Synthesis of 2-aminofurans and 2-unsubstituted furans via carbenoid-mediated [3 + 2] cycloaddition

Article abstract of DOI:10.1039/c2cc18139h

An efficient dual synthetic manifold for 2-aminofurans and 2-unsubstituted furans has been developed. The carbenoid-mediated [3 + 2] cycloaddition of copper carbenoids with enamines provides 2-amino-2,3-dihydrofurans which serve as common intermediates for both 2-aminofurans and 2-unsubstituted furans. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc18139h

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COMMUNICATION
Synthesis of 2-aminofurans and 2-unsubstituted furans via
carbenoid-mediated [3 + 2] cycloadditionw
Yaojia Jiang, Vanessa Zhong Yue Khong, Emmanuvel Lourdusamy and Cheol-Min Park*
Received 29th December 2011, Accepted 30th January 2012
DOI: 10.1039/c2cc18139h
An efficient dual synthetic manifold for 2-aminofurans and
2-unsubstituted furans has been developed. The carbenoid-mediated
[3 + 2] cycloaddition of copper carbenoids with enamines provides
2-amino-2,3-dihydrofurans which serve as common intermediates
for both 2-aminofurans and 2-unsubstituted furans.
ð1Þ
Furans represent an important class of heterocycles due to
We commenced with screening of various metal salts for the
cycloaddition of 1a with 2a (Table 1). The resulting cycloadducts
were exposed to ambient air for oxidation to give 3aa, which was
identified as an optimal oxidant while screening various oxidation
conditions (Table 2). While Rh2(OAc)4 failed to give the
corresponding cycloadduct, use of copper salts gave more
promising results, among which Cu(hfacac)2 was found to be
optimal, affording the product in 72% yield (Table 1, entry 6).
A brief examination of reaction temperature and solvents revealed
that the reaction proceeds most efficiently in dichloroethane at
60 1C. The yield of 3aa was substantially lower when refluxing
dichloroethane was employed (Table 1, entry 7). Among the
solvents examined, dichloroethane was found to be optimal
(Table 1, entries 6 vs. 8–10).
their prevalence in many biologically active compounds
including natural products and pharmaceuticals.1 2-Aminofurans
serve as versatile synthetic intermediates that have found their
utility in the synthesis of various useful compounds including
aniline derivatives,2 cyclohexenones,3 pyrroles,4 and maleic
anhydrides.5 Despite their broad utility, the availability of
synthetic methods is rather limited, typically relying on cyclization
of nitriles6 and reduction of 2-nitrofurans.7 Limitations of these
methods, however, include requirement of multistep synthesis and
inability to provide furans with a wide range of amino groups,
typically limited to those with primary amines. Nucleophilic
displacement of activated furans with amines has also been
reported.8 While several synthetic methods for 2-amidofurans
have been developed,9 those that provide 2-aminofurans bearing
substituted amines with simultaneous formation of furan cores
are scarce.10
With the optimal conditions for the cycloaddition in hand,
we turned our attention to the oxidation of 2-amino-2,
3-dihydrofurans to 2-aminofurans (Table 2). Exposure of
cycloadduct 30aa to various oxidants provided 2-aminofuran
Carbenoids have shown their versatility in the synthesis of
various heterocycles11 for which effective strategies have been
developed including insertion reaction,12 cyclopropanation
followed by rearrangement,13 and cycloaddition.14 Synthesis
of furans based on the reaction of carbenoids has also been
reported.15 Given that enamines can be readily prepared with
a variety of amines, we envisioned that cycloaddition of
carbenoids with enamines may give rise to 2-aminofurans upon
oxidation of the cycloadducts 2-amino-2,3-dihydrofurans
(eqn (1)). Alternatively, this approach may also provide an
efficient route to 2-unsubstituted furans by elimination of amines
from the common intermediate, 2-amino-2,3-dihydrofurans.
Herein, we wish to describe an efficient dual synthetic manifold
for 2-aminofurans and 2-unsubstituted furans.
Table 1 Optimization of cycloaddition
Entry
Catalysta
Solventb
Yieldc (%)
1
2
3
4
5
6
7
8
Rh2(OAc)4
Cu(OTf)
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Benzene
PhCF3
1,4-Dioxane
0
31
33
19
20
72
48d
36
45
trace
Cu(acac)2
Cu(OAc)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore. E-mail: cmpark@ntu.edu.sg;
Fax: +65-6513-2748; Tel: +65-6513-2748
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc18139h
9
10
a
acac = acetylacetonate, hfacac = hexafluoroacetylacetonate. b DCE =
dichloroethane. c Determined by NMR vs. standard. d Reaction performed
at 80 1C.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3133–3135 3133

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Table 2 Optimization of oxidation of 2-amino-2,3-dihydrofuran
nature of 2-aminofurans requires extremely mild oxidation
conditions.
Next, we examined the substrate scope for the synthesis of
2-aminofurans (Table 3). The reaction of various diazo compounds
with enamines was shown to produce 2-aminofurans in good
yields. Examination of b-amino acrylates bearing different amino
substituents revealed that the reaction tolerates a wide range of
amines including acyclic, cyclic, and aromatic amines to give
the corresponding 2-aminofurans (Table 3, 3ba–bd). In addition,
2-aminofurans functionalized with ketones could be readily
prepared by employing 3-amino-2-alkenones in place of b-amino
acrylates (Table 3, 3b0e).
Entry
Oxidanta
Solventb
Yieldc (%)
1
2
3
4
5
6
7
8
MCPBA
DDQ
Ag2O
Cu(OAc)2
Mn(OAc)3
CAN
DCM
34
52
36
42
45
49
—
72
Toluene
Benzene
DCE
AcOH
CH3CN
DCE
1 atm O2
1 atm Air
The generality of the reaction was also examined with a
variety of a-diazo-b-keto esters bearing substituents with
distinct steric and electronic influences. Alkyl substituted
diazo compounds afforded the corresponding 2-aminofurans
in good yields (Table 3, 3ca–ea). Furthermore, vinyl substituted
diazo compound 1f also gave the corresponding 2-aminofuran
3fa in 76% yield. Diazo compounds with electron-rich and
deficient aryl groups also gave the corresponding products in
good yields (Table 3, 3aa, 3ga, and 3ha). In addition, use of
g-ethoxycarbonyl diazo compound 1i led to the formation of
the highly functionalized 2-aminofuran 3ia in 60% yield. Reaction
of a-diazo-b-diketones also smoothly provided 2-aminofurans
functionalized with ketone moieties (Table 3, 3ja and 3ka).
Furthermore, reaction of unsymmetrical a-diazo-b-diketone 1l
with 2a led to regioselective formation of 3la arising from the
more reactive aliphatic ketone participating in the cycloaddition.
Next, we examined the feasibility of access to 2-unsubstituted
furans by elimination of amines from 2-amino-2,3-dihydrofuran
intermediates. Thus, subjection of a-diazo-b-diketone 1j and
b-amino acrylate 2a to the same reaction conditions (6 mol%
Cu(hfacac)2, dichloroethane, 60 1C, 4 h) provided 2-amino-2,
DCE
a
MCPBA = meta-chloroperbenzoic acid, DDQ = 2,3-dichloro-5,
6-dicyano-1,4-benzoquinone, CAN = cerium ammonium nitrate.
b
c
DCE = dichloroethane. Determined by NMR vs. standard.
3aa in albeit low to moderate yields (Table 2, entries 1–6).
Also, use of 1 atm of oxygen resulted in complete decomposition
of the substrate (Table 2, entry 7). Gratifyingly, when ambient air
was used as an oxidant, the reaction proceeded smoothly to give
3aa in 72% yield (Table 2, entry 8). Presumably, the sensitive
Table 3 Substrate scope for 2-aminofuransa
Table 4 Substrate scope for 2-unsubstituted furansa
a
Yield of isolated products. b Reaction performed at 60 1C. c Reaction
performed at 80 1C. d Product obtained without acid treatment. e Reaction
performed at RT. f Reaction performed overnight.
a
Yield of isolated products.
c
3134 Chem. Commun., 2012, 48, 3133–3135
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3-dihydrofuran which upon heating in the presence of
p-toluenesulfonic acid afforded furan 4ja. Encouraged by this
result, we examined the influence of structural alteration of
coupling partners (Table 4). We observed that elimination of
amines occurs spontaneously for the diazo compounds with
mono ketones obviating acid treatment (see the footnotes to
Table 4). Use of 3-amino-2-alkenone 2e in place of b-amino
acrylate also gave 4je in 71% yield. Reaction of cyclic a-diazo-
b-diketone 1m smoothly proceeded to give fused bicyclic furan
4me. In addition to a-diazo-b-dicarbonyl compounds, a-diazo-a-
aryl ketone 1n afforded aryl substituted furan 4na. More elaborate
a-diazo-a-aryl ketones bearing alkyl and aryl moieties allowed for
the formation of the corresponding furans (Table 4, 4oe and 4pe).
Furthermore, reaction of diazo compound 1q bearing a 2-furanyl
group with 1a also smoothly proceeded to give 4qa in 61% yield.
Use of b-tetralone-derived diazo compound 1r gave the tricyclic
furan 4re in good yield, resulting from spontaneous oxidation.
Mechanistically, we propose that nucleophilic attack of B
on carbenoid A leads to formation of C that may undergo
either cyclopropanation to give D followed by ring expansion
or direct cyclization of E via metallotropy to afford F (eqn (2)).
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ð2Þ
In summary, we described an efficient dual synthetic manifold
for both 2-aminofurans and 2-unsubstituted furans. This has been
achieved by reaction of carbenoids with enamines to afford
2-amino-2,3-dihydrofurans, which depending on the choice
of subsequent conditions furnish either 2-aminofurans or
2-unsubstituted furans in good yields.
We gratefully acknowledge Nanyang Technological University
Start Up Grant and Tier 1 Grant RG 25/09 for the funding of
this research.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3133–3135 3135