Gold-catalyzed synthesis of substituted 2-aminofurans via formal [4+1]-cycloadditions on 3-en-1-ynamides

Article abstract of DOI:10.1039/c2cc33030j

Gold-catalyzed formal [4+1]-cycloadditions between 3-en-1-ynamides 1 and 8-methylquinoline oxide are reported. The success of this reaction relies on a hypothetic oxa-Nazarov cyclization on gold-stabilized allylic cations. Preliminary results on a new 1,2-difunctionalization of 3-en-1-ynamide are also reported.

Full text of DOI:10.1039/c2cc33030j

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COMMUNICATION
Gold-catalyzed synthesis of substituted 2-aminofurans via
formal [4+1]-cycloadditions on 3-en-1-ynamidesw
Ramesh B. Dateer, Kamalkishore Pati and Rai-Shung Liu*
Received 27th April 2012, Accepted 18th May 2012
DOI: 10.1039/c2cc33030j
Gold-catalyzed formal [4+1]-cycloadditions between 3-en-1-
ynamides 1 and 8-methylquinoline oxide are reported. The success
of this reaction relies on a hypothetic oxa-Nazarov cyclization
on gold-stabilized allylic cations. Preliminary results on a new
1,2-difunctionalization of 3-en-1-ynamide are also reported.
Scheme 1 shows a working mechanism to realize a
[4+1]-cycloaddition of 3-en-1-ynamide 1a with an oxide. We
selected compounds 1 as a target because its p-alkyne structure
A is visualized as a vinyl ketenimine A0,11 which poses a framework
similar to those in the literature (eqn (1)). We envisage that an
intermolecular addition of organic oxide to species A0 is a viable
route for the synthesis of highly substituted 2-aminofurans 2,12
providing that an oxa-Nazarov cyclization13 is operable on
gold-stabilized allylic cation C0 that is an important contribu-
tion of alkenyl gold carbenoids C.14 Herein, we report the
success of this cycloaddition using a cationic gold catalyst.
Table 1 presents the realization of an intermolecular [4+1]-
cycloaddition of 3-en-1-ynamide 1a using various oxides
(1.2 equiv.) and gold catalysts (5 mol%). We isolated three
products 2a–4a in various proportions with a complete
consumption of starting 1a. Dicarbonyl compound 3a was
generated from a second oxidation of gold carbenoid C whereas
3-alkenylamide 4a was derived from an alkyne hydration.15,16
We examined the reaction using PPh3AuCl/AgSbF6 and
8-methylquinoline oxide I in DCE (80 1C, 15 h), from which
we obtained three compounds, i.e. 2a, 3a and 4a in 11, 27
and 55% yields, respectively (entry 1). To our satisfaction,
the use of P(t-Bu)2(o-biphenyl)AuCl/AgSbF6 greatly improved
the chemoselectivity to give 2-aminofuran species 2a (88%)
exclusively (entry 2). We varied the gold catalysts with
P(t-Bu)2(o-biphenyl)AuCl/AgNTf2 and IPrAuCl/AgSbF6
(IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene), which
showed inferior chemoselectivity, giving additional dicarbonyl
compound 3a in 10 and 40% yields, respectively (entries 3, 4).
IPrAuSbF6 seems to show a strong alkenylgold carbenoid
Transition-metal catalyzed [4+1]-cycloaddition reactions of
1,3-conjugated compounds with small molecules have found
widespread applications in the synthesis of five-membered
carbo- or heterocycles.1 Eqn (1) shows the general patterns
of reported reactions, including enones,2 unsaturated imines,3
vinylallenes,4 diallenes,5 allenylketones6 and allenylimines6
serving as four-atom building units, and carbon monoxide,
isocyanides and diazocarbonyl species acting as one-atom
units (eqn (1)).2–6 3-En-1-ynes are readily available as
1,3-dienes, but their metal-catalyzed cycloadditions are much
less explored. Only few [4+2]-reactions of 3-en-1-ynes with
alkynes have been documented.7,8 We are aware of no reports
on the [4+1]-cycloadditons of 3-en-1-ynes with a suitable
one-atom donor. In this work, we report a new formal
[4+1]-cycloaddition on activated 3-en-1-ynes using organic
oxides as an oxygen donor,9 as depicted in eqn (2). Zhang
reported10 that gold complexes catalyzed the intermolecular
oxidations of alkynes with pyridine-based oxides, generating
a-oxo gold carbenoids (eqn (3))
ð1Þ
ð2Þ
ð3Þ
character
C (Scheme 1) to give preferably dicarbonyl
species 3a, whereas P(t-Bu)2(o-biphenyl)AuSbF6 tends to
exhibit a Au(I)-stabilized allyl cation C0 to achieve an oxa-
Nazarov cyclization. We also tested other commonly used
Department of Chemistry, National Tsing-Hua University, Hsinchu,
Taiwan, ROC. E-mail: rsliu@mx.nthu.edu.tw
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for new compounds. CCDC
876013. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc33030j
Scheme 1 A proposed mechanism for [4+1]-cycloaddition.
c
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Table 2 [4+1]-cycloaddition reactions on various 3-en-1-ynamidesa
Table 1 Catalytic reactions on various gold catalysts
Entry
[Au]b
Oxide
t/h (T/1C)
2ac
3a
4a
1
2
3
4
5
6
7
PPh3AuSbF6
LAuSbF6
LAuNTf2
IPrAuSbF6
LAuSbF6
LAuSbF6
LAuSbF6
I
I
I
I
II
III
IV
15 (80)
10 (80)
12 (80)
10 (80)
20 (80)
15 (28)
8 (28)
11
88
78
30
75
58
45
27
—
10
40
—
5
55
—
—
—
20
—
20
10
a
Oxides: I = 8-methylquinoline oxide; II = 3,5-dichloropyridine
oxide; III = N-benzylideneaniline oxide; IV = diphenyl sulfoxide.
b
[1a] = 0.01 M, L. = P(t-Bu)2(o-biphenyl), IPr = 1,3-bis(diisopropyl-
phenyl)imidazol-2-ylidene. c Product yields are reported after separation
from a silica column.
organic oxides (1.2 equiv. entries 5–7) at optimized conditions;
only 3,5-dichloropyridine oxide (II) gave a satisfactory yield
(75%) of 2-aminofuran 2a whereas N-benzylideneaniline oxide
(III), and diphenyl sulfoxide (IV) gave 2-aminofuran 2a in
decreased yields (58–45%), together with undesired products 3a
and 4a in 5–20% yields. The frequent occurrence of dicarbonyl
compound 3a among our tests reveals the intermediacy of gold
carbenoids C.
We prepared various 3-en-1-ynamides 1b–o to assess the
scope of substrate and results are presented in Table 2. For
substrates 1b–g bearing various sulfonamides (entries 1–6), we
obtained their 2-aminofuran products 2b–g in satisfactory
yields (68–91%), but their optimized conditions have various
temperature ranges (28–80 1C). Room-temperature reactions
were achieved for 2-aminofuran products 2d, 2e and 2g bearing
N-phenylmethanesulfonamide, N-cyclopropylmethanesulfonamide
and butan-4-sultam, whereas the other substrates were run with
elevated temperatures (60–80 1C). The molecular structure of
2-aminofuran product 2d was determined by X-ray diffraction
studyw. We speculate that sulfonamides bearing an electron-
withdrawing group (R1 = Ph, cyclopropyl) enhance the
electrophilicity of vinyl ketenimine A0 to accelerate the
cycloaddition. For butane-4-sultam species 1g, its cyclic sulfona-
mide geometry around the electrophilic ketenimine generates a less
hindered environment to facilitate an oxide attack. We prepared
3-en-1-ynamide 1h bearing R2 = n-propyl, giving desired product
2h in 56% yield (entry 7). This reaction is compatible with
substrates 1i–l bearing both electron-deficient and rich benzenes
Ar = 4-XC6H4 (X = F, Cl, Me, MeO, entries 8–11), giving
expected 2-aminofurans 2i–l in satisfactory yields (76–83%).
This new cycloaddition is efficient for the room-temperature
synthesis of heterobiaryl compounds including 2-(furanyl)-
thiophene (2m, 67%), 2-(furanyl)benzothiophene (2n, 74%) and
2-(furanyl)benzofuran 2o (71%, entries 12–14).
a
L = P(t-Bu)2(o-biphenyl), [enyne] = 0.01 M; product yields are
reported after separation from a silica column.
Scheme 2 Reactions on 3-en-1-ynamides 1p and 1q.
cyclization in DCE (28 1C, 12 h) gave dicarbonyl compound
3p (52% yield) and unreacted 1p (28% recovery), reflecting
that the intermediate has a strong gold carbene character C.
We also prepared 2-cyclohexenyl-1-ethynylamide 1q, which
upon gold-catalyzed oxidative cyclization gave dienylamide 5q
in 65% yield via a rapid loss of a proton from the gold-
stabilized allylic cation C0.
Scheme 3 shows a new development of the difunctionalization
of 3-en-1-ynamide 1a via an initial [4+1]-cycloaddition, followed
by iodination with N-iodosuccinimide (NIS, 1.1 equiv.); the
resulting 2-amino-3-iodofuran derivative 6 was obtained in
63% yield. This reaction proceeded rapidly in DCE at 28 1C
(3 h) whereas the [4+1]-cycloaddition of starting 1a was
only achieved at 80 1C (10 h); accordingly, protodeauration
The presence of an alkyl at the C(3)-carbon of 3-en-1-
ynamides increases the character of gold-stabilized allylic
cation C0 to facilitate an oxa-Nazarov cyclization. As shown
in Scheme 2, we prepared 4-phenyl-3-en-1-ynamide 1p bearing
a reactive NPhMs substituent, but its gold-catalyzed oxidative
c
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Scheme 3 Gold-catalyzed difunctionalizations of 3-en-1-ynamides.
of species E appears to be very slow.17 In a separate experi-
ment, the treatment of 2-aminofuran 2a with NIS (1.1 equiv.)
in DCE 28 1C (6 h) gave 2-en-1,4-dione 7 in 81% yield via
hydration of oxidized cationic species F. As depicted in
Scheme 4, this new synthetic method is applicable also to an
efficient synthesis (76%) of new oligomer 9 with 76% yield,
via a two-fold [4+1]-cycloaddition of benzene compound 8
bearing two para-3-en-1-ynamide groups.
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Scheme 4 Two-fold [4+1]-cycloaddition reactions.
In summary, we report here a new gold-catalyzed [4+1]-
12 For synthesis of 2-aminofuran derivatives, see selected examples:
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cycloaddition reaction between 3-en-1-ynamides
1 and
8-methylquinoline oxide. This reaction is efficient for the
synthesis of highly substituted furans from readily available
3-en-1-ynamides. The success of this reaction relies on a
hypothetic oxa-Nazarov cyclization on gold-stabilized allylic
cation C0. The efficiency of the reaction is influenced by the
types of sulfonamide and aryl substituents on 3-en-1-ynamides.
This work will help to design new cycloaddition reactions
on 3-en-1-ynes which has been largely ignored in organic
synthesis.
13 Unlike aza-Nazarov cyclizations,13b,c gold-catalyzed oxa-Nazarov reac-
tion was just reported when we prepared this manuscript. See ref. 13a for
a completely different reaction. (a) S. Kramer and T. Skrydstrup, Angew.
Chem., Int. Ed., 2012, DOI: 10.1002/anie201200307; (b) D. A. Klumpp,
Y. Zhang, M. J. O’Connor, P. M. Esteves and L. S. de Almeida,
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This work was supported by National Science Council,
National Tsing-Hua University and the Ministry of Education
in Taiwan.
Notes and references
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15 In the presence of external water (1.0 equiv.), the use of
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7202 Chem. Commun., 2012, 48, 7200–7202
This journal is The Royal Society of Chemistry 2012