Organic Letters
Letter
well tolerated in the reactions with glyceraldehydes 1 and
alkynes 3, thus producing the corresponding cycloadducts in
43−86% yields. Notably, the tetrahydroisoquinoline derivatives
(2a−2e) were well-tolerated in the reaction. Besides, the larger
ring amine azocane 2h also provided the product 4h, though a
slightly lower yield was obtained compared to smaller ring
sizes. Open chained amines were also suitable substrates, which
was demonstrated by the synthesis of products 4i. Substrates
containing terminal olefin groups (2j, 2k) were also suitable in
this A3-coupling/cyclization process. In addition, methyl
substituted amines can be applied, N-methylprop-2-en-1-
amine 2k, 1-(3-bromophenyl)-N-methylmethanamine 2l, and
N-methyl-1-(naphthalene-2-yl)methanamine 2m also afforded
the expected products 4k, 4l, and 4m in reasonable yields.
Terminal arylalkynes with both electron-withdrawing and
electron-donating substituents on the aromatic moiety are well
tolerated (Scheme 4), as demonstrated by the formation of the
desired cyclopentenones under these conditions. To demon-
strate the potential of the product a transformation of 4-(2-
bromophenyl)-2-(dibenzylamino) cyclopent-2-en-1-one 5e
was conducted. Due to the enamine substructure, the obtained
products can also be regarded as masked 1,2-dicarbonyl
compounds, valuable precursors in organic synthesis. A first
exploitation of this reactivity was demonstrated by the
synthesis of cyclopenta[b]quinoxaline derivative 6 that was
synthesized from compound 5e on treatment with benzene-
1,2-diamine (Scheme 5).20
Scheme 5. 1,2-Diketone Reactivity of Products 5
a b
,
Scheme 4. Substrate Scope of Alkynes
To gain some mechanistic insight, isotope-labeling experi-
ments using glyceraldehydes 1, morpholine 2f, and 1-tert-butyl-
4-ethynylbenzene 3b as the model reaction under standard
in detail). Otherwise, propargylamines as the possible reaction
intermediate were treated under the standard conditions, but
no trace of the target compound was found; only a trace of
furan alcohol product could be detected by NMR (see SI in
detail). This clearly demonstrates that the reaction cascade
toward compounds 4 or 5 is not initiated by an A3-coupling
reaction of substrates 1, 2f, and 3i. Furthermore, in order to
prove whether the reaction obtained the target product
through Piancatelli rearrangement, furan alcohol was inves-
tigated with morpholine 2f, but target compound 5i was not
found after 20 h (see SI in detail).
The experiments described above gave us valuable
information on the mechanism of the reaction (Figure 2). A
a
Reaction conditions: A solution of 1 (0.3 mmol), 2 (0.45 mmol), 3
(0.45 mmol), and AuBr3 (5 mol %) were stirred in TFE (1.0 mL) at
b
60 °C for 24 h. Isolated yield.
desired 2,4-substitued cyclopentenone products 5a−5r in
moderate to good yields (40−86%). Moreover, substituents
can be placed in the para-, ortho-, or meta- position of the
aromatic moiety, as shown by the synthesis of products 5a−5f
and 5h−5r. A disubstituted 1-ethynyl-3,5-bis(trifluoromethyl)-
benzene 3r gave the corresponding product 5r in 45% yield.
Among the applied aromatic alkynes, it becomes obvious that
para- substitution in general gives rise to the highest yields,
which indicates that steric parameters might play an influential
role. Among these systems the best yield was obtained for 1-
(tert-butyl)-4-ethynylbenzene 3b that led to the desired
cyclopentenone 5b in excellent 85% yield. Importantly,
heterocyclic arylalkynes (2-ethynylthiophene) was also a
suitable substrate, providing the thiophene product (5g) in
40% yield. Prop-2-ynyl benzene and hex-1-yne, as aliphatic
alkynes, were completely unreactive and did not provide the
Figure 2. Proposed mechanism for the cyclopentenone formation.
possible reaction mechanism using substrate 1, 2a, and 3a as
an example is depicted in Figure 1. Initially, glyceraldehyde 1
and morpholine 2a gives rise to the condensation product A;
this could be followed by dehydration to afford the iminium
ion enol B catalyzed by the acidic TFE. Phenyl acetylene 3a,
which would be activated by the gold catalyst to generate the
corresponding gold acetylide,16a reacts with the iminium ion B
to give the corresponding propargylamines C, which can be
detected with Mass Spectrometry (MS). Nucleophilic attack of
the enol onto the gold activated triple bond then affords D
which after elimination of a proton under release of the catalyst
delivers the final product 4a.
C
Org. Lett. XXXX, XXX, XXX−XXX