An efficient synthesis of 2,5-diimino-furans via Pd-catalyzed cyclization of bromoacrylamides and isocyanides

Article abstract of DOI:10.1039/c3cc47724j

A novel palladium-catalyzed cyclization of bromoacrylamides with isocyanides gives substituted 2,5-diimino-furans, which can be used as the precursor of maleamides. This reaction presumably proceeds through the oxygen atom of the amide moiety of the bromoacrylamides coordinated to the Pd(ii) centre as a key step.

Full text of DOI:10.1039/c3cc47724j

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An efficient synthesis of 2,5-diimino-furans via
Pd-catalyzed cyclization of bromoacrylamides
and isocyanides†
Cite this: Chem. Commun., 2014,
50, 2037
Received 8th October 2013,
Accepted 19th December 2013
Huanfeng Jiang,* Meizhou Yin, Yibiao Li, Bifu Liu, Jinwu Zhao and Wanqing Wu
DOI: 10.1039/c3cc47724j
www.rsc.org/chemcomm
A novel palladium-catalyzed cyclization of bromoacrylamides with 2,5-diimino-furans from bromoacrylamides and isocyanides in
isocyanides gives substituted 2,5-diimino-furans, which can be used the presence of a palladium catalyst.12
as the precursor of maleamides. This synthesis likely proceeds, after
We initiated the investigation by using N-(tert-butyl)-3-
isonitrile insertion into C–Pd(II) bond, through the coordination of bromo-2-phenylacrylamide (1a) and tert-butyl isocyanide (2a)
the amide oxygen atom to the Pd(II) centre as a key step.
as the model substrates for optimization of this process. The
screening of conditions was conducted with respect to different
Furan derivatives, as featured moieties, occur as important scaffolds bases, palladium catalysts, solvents, and the results are summar-
in a number of pharmaceuticals and organic materials.1 Moreover, ized in Table 1. When the reaction was carried out in the presence
functionalized furans are widely employed as versatile building blocks of Pd(OAc)2 (5 mol%), CsF (2.0 equiv.) and DMSO (2 mL) at 90 1C
to fabricate complicated natural products and biologically active for 12 h, 2,5-diimino-3-phenyl-furan (3a) was obtained in 75%
molecules.2 Thus, the development of novel and efficient strategies GC yield (Table 1, entry 1). Then, the effect of base on this
for the assembly of furan derivatives is one of the most active areas of
modern synthetic organic chemistry. Although numerous strategies
Table 1 Screening for optimal reaction conditionsa
have been developed for the synthesis of furans,3 there are still
opportunities for the development of novel procedures for the
synthesis of new and interesting furan derivatives.
Isocyanides are versatile synthons in organic chemistry, acting as
isoelectronic species of carbon monoxide.4 Accompanied with the
prosperous development of the transition metal-catalyzed reactions
in the past decades, using isocyanides as precursors for the synthesis
of various heterocycles has become a very attractive branch of
modern organic synthesis.5–9 Among them, the noble metal
palladium-catalyzed reactions represent an important subclass and
have attracted great attention.5 Besides palladium catalysts, copper,6
titanium,7 silver8 and rhodium9 have also been employed in catalytic
reactions involving isocyanides to construct various useful hetero-
cycles. Bromoacrylamides are an important class of Br-containing
amides and potential precursors for the synthesis of numerous
natural products and potent pharmaceuticals.10 Based on our interest
in the palladium-catalyzed reactions involving Br-containing mole-
cules such as bromoalkynes or isocyanides,11 herein, for the first time,
we present a facile and efficient method for the construction of
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(PPh3)4
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CsF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
Dioxane
DMSO
DMSO
DMSO
75
90
37
71
n.d.
86
82
85
80
n.d.
54
n.d.
n.d.
95 (93)
71
K2CO3
t-BuOK
Cs2CO3
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14c
15d
16e
43
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn;
Fax: +86 20-87112906; Tel: +86 20-87112906
a
Unless otherwise noted, all reactions were performed with 1a
(0.2 mmol), 2a (0.24 mmol), palladium catalyst (5 mol%), base
(0.4 mmol) and 2.0 mL solvent. The reaction mixture was stirred at
b
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, copies of 1H and 13C NMR spectra for selected
compounds. See DOI: 10.1039/c3cc47724j
90 1C for 12 h. n.d. = not determined. GC yields determined for 1a
c
are given. Number in parentheses is isolated yield. At 90 1C for 2 h.
d
e
2 mol% Pd(OAc)2 was used at 90 1C for 2 h. At 70 1C for 2 h.
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reaction was examined. To our delight, the yield was improved to to excellent yields (Table 2, 3a–3i, 3x). To our delight, 2-alkyl
90% when K2CO3 was employed (Table 1, entry 2). No desired substituted bromoacrylamides, such as N-(tert-butyl)-2-(bromo-
product was obtained in the absence of a base (Table 1, entry 5). methylene)-octanamide and N-(tert-butyl)-2-(bromomethylene)-4-
These results suggested that base was critical for this reaction. cyanobutanamide, could efficiently undergo the transformation
Replacing K2CO3 by t-BuOK or Cs2CO3 only gave 37% and 71% to yield the target products in 95% and 93% yields, respectively
yields respectively (Table 1, entries 3 and 4). After testing different (Table 2, 3j and 3k). Even N-(tert-butyl)-3-bromo-2-(thiophen-2-
palladium catalysts, it was found that the yield of the desired yl)acrylamide could provide the corresponding product in very
product 3a decreased when using other Pd catalysts instead of good yield (Table 2, 3w). Furthermore, when the tert-butyl group
Pd(OAc)2 (Table 1, entries 6–9). And without palladium species the was replaced by other functional groups, such as sterically-hindered
reaction could not occur (Table 1, entry 10). Solvent screening 1,1,3,3-tetramethylbutyl or cyclohexyl in the N-(tert-butyl)-3-
revealed that DMSO appeared to be the best solvent. Other solvents bromo-2-(4-chlorophenyl)acrylamide species, the process gave
such as N,N-dimethylformamide (DMF), CH3CN, and 1,4-dioxane the desired 2,5-diimino-furans in 90% and 83% yields, respec-
all showed inferior results and no product or only low yield was tively (Table 2, 3l and 3m).
obtained (Table 1, entries 11–13). Moreover, reducing the reaction
Diverse isocyanides were then tested. It was found that
time to 2 h led to a higher yield of 95% (Table 1, entry 14). However, 2,6-dimethylphenyl isocyanide could undergo the reaction
when the Pd(OAc)2 loading was reduced to 2 mol%, lower yield smoothly and the target product was obtained in 88% isolated
was obtained (Table 1, entry 15). Then the reaction temperature yield (Table 2, 3n). However, when 1-isocyano-4-methoxybenzene
was lowered to 70 1C, the yield of the target product decreased was used, no desired product was detected (Table 2, 3o). Even when
to only 43% (Table 1, entry 16). Taking all the above results into the sterically bulky isocyanides such as 1,1,3,3-tetramethylbutyl
account, the factors reported in entry 14 of Table 1 were chosen isocyanide and cyclohexyl isocyanide were used, the reaction
as the optimal reaction conditions.
afforded the corresponding products in 90% and 74% yields
To evaluate the efficiency and generality of this process, a number (Table 2, 3p and 3q). Our experimental results also showed that
of bromoacrylamides and isocyanides were examined under our primary isocyanides were qualified reaction partners and gave
optimized reaction conditions (Table 2). Various bromoacrylamides the expected 2,5-diimino-furans in moderate to good yields
were firstly screened. As shown in Table 2, 2-substituted benzene (Table 2, 3r and 3s).
bromoacrylamides were all good substrates and bromoacrylamides
During the course of our study, we found that when the
possessing either electron-donating or electron-withdrawing groups 2,5-diimino-furan derivatives were treated with silica gel in
on 2-benzene gave the corresponding 2,5-diimino-furans in good CH2Cl2 at room temperature for 12 h, 2,5-diimino-furans could
undergo hydrolysis readily to afford the corresponding maleamide
skeletons in nearly quantitative yields which are an important class
Table 2 Palladium-catalyzed synthesis of 2,5-diimino-furans from bromo-
acrylamides and isocyanidesa
of amides and have a very wide range of applications in the synthesis
of numerous pesticides, potent pharmaceuticals as well as in
electrochemistry.13 All furans we obtained could undergo hydrolysis,
and some examples have been shown below (Fig. 1).
A plausible reaction mechanism is depicted in Fig. 2.5,11 Initial
oxidative addition of bromoacrylamide 1 to Pd(0) species affords
the vinyl palladium intermediate A, which is converted into inter-
mediate B by the migratory insertion of isocyanide 2. Subsequently,
the amide oxygen atom of B coordinates to the Pd(II) center to give
intermediate C. Then in the presence of a base, a molecule of HBr
will be eliminated to give complex D.14 Finally, the annulated
product 3 was formed through the reductive elimination of D with
simultaneous formation of Pd(0) species.
a
Reagents and conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2
(5 mol%) and DMSO (2.0 mL), at 90 1C for 2 h unless otherwise noted. Fig. 1 Transformations of maleamides.
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In summary, we have developed a facile and efficient method
for the synthesis of 2,5-diimino-furans from bromoacrylamides
and isocyanides. The reaction proceeded smoothly and rapidly to
afford the desired furan products in good yields and selectivity.
Moreover, the reaction could be completed at a very rapid stage
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Research Program of China (973 Program) (2011CB808600),
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