Assembly of 5-Aminoimidazoles via Palladium-Catalysed Double Isocyanide Insertion Reaction

Article abstract of DOI:10.1002/adsc.202100142

A palladium-catalysed tandem cyclisation reaction of amidoximes, isocyanides and amines to produce 5-aminoimidazoles was developed. Various 5-aminoimidazoles were prepared in good to excellent yields under mild conditions. This elegant domino process involves the effective cleavage of the N?O bond and the formation of new C?C and C?N bonds in a single operation. (Figure presented.).

Full text of DOI:10.1002/adsc.202100142

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DOI: 10.1002/adsc.202100142
Assembly of 5-Aminoimidazoles via Palladium-Catalysed Double
Isocyanide Insertion Reaction
Xu Wang,+a, b,* Jin-Ping Fu,+b Jia-Hui Mo,b Yu-Hong Tian,b Chun-You Liu,b
Hai-Tao Tang,a Zi-Jun Sun,c,* and Ying-Ming Pana,*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China
E-mail: wangxu504@126.com; panym@mailbox.gxnu.edu.cn
Guangxi Key Laboratory of Green Processing of Sugar Resources, College of Biological and Chemical Engineering, Guangxi
b
University of Science and Technology, Liuzhou 545006, People’s Republic of China
Research Centre for Materials Science and Engineering, Guangxi University of Science and Technology, Liuzhou 545006,
c
People’s Republic of China
E-mail: sunzijun@gxust.edu.cn
+
These authors contributed equally to this work.
Manuscript received: February 1, 2021; Revised manuscript received: March 30, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100142
Rh-catalysed transannulation of 1,2,4-oxadiazoles with
Abstract: A palladium-catalysed tandem cyclisa-
tion reaction of amidoximes, isocyanides and
1-sulfonyl-1,2,3-triazoles (Scheme 1c) are notable
examples.[10] Despite this considerable progress, the
amines to produce 5-aminoimidazoles was devel-
syntheses of 5-aminoimidazoles are largely less devel-
oped. Various 5-aminoimidazoles were prepared in
oped, and they are often restricted by various draw-
good to excellent yields under mild conditions. This
backs (e.g., tedious synthetic sequences, harsh syn-
elegant domino process involves the effective
thesis conditions, special starting materials and use of
cleavage of the NÀ O bond and the formation of new
expensive catalysts), which seriously limit their further
applications. Therefore, the development of a more
efficient protocol for synthesising 5-aminoimidazoles
CÀ C and CÀ N bonds in a single operation.
is highly desirable.
Keywords: Palladium-catalysed; Tandem cyclisation
Isocyanides serve as highly versatile building
reaction; Isocyanide insertion; 5-Aminoimidazole
blocks in organic synthesis owing to the carbene-like
derivatives
reactivity of their divalent carbon atom.[12] Palladium-
catalysed isocyanide insertion reaction is a powerful
route
for
constructing
nitrogen-containing
compounds.[13] Most methods involve aryl- or alkenyl-
palladium species formation and sequential coupling
with different nucleophilic partners to afford the target
Introduction
Imidazoles are an important class of heterocycles with molecules. However, relatively few works have fo-
wide applications in natural
products,[1] cused on multiple insertion of isocyanides.[14] In this
pharmaceuticals[2] and materials.[3] Among functionally regard, the exploration of novel palladium intermedi-
substituted imidazole derivatives, 5-aminoimidazoles ates to merge with multiple isocyanide insertions is
have attracted increased attention owing to their very important. Recently, we reported a palladium-
excellent biological activities, such as Hsp90 catalysed multiple isocyanide insertion reaction to
inhibition,[4] adenosine A2A receptor antagonism[5] and synthesise thiazole derivatives.[15] Inspired by this
antiplatelet[6] and antimicrobial activities.[7] Accord- previous work and in continuation of our interest in the
ingly, great efforts have been devoted to the prepara- development of isocyanides,[16] we report herein a
tion of 5-aminoimidazole derivatives.[6,8–11] Multistep convenient approach for synthesising 5-aminoimida-
cascade reaction (Scheme 1a),[8] microwave-assisted zoles from amidoximes, isocyanides and amines. This
multicomponent domino cyclisation (Scheme 1b)[9] and strategy enables effective assembly of 5-aminoimida-
Adv. Synth. Catal. 2021, 363, 1–6
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Scheme 1. Reported methods for the synthesis of 5-amino-
imidazoles.
zoles through CÀ C and CÀ N bond formations and
NÀ O bond cleavage.
Initially,
N’-hydroxybenzimidamide
(1a,
0.2 mmol), tert-butyl isocyanide (2a, 0.4 mmol) and
amines (3a, 0.3 mmol) were used as model substrates
to optimise reaction conditions (Table 1). Fortunately,
the target compound 4aaa was obtained in 47% yield
with PdCl2 (5 mol%) as catalyst, PPh3 (10 mol%) as
°
ligand in DMSO and sealed tube at 80 C for 6 h
(Table 1, entry 1). Subsequently, various palladium
salts were tested, among which Pd(OAc)2 provided the
best result (Table 1, entries 2–7). In the absence of
PPh3, no product 4aaa was detected (Table 1, entry 8).
By contrast, poor results were achieved with PCy3,
PMe3, PBu3 and DPPP ligands compared with PPh3
(Table 1, entries 9–12). Other solvents, such as DMF,
NMP, DMA, toluene and 1,4-dioxane, also gave
compound 4aaa but in lower yields (Table 1, en-
tries 13–17). When the reaction was conducted in DCE
or CH3CN, no 4aaa was formed (Table 1, entries 18
°
and 19). Further investigation indicated that 100 C
was the most appropriate temperature, producing 4aaa
in 84% yield (entries 20–22). Notably, reducing the
amount of solvent to 0.5 mL increased the yield of
4aaa to 92% (entries 21 vs. 23).
However, reduction of PPh3 to 5 mol% led to a
sharp decrease in yield to 79% (Table 1, entry 24).
Hence, 1a (0.2 mmol), 2a (0.4 mmol), 3a (0.3 mmol),
Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) in DMSO
Scheme 2. Synthesis of 5-aminoimidazoles 4.[a,b]
°
(0.5 mL) and sealed tube at 100 C were deemed as the
optimised conditions.
Under the optimised conditions, various substituted (Scheme 2). Reactions with hydroxybenzimidamide
amidoximes, isocyanides and anilines were examined containing electron-donating groups (e.g., 4-Me,
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Table 1. Optimisation of reaction conditions.[a]
°
Entry
Catalyst
Ligand
Solvent
Temp ( C)
Yield (%)[b]
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
PdBr2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
90
100
110
100
100
47
62
32
45
29
26
52
ND
34
27
31
40
50
29
43
11
trace
ND
ND
72
84
77
92
79
PdCl2(PPh3)2
Pd(acac)2
Pd(dba)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
PCy3
PMe3
PBu3
DPPP
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
23[c]
24[c,d]
NMP
DMA
toluene
1,4-dioxane
DCE
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a (0.3 mmol), Pd catalyst (5 mol%), ligand (10 mol%), solvents (1 mL),
6 h, sealed tube.
[b] Isolated yield of the pure product based on 1a.
[c] Solvents (0.5 mL).
[d] ligand (5 mol%). ND=not detected.
4-OMe, 2-Me, 3,4-dimethyl and 3,2-dimethyl groups) 4-OMe and 4-OH, at the aryl ring could lead to the
and electron-withdrawing groups (e.g., 4-Cl and 4- target products 4aab–4aad in 80%–88% yields, and
CF3) on the phenyl rings were well tolerated, obtaining some substrates bearing an electron-withdrawing
the corresponding products (4baa–4hac) in good to group, including 4-Cl, 4-F 4-CF3, 4-CN and 4-
excellent yields (75%–91%). The slightly lower yields CO2CH3, at the benzene ring also performed smoothly
of 4fac and 4hac were attributed to the ortho steric and gave the desired products 4aae–4aai in 57%–86%
hindrance of the hydroxybenzimidamide. The yields. Delightfully, 6-amino-1H-indazole (3k) could
naphthyl-substituted amidoxime was still effective at also be successfully transferred to the desired product
forming the desired products 4iaa and 4iac in 86% 4aak in 87% yield. Nevertheless, the alkyl amines
and 90% yields, respectively. The structure of 4iaa were not applicable for this reaction under the current
was confirmed by X-ray crystal structure analysis (for conditions, the alkyl amines presumably are not
details see the Supporting Information).[17] Further- conducive to the amine exchange process Moreover,
more, 2-thienyl-bearing amidoximes were found to be 1,1,3,3-tetramethylbutyl isocyanide (2b) and adaman-
good substrates, affording the products 4jab and 4jac tyl isocyanide (2c) were tolerated in this transforma-
in 70% and 72% yields, respectively. We then tion, affording the desired products 4bbb and 4bcc in
investigated the substrate scope with respect to amines 76% and 71% yields, respectively. Unfortunately,
(3b–3k). Various anilines were compatible with the when the functional isocyanide 2d was used, the
reaction conditions, delivering the desired products in product 4ada was afforded in poor yield, and no
moderate to good yields. Anilines 3b, 3c and 3d desired products were detected when isocyanides
possessing an electron-donating group, such as 4-Me,
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substituted with a primary alkyl group (2e) or an aryl
group (2f) were used.
To probe the reaction mechanism, we performed
several control experiments (Scheme 4). N’-Hydroxy-
To demonstrate the synthetic utility of this reaction, benzenecarboximidamide (1a) was subjected to the
we conducted the reaction in a gram-scale (Scheme 3). optimised reaction conditions, and the compound
The multicomponent reaction could be easily scaled up benzamidine (1a’) could be isolated in 93% yield
to 4 mmol under the standard conditions, and the (Scheme 4a). However, when the reaction of benzami-
corresponding product 4aaa was formed in 87% yield. dine (1a’), tertbutylisonitrile (2a) and aniline (3a) was
treated under standard conditions, no target product
4aaa was observed (Scheme 4b), indicating that 1a’
was not a possible intermediate of the transformation.
We then conducted the reaction of 1a with 2a under
standard conditions (Scheme 4c); (Z)-N-(tert-butyl)-4-
(tert-butylimino)-2-phenyl-4H-imidazol-5-amine 5aa
([M+Na]+ =307.1884) was detected in 94% GC-
yield. Subsequently, 3a was added, and the reaction
°
mixture was heated at 100 C for 1 h; the desired
product 4aaa was obtained in 91% yield, suggesting
that 5aa was an intermediate in the current reaction.
According to the above observations and previous
reports,[14f,18] a plausible reaction mechanism for this
transformation was outlined and depicted in Scheme 5.
The first step is the formation of palladium species A
via the oxidative addition of 1a with L2Pd(0), followed
by the double insertion of isocyanide 2a to generate
intermediate B, which can undergo cyclopalladation to
give the palladacyclic complex C. Subsequent reduc-
tive elimination process in C lead to intermediate D.
Isomerisation of intermediate D provides compound
5aa. Eventually, the target product 4aaa is obtained
by an amine exchange process between aniline 3a and
5aa.
Scheme 3. Gram scale experiment.
Scheme 4. Control experiments.
In conclusion, we discovered an efficient method
for synthesising 5-aminoimidazole derivatives via
palladium-catalysed multicomponent reactions involv-
ing isocyanide insertion. In view of this method’s
desirable features, such as readily available starting
materials, operational simplicity, mild reaction condi-
tions, moderate to excellent yields and good tolerance
to scale-up synthesis, it is a powerful and appealing
route for the rapid assembly of diverse 5-amino-
imidazoles.
Experimental Section
The reaction mixture of 1 (0.2 mmol), 2 (0.4 mmol), 3
(0.3 mmol), Pd(OAc)2 (5 mol%), PPh3 (10 mol%) and DMSO
°
(0.5 mL) at 100 C for 6 h in sealed tube was monitored
periodically via TLC. Upon completion, the reaction mixture
was diluted with water (30 mL) and extracted with ethyl acetate
(3×30 mL). The combined organic layers were washed with
water and brine, dried over Na2SO4 and filtered. The solvent
was removed under vacuum. The residue was purified by flash
column chromatography to afford 5-aminoimidazole 4.
Scheme 5. Possible reaction mechanism.
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