carbonyl-α-iminonitrile
product 2m. The reason may be attributed to the deactivation
effect of the formed β-carbonyl-α-iminonitrile group by
prohibiting the formation of the second oxonium. Interestingly,
when the two potential reactive sites of substrate 1v were
detached by a biphenyl, the two positions reacted almost
independently and afforded the di-iminonitrile product 2v in
high yield. However, trying to use [3-(tert-butoxy)propyl]-
benzene, (tert-butoxymethyl)pyridine, or 2-methyl-1,2,3,4-
tetrahydroisoquinoline as substrates failed under the standard
conditions. No product was observed when cyclohexyl-, 2,6-
dimethylphenyl-, or 1-adamantyl isocyanide was used instead
to react with 1a. Furthermore, this reaction can be performed
on a gram scale. The reaction of 1a (10.0 mmol) with tert-butyl
isocyanide could afford 2a in 75% yield under the optimized
reaction conditions (Scheme 3).
with benzene 1,2-diamine, the use of alkyl diamines gave
different results with substitution of the cyanide group and
afforded dihydropyrazins 6 and 7 in almost quantitative yields
in the absence of external additives. The selective reduction of
the β-carbonyl group in the presence of α-iminonitrile is
challenging. After tedious reductant screening, selective
reduction of carbonyl group of 2a was realized using
LiAlH(OtBu)3 as the reducing reagent, affording β-hydroxy-
α-iminonitrile 8 in 95% yield. Notably, only LiAlH(OtBu)3 was
viable for this transformation since other reducing reagents
including DIBAL-H, L-selectride, NaBH3CN, and NaBH4
resulted in a complicated mixture. Product 8 was subjected
to a further reduction with NaBH4, affording trans-β-hydroxy-
α-aminopropanenitrile 9 in 93% yield with 20:1 dr. This
approach represents a stereoselective and efficient route to β-
hydroxy-α-aminopropanenitrile, avoiding the use of a toxic
cyanide source, which was usually employed by the well-known
methods.15 The trans configuration of product 9 was
determined by converting it into the corresponding oxazoli-
din-2-one 10 in which the cis configuration was assigned by
NOE experiment.16 The above transformations demonstrated
that β-carbonyl α-iminonitriles exhibited diverse reactivity
toward nucleophiles and allowed the straightforward assembly
of molecular complexity, indicating them as a promising and
valuable building block in organic synthesis.
To define the possible intermediates and pathway, several
control experiments were carried out as shown in Scheme 4.
Scheme 3. Synthetic Applications of Product 2a
Scheme 4. Preliminary Mechanistic Studies
To illustrate the synthetic utility and demonstrate the broad
application prospects of the reaction, further transformations
of given product 2a were investigated, as shown in Scheme 3.
The cyclization of 2a with 1,2-diaminobenzene proceeded
smoothly to afford 2-cyano quinoxaline 3 in 95% yield in the
presence of AcOH and NaOAc,9c which could be subsequently
oxidized to the corresponding 1,4-di-N-oxide 4. It is worth
noting that quinoxaline 1,4-di-N-oxides are the core structure
of natural products and bioactive compounds,14 for example, 3-
aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives have
been reported as hypoxic selective antitumor agents.14b
Interestingly, the reaction of 2a with 2-aminophenol or 2-
aminobenzenethiol occurred selectively at the α-iminonitrile
group, providing benzo[d]oxazole 5a and benzo[d]thiazole 5b
in 80% and 58% yield, respectively. In contrast to the reaction
When [(tert-pentyloxy)methyl]benzene (1w) was used as the
starting material under standard reaction conditions, Bu-
t
substituted 2a could be isolated in 72% yield without
observation of tAm-substituted byproduct 2a′, which suggested
that the tert-pentyloxy group of 1w was cleaved during the
t
reaction, and the Bu substitution in 2a was derived from tert-
butyl isocyanide (eq 1, Scheme 4). To determine the ether
transformation and capture the cleaved fragmentation, [1-
(benzyloxy)-ethane-1,1-diyl]-dibenzene (1x) was applied to
react with tert-butyl isocyanide, providing 2a and ethene-1,1-
diyldibenzene in 7% and 84% yield, respectively (eq 2), which
indicated that the cleaved group of ether substrate was
converted into an alkene. Considering the results that the
reaction was not significantly inhibited upon addition of 1,4-
dinitrobenzene, TEMPO, pent-1-en-3-one, or ethene-1,1-
C
DOI: 10.1021/acs.orglett.9b03590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diyldibenzene (eq 3), a radical pathway might be ruled out at
this stage.
Although the detailed reaction pathway remained to be
clarified, a plausible mechanism for this reaction was proposed
on the basis of the above results (Scheme 5). Initially, benzyl
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xubin@shu.edu.cn.
*E-mail: dingchanghua@shu.edu.cn.
ORCID
Scheme 5. Plausible Mechanism
Qitao Tan: 0000-0002-6220-651X
Chang-Hua Ding: 0000-0002-4628-4016
Bin Xu: 0000-0002-9251-6930
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21672136, 21871174, 21772215) and Innovation
Program of Shanghai Municipal Education Commission
(2019-01-07-00-09-E00008) for financial support. The authors
thank Prof. Hongmei Deng (Laboratory for Microstructures,
SHU) and Mr. Hui Wang (Department of Chemistry, SHU)
for spectroscopic measurements.
tert-butyl ether 1a was oxidized by DDQ through a reversible
process to form a highly reactive benzoxy cation intermediate
A,17 followed by the isocyanide addition to give the nitrilium
ion intermediate B. The role of silver triflate may be attributed
to the formation of a coordinated silver-isocyanide complex to
increase the nucleophilic reactivity of isocyanide.18 The attack
by a second molecule of isocyanide on cation B afforded
intermediate C, which would furnish the double isocyanide
insertion product D by the leaving of a tert-butyl cation
through β-scission of the imidoyl cation. Finally, the product
2a could be afforded smoothly from intermediate D via
eliminating tert-butyl carbon cation with concomitant ex-
pulsion of isobutene.
In summary, we have developed a silver-assisted oxidative
coupling of ethers with tert-butyl isocyanide, which cultivated
the direct synthesis of β-carbonyl α-iminonitriles in one pot
with high yield. The reaction was achieved through the
synergetic cascade isocyanide insertion into C(sp3)−H bond.
Both the crucial “CN” and “CN” sources originated from
isocyanide, while tert-butoxyl group acted as the carbonyl
source. This protocol featured operational simplicity, good
functional group tolerance, and wide substrate scope. Various
applications of given products allowed the straightforward
assembly of molecular complexity and indicated them as
promising and valuable building blocks in organic synthesis.
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