Gold-Catalyzed Cascade Cyclization of 2-Alkynyl-N-Propargylanilines by Rearrangement of a Propargyl Group

Article abstract of DOI:10.1002/anie.201502256

Gold catalysis enables direct construction of tetracyclic fused indolines through the migration of a propargyl substituent from an aniline nitrogen atom to the C3-position of an indole from 2-alkynyl-N-propargylanilines. This reaction provides rapid access to fused three-dimensional indolines in a single operation with the formation of four bonds and three rings.

Full text of DOI:10.1002/anie.201502256

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International Edition: DOI: 10.1002/anie.201502256
German Edition: DOI: 10.1002/ange.201502256
Homogeneous Gold Catalysis
Gold-Catalyzed Cascade Cyclization of 2-Alkynyl-N-Propargylanilines
by Rearrangement of a Propargyl Group**
Yusuke Tokimizu, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Abstract: Gold catalysis enables direct construction of tetra-
cyclic fused indolines through the migration of a propargyl
substituent from an aniline nitrogen atom to the C3-position of
an indole from 2-alkynyl-N-propargylanilines. This reaction
provides rapid access to fused three-dimensional indolines in
a single operation with the formation of four bonds and three
rings.
H
omogeneous gold catalysts have emerged as a powerful
tool for the syntheses of natural products and complex
molecules.[1] Their p-acidity enables the activation of C C
À
multiple bonds, which undergo various kinds of transforma-
tions.[2] Among the compounds involved in these transforma-
tions, allenes are well known as useful building blocks for the
construction of cyclic compounds.[2a,c,h,k,m] Despite a variety of
efficient reactions, including hydroalkoxylation,[3] hydroami-
nation,[3c,4] and hydroarylation,[3c,5] having so far been devel-
oped, the cyclization reactions of allenes bearing two
nucleophilic sites[6] are still limited because of chemoselec-
tivity issues. We propose that indole formation and a rear-
rangement cascade of N-propargylanilines is a promising
strategy for the in situ preparation of this class of allenes.
The transition-metal-catalyzed cyclization of o-alkynyl-
anilines is an efficient method for the construction of
indoles.[7] Recently, several research groups have reported
that certain substituents on the aniline nitrogen atom,
including sulfonyl,[8] allyl,[9] and acyl groups,[10] can migrate
to the C3-position of the indole via indolylmetal intermedi-
ates (Scheme 1).[11] Although these reactions are valuable for
the preparation of synthetically useful 2,3-disubstituted
indole derivatives, there have been no reports in which this
type of migration reaction has been applied to cascade
cyclizations. As part of our ongoing research on the develop-
ment of gold-catalyzed cascade reactions for the direct
construction of polycyclic heterocycles,[12] we envisaged that
the migration of a propargyl group would generate an allene,
which could undergo further cyclization reactions. Specifi-
cally, we postulated that the use of 2-alkynyl-N-propargylani-
Scheme 1. Transition-metal-catalyzed indole formation and rearrange-
ment of N substituents.
line A as a substrate would lead to the formation of an indole
B bearing an allenyl group, and the subsequent hydroalkox-
ylation/amination with an internal nucleophile (pathways a
and b) or hydroarylation with indole (pathway c) would
produce the corresponding fused indoles C or D, or indoline E
in a one-pot manner. The challenge of this strategy is favoring
indole formation and migration over cyclization from an
internal nucleophile (pathway d). Herein, we describe the
gold-catalyzed cascade cyclization of 2-alkynyl-N-propargyl-
anilines A, in which migration of the propargyl group and
hydroarylation of an allene take place to give tetracyclic
indolines of type E. To the best of our knowledge, this study
represents the first example of the migration of a propargyl
substituent from the aniline nitrogen atom.
Work to examine the feasibility of this strategy initially
focused on the cyclization of N-propargylaniline 1a (Table 1).
The reaction of 1a with 5 mol% [PPh3AuCl]/AgSbF6 in THF
at 608C gave cyclization product 2a in 13% yield (entry 1).
Among the gold catalysts examined for this reaction,
[IPrAuCl]/AgSbF6 and [JohnPhosAuSbF6]·MeCN showed
the highest activities, with compound 2a being isolated in
74% yield in both cases (entries 3 and 4). Several other
solvents were tested for the reaction, including toluene, 1,2-
dichloroethane (DCE), CH3NO2, CH3CN, and dioxane, but
all these solvents led to a decrease in the yield of 2a
(entries 5–9). In contrast, the use of 2-propanol (iPrOH) led
[*] Y. Tokimizu, Dr. S. Oishi, Prof. Dr. N. Fujii, Prof. Dr. H. Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: nfujii@pharm.kyoto-u.ac.jp
hohno@pharm.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for the Encouragement
of Young Scientists (A) and Platform for Drug Design, Discovery,
and Development from the MEXT (Japan). Y.T. is grateful for
Research Fellowships from the Japan Society for the Promotion of
Science (JSPS) for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502256.
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Table 1: Optimization of reaction conditions.
Table 2: Gold-catalyzed cyclization of 2-alkynyl-N-propargylanilines.[a]
Entry Catalyst
Solvent
THF
Conditions Yield [%][a]
R1
R2
R3 Nu
n
R1 R2
R3
Nu
n
1
[PPh3AuCl]/AgSbF6
608C, 5 h
608C, 1 h
608C, 1 h
608C, 1 h
608C, 2 h
608C, 1 h
13
49
74
74
41
16
b
c
d
e
f
H
H
Me
Me
Me
Me
H
H
H
H
H
H
NTs
NBoc
O
O
O
0
0
0
1
1
0
h
i
j
k
l
m
H
H
H
H
H
H
Et
Ph
H
H
O
O
O
O
O
O
0
0
0
0
0
0
2
3
[BrettPhosAuSbF6]·MeCN THF
[IPrAuCl]/AgSbF6 THF
Me
H
CH2Cl Me
Me OMe
Me Me
Me Br
4
5
6
[JohnPhosAuSbF6]·MeCN THF
[JohnPhosAuSbF6]·MeCN toluene
[JohnPhosAuSbF6]·MeCN DCE
g
H
H
O
Me
F
7
[JohnPhosAuSbF6]·MeCN CH3NO2 608C, 2 h
13
[a] Yields of isolated products.
8
9
10
11
12
13
[JohnPhosAuSbF6]·MeCN CH3CN
[JohnPhosAuSbF6]·MeCN dioxane
[JohnPhosAuSbF6]·MeCN iPrOH
[IPrAuCl]/AgSbF6
[IPrAuSbF6]·MeCN
AgSbF6
608C, 2 h
608C, 4 h
608C, 2 h
608C, 1 h
608C, 1 h
RT, 2 h
58
58
81
81
iPrOH
iPrOH
iPrOH
89
decomp[b]
[a] Yields of isolated products. [b] Complete consumption of starting
material was observed.
to an improvement in the yield to 81% (entry 10). The results
of an extensive period of screening revealed that the
advanced
preparation
of
the
gold
catalyst
([IPrAuSbF6]·MeCN) led to a further improvement in the
yield of the desired reaction to 89% (entry 12 versus
entry 11). This increase was attributed to avoiding the
detrimental effect of the remaining AgSbF6 present in the
reaction mixture. Actually, the treatment of 1a with AgSbF6
led to decomposition of aniline 1a (entry 13).
groups, including synthetically useful halogen substituents,
were tolerated in the para position of the aniline moiety.
Methoxy- or methyl-substituted anilines 1j and 1k provided
indolines 2j and 2k in excellent yields (92% and 89%,
respectively), while bromo- and fluoro-substituted anilines 1l
and 1m gave the indolines 2l and 2m in slightly lower yields
(59% and 66%, respectively). The decrease in the yields of 2l
and 2m can be rationalized by the relatively low nucleophi-
licity of the indoles.[14]
Benzyl groups have been reported to migrate in some
transition-metal-catalyzed cyclization reactions.[10b,11a] To
determine the migratory aptitude of different functional
groups towards the C3-position of the indole, aniline 1n
bearing propargyl and benzyl groups was subjected to the
optimized conditions (Scheme 2). In this case, the propargyl
group exhibited a greater migratory aptitude than the benzyl
group, to give indoline 2n as the major product in 73% yield.
This result revealed that benzyl-type substituents can be used
as nitrogen protecting groups for the current indoline
formation.
With the optimized conditions in hand (Table 1, entry 12),
we investigated the scope of the reaction using a variety of
different substrates (Table 2). Changing the internal nucleo-
phile from an alcohol to a tosylamide or tert-butylcarbamate
(NuH = NHTs or NHBoc; Ts = 4-toluenesulfonyl, Boc = tert-
butoxycarbonyl) led to the formation of the pyrrolidine-fused
indolines 2b and 2c in excellent yields (94% and 90%,
respectively). The structure of indoline 2b was confirmed by
X-ray crystallography.[13] Aniline 1d (R1 = Me) bearing a steri-
cally hindered alcohol also reacted efficiently to give 2d
(83%). Furthermore, anilines 1e and 1 f bearing a longer
carbon tether (n = 1) were smoothly converted into the
corresponding indolines with a fused tetrahydropyran ring
(2e and 2 f, 85% and 91%, respectively). Although aniline 1g
(R2 = H) bearing a terminal alkyne decomposed under these
conditions, anilines 1h (R2 = Et) and 1i (R2 = Ph) bearing an
internal alkyne reacted to give indolines 2h (87%) and 2i
(92%). Electron-donating and -withdrawing functional
Several experiments were subsequently conducted to
develop a deeper understanding of the mechanism of this
reaction. In the first of these, the reaction of 1h at 408C with
3 mol% of the catalyst was quenched after 100 min to give
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Scheme 2. Gold-catalyzed cyclization of N-benzylaniline 1n.
Figure 1. NMR spectroscopic monitoring of the reaction of 1h. Reac-
tion conditions: [IPrAuSbF6]·MeCN (3 mol%), CD3OD (0.01m),
CHCl2CHCl2 (internal standard), 408C.
Scheme 3. Gold-catalyzed cyclization of N-propargylaniline 1h.
catalyst to o-alkynylaniline 1 to give complex 4, which
undergoes a nucleophilic cyclization from the aniline nitrogen
atom to give indole 5. The subsequent 1,3-migration of the
propargyl group from the nitrogen atom of indolylgold
intermediate 5 to the C3-position of the indole gives allene
3, which is activated by the gold catalyst to give complex 6.
Cyclization of the activated allene, followed by ring expansion
of the resulting vinylgold intermediate 7 gives cationic
intermediate 8, which can be stabilized by the vinylgold
moiety, as shown in 8’. The reaction is then terminated by
intramolecular nucleophilic addition and subsequent proto-
deauration of 9 to produce the fused indoline 2.
allene 3h as a mixture containing a small amount of the
starting material [Scheme 3, Eq. (1); 3h/1h = 5.5:1, 68%
combined yield]. The low yield of isolated 3h was attributed
to the instability of the allene, which gradually decomposed
during purification by column chromatography. When the
reaction time was extended to 135 min, indoline 2h was
obtained in 86% yield [Eq. (2)]. The reaction of 1h with
3 mol% [IPrAuSbF6]·MeCN in CD3OD at 408C was then
1
monitored by H NMR spectroscopy, using CHCl2CHCl2 as
an internal standard (Figure 1). During the first period of the
reaction, the conversion of ani-
line 1h into allene 3h proceeded
at a constant rate. After 165 min,
only 4% of the original amount
of aniline 1h remained in the
reaction mixture, and 3h was
produced in 95% yield. Interest-
ingly, the formation of indoline
2h was only observed after
almost complete consumption
of 1h, with
a
substantial
amount of 2h having been gen-
erated at 200 min. This result
clearly demonstrates that the
formation of indoline 2h does
not proceed without the gold
catalyst. Furthermore, the gold
catalyst selectively promotes the
allene formation during the first
part of the reaction.
A reaction mechanism was
proposed based on the results of
these experiments (Scheme 4).
The reaction begins with the
coordination of a cationic gold
Scheme 4. Postulated reaction mechanism.
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The result of the NMR experiment can be rationalized as
follows: cycle A is much slower than cycle B,[15] because of the
slow nature of the propargyl migration step (Scheme 4), even
though the indole formation step (i.e. 4 to 5) is relatively fast.
In other words, the presence of the relatively stable inter-
mediate 5 in cycle A traps the gold catalyst, which therefore
prevents cycle B from progressing prior to the completion of
cycle A. It was hypothesized that the turnover-limiting step of
this reaction would be the 1,3-migration of the propargyl
group (i.e. 5 to 3), and this result was supported in part by the
fact that a related N,N-dimethylindolylgold intermediate has
been isolated.[16,17]
A cross-over reaction was also conducted to provide
further insights into the reaction mechanism (Scheme 5).
Exposure of a mixture of anilines 1b and 1i to the optimized
conditions gave the corresponding indolines 2b and 2i,
respectively. Notably, the corresponding cross-over products
2b’ and 2a were not detected in the reaction mixture. This
result suggests that the migration of the propargyl group
occurs in an intramolecular fashion.[18,19]
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Scheme 5. Cross-over experiment.
In conclusion, we have developed a novel gold-catalyzed
cascade cyclization reaction of 2-alkynyl-N-propargylanilines.
The migration of the propargyl group leads to the formation
of an indole bearing an allene moiety at the C3-position,
which undergoes an intramolecular cyclization reaction with
a pendant nucleophile to give a fused indoline. This reaction
provides rapid access to fused indolines with three-dimen-
sional shapes from starting materials having one-dimensional
alkyne structures in a single operation that involves the
formation of four bonds and three rings. NMR spectroscopic
analysis revealed that the formation of the fused indoline only
begins after the consumption of the 2-alkynyl-N-propargyl-
aniline starting material. This approach could be used in
combination with the versatile reactivity of allenes to allow
the synthesis of fused indolines and indoles in a one-pot
manner.
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Keywords: allenes · gold · homogeneous catalysis · indolines ·
rearrangement
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[13] See the Supporting Information for the X-ray crystal structure of
indoline 2b.
[14] In the reaction of 1l, 10 (18%) and 11 (20%) were obtained as
side products, through pathways a and b, respectively (see
Scheme 1).
[18] For intramolecular migrations, see Refs. [10c,11d,g,i,m].
[19] For intermolecular migrations, see Refs. [8,11c,h,k].
Received: March 11, 2015
Published online: May 26, 2015
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Angew. Chem. Int. Ed. 2015, 54, 7862 –7866