Gold-catalyzed transformation of 2-alkynyl arylazides: Efficient access to the valuable pseudoindoxyl and indolyl frameworks

Article abstract of DOI:10.1002/anie.201102707

An element of surprise: A series of functionalized 2-alkynyl arylazides has beed converted into 3-substituted indoles or 2,2-disubstituted indolin-3-ones in the presence of a gold(I) complex. Various oxygen or aryl nucleophiles can be used in this process to trap the intermediate α-imino gold carbene. The structural motifs of the products are found in a large variety of biologically active compounds and natural products. Copyright

Full text of DOI:10.1002/anie.201102707

Communications
DOI: 10.1002/anie.201102707
Homogeneous Gold Catalysis
Gold-Catalyzed Transformation of 2-Alkynyl Arylazides: Efficient
Access to the Valuable Pseudoindoxyl and Indolyl Frameworks**
Alexander Wetzel and Fabien Gagosz*
Gold catalysis has recently emerged as a “convenient tool for
generating molecular complexity”[1] and diversity.[2] The
majority of the synthetic chemistry that has been developed
in this field is intimately linked to the p Lewis acidic property
of electrophilic gold species.[3] These catalysts have indeed
proven to be particularly useful for the activation of
p systems, such as alkynes or allenes, towards the addition
of various nucleophiles. In addition to this acidic character,
gold can also act as an electron donor thus stabilizing the
intermediate cationic species and favoring reaction pathways
that are not accessible with other Lewis acids.[4] This p acid/
electron donor dual reactivity is highlighted, for instance, in
the gold(I)-catalyzed reaction of an alkyne with an azide
[Scheme 1, Eq. (1)], where an a-imino gold carbene 1 can be
generated by a sequence of nucleophlic azide addition
followed by gold-assisted expulsion of N2.
acetylenic Schmidt reaction, which converts an homopropar-
gylazide 2 into a pyrrole 4 [Scheme 1, Eq. (2)].[5,6] In this
transformation, the key intermediate a-imino gold carbene 3
undergoes a 1,2-hydride, 1,2-alkyl, or 1,2-aryl shift that
ultimately furnishes compound 4. Surprisingly, following this
seminal study, little work was done to further exploit this
reaction. A single example, in which intermediate 3 was
oxidized to the corresponding ketone by diphenyl sulfoxide,
was later reported by Toste and co-workers.[7] Although
efficient, this oxidative process was, however, in competition
with the 1,2-shift initially reported. In this context and in
relation with our continuous interest in gold catalysis,[8] we
were curious about how the a-imino gold carbene could
evolve if the 1,2-shift reaction pathway was impossible. We
surmized that a 2-alkynyl arylazide 5 might be a suitable
substrate to answer this question and were particulary
interested by the possibility of trapping the corresponding
a-imino gold carbene 6 by a nucleophile [Scheme 1, Eq. (3)].
This trapping would not only increase the complexity of the
transformation but might also lead to the formation of
functionalized indoles of type 7, which are privileged
structures in medicinal chemistry.[9]
This reactivity pattern was exploited by Toste and co-
workers in the design of a gold(I)-catalyzed intramolecular
To validate our hypothesis, model substrate 8 was treated
with 8 mol% of the gold catalyst [(Ph3P)AuOTf] in chloro-
form and in the presence of a large excess of allylic alcohol
(85 equiv; Scheme 2). Although no conversion of 8 could be
observed at room temperature, a rapid (1 h) and clean
transformation took place when the temperature was raised
to 558C. However, the expected 3-allyloxyindole 10 that
would result from the nucleophilic trapping of the a-imino
gold carbene 9 by allyl alcohol could not be isolated. Indolin-
3-one 11 was obtained instead in a good 87% yield probably
as a result of a Claisen rearrangement, which proceeds from
the desired 3-allyloxyindole 10.[10–12]
This rapid and efficient formation of 11 is remarkable
since it formally corresponds to an amino-oxy-allylation of
Scheme 1. Synthetic design for the trapping of a-imino gold carbene.
R1 =H, alkyl, aryl.
[*] Dr. A. Wetzel, Dr. F. Gagosz
Dꢀpartement de Chimie, UMR 7652 CNRS
Ecole Polytechnique, 91128 Palaiseau (France)
E-mail: gagosz@dcso.polytechnique.fr
[**] We are deeply appreciative of financial support from the French
Ambassy in Germany to A.W. and thank Rhodia Chimie Fine (Dr. F.
Metz) for a generous gift of HNTf2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102707.
Scheme 2. First attempt of trapping with allylic alcohol.
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the alkyne moiety in 8 with the additional formation of a new
quaternary carbon center (Scheme 3). Moreover, it is of
potential synthetic interest since the 2,2-disubstituted indolin-
3-one core is present not only in the structure of several
biologically active compounds,[13] but also in that of a variety
[(IAd)AuNTf2] 13[17] (45 min, 96%; Table 1, entry 4). We next
optimized the catalyst loading and the number of equivalents
of allyl alcohol (Table 1, entries 5–9). We finally found that
indolin-3-one 11 could be obtained in an excellent 96% yield
by treating 8 with 4 mol% of 13 and 10 equiv of allyl alcohol
in 1,2-dichloroethane at 558C for 4 h (Table 1, entry 8). It
should be noted that neither the silver salt AgNTf2, nor the
Brønsted acid HNTf2 was a suitable catalyst for this trans-
formation (Table 1, entries 10 and 11). Also, the reaction
could not be performed under simple thermal reaction
conditions (Table 1, entry 12).
With a set of optimized reaction conditions to hand
(Table 1, entry 8), we then explored the scope of the reaction.
We first focused our attention on the variation of the allylic
alcohol and the substitution on the aryl moiety. As seen from
the results compiled in Table 2, a series of indolin-3-ones 15a–
i could be obtained in good to excellent yields (65–92%), by
reacting a series of aryl azides 8 and 14a–i with a range of
allylic alcohols for 1–24 h. An additional asymmetric center
could be generated when allylic alcohols substituted at the
C3-position were used as the nucleophiles (Table 2, entries 1–
3, 5, and 6). There was, however, only moderate or no
diastereoselectivity in these cases. Remarkably, it was even
possible to produce indolin-3-ones possessing two vicinal
quaternary centers under mild reaction conditions and with-
out loss of efficiency (Table 2, entries 4, 5, 8, and 9).[11] This
transformation would be of special interest for the synthesis
of austamide and aristotelone, both of which have such a
substitution pattern (see Scheme 3). Finally, the reaction
could also be performed with substrates possessing a range of
substituents with differing electronic natures on the aromatic
ring (Cl, OMe, CF3, ester; Table 2, entries 6–9).
Scheme 3. Amino-oxy-allylation principle and examples of pseudo-
indoxyl alkaloids.
of natural products such as the pseudoindoxyl alkaloids
austamide, aristotelone, and fluorocarpamine (Scheme 3).[14]
We therefore decided to study this unprecedented trans-
formation and first focused our attention on the optimization
of the reaction conditions (Table 1). An initial screening of
different gold catalysts (8 mol%) showed that the phosphine
gold complexes [(Ph3P)AuNTf2][15] and [(JohnPhos)AuNTf2]
12[16] were also suitable for this transformation, although the
reaction times were slightly increased in these cases (Table 1,
entries 2 and 3). The best result in terms of efficiency and
reaction rate was obtained with the NHC-gold complex
We also attempted to react azide 8 with a range of other
nucleophiles that would not be suitable for the Claisen
Table 1: Optimization of the catalytic system.
Entry Catalyst
Cat.
[mol%]
n
Solvent
t
[h]
Yield
[%][a]
1
2
[(Ph3P)AuCl], AgOTf 8, 8
85 CHCl3
85 CHCl3
1
1.5
87
72
(Ph3P)AuNTf2
8
3
4
8
85 CHCl3
85 CHCl3
2
89
8
0.75 96
5
6
7
8
13
13
13
13
2
2
4
4
4
4
4
–
85 CHCl3
85 (CH2Cl)2 10
85 (CH2Cl)2
10 (CH2Cl)2
19.5
33
54
94
96
32
4
4
8
3
3
3
9
13
2
(CCl)2
[b]
10
11
12[c]
AgNTf2
HNTf2
–
10 (CH2Cl)2
10 (CH2Cl)2
10 (CH2Cl)2
–
–
[b]
[b]
–
[a] Yield of the isolated product. [b] No reaction was observed. [c] No
catalyst was used. Tf=trifluoromethanesulfonyl.
Scheme 4. Mechanistic proposal.
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Communications
Table 2: Substrate scope.
tivity was observed when the reac-
tion was performed with 2,6-dime-
thylaniline (Table 3, entry 6).
A mechanistic proposal for the
formation of indole 7 and indolin-3-
one 22 from azide 5 is presented in
Scheme 4. The activation of the
alkyne moiety in 5 by the gold(I)
complex could lead, after extrusion
of N2, to the formation of an
intermediate a-imino gold carbene
6. This species could undergo a
subsequent nucleophilic addition
that would furnish 17. Indole 7
could then be produced from 19
either via iminium 18 by a proto-
tropy/demetalation sequence or via
19 by a protodemetalation/tauto-
merization sequence.[19] Alterna-
tively, intermediate 19 might be
produced by a direct insertion of
Entry Substrate
NuH
t
[h]
Product
d.r.[b] Yield
[%][a]
8
1
1
15a 3:1
92
81
R1 =H
8
2
1.5
15b 4:1
15c 3:1
R1 =H
8
3
2
76
79
R1 =H
8
4
1.5
15d
-
R1 =H
À
the gold-carbene 6 into the Nu H
bond.[20] However, this carbenoid
reactivity seems to be less probable
since no cyclopropanation product
could be formed when an alkene
was used as a trapping agent.[21,22]
The formation of indolin-3-one 22,
which was observed when an allylic
alcohol was used as the nucleophile,
can be rationalized by a Claisen
rearrangement of 20.[23,24] This
transformation could be thermally
induced, or more probably gold
catalyzed (via gold complex 21)
given the mildness of the reaction
conditions under which the trans-
formation is performed (50–608C).
Indolin-3-one 22 could alternatively
be formed from iminum 18 via
intermediate 23.
8
5
12
15e 9:1
59
79
R1 =H
14a
6
2
15 f
4:1
R1 =3-Cl
14b
7
24
16
15g
15h
–
–
79
65
R1 =3-OMe
14c
8
R1 =3-CF3
14d
9
1.5
15i
–
91
R1 =4-CO2Me
To futher highlight the synthetic
potential of this new gold-catalyzed
transformation and its usefulness
for the rapid and efficient produc-
tion of a range of heterocyclic
[a] Isolated yield. [b] Determined by 1H NMR spectroscopy. 1,2-DCE=1,2-dichloroethane.
rearrangement (Table 3). The reaction could be performed
with a primary and a secondary alcohol, as exemplified by the
efficient formation of the 3-alkoxyindoles 16a and 16b (99%
and 80%; Table 3, entries 1 and 2). Surprisingly, the poorly
nucleophilic tert-butanol could also be used in this trans-
formation (Table 3, entry 3) and the corresponding 3-tert-
butoxyindole 16c was obtained in a moderate 41% yield.
Water also proved to be a good nucleophilic partner, as
attested by the efficient formation of indolin-3-one 16d
(Table 3, entry 4). The use of phenol did not result in the
formation of the corresponding 3-phenoxyindole. 3-Arylin-
dole 16e was obtained instead in 69% yield as the result of a
Friedel–Crafts reaction (Table 3, entry 5).[18] A similar reac-
compounds, a series of aryl azides, possessing various
substituents at the alkyne terminus, were converted under
the optimized reaction conditions (Table 1, entry 8) into
either 3-substituted indoles or indolin-3-ones in the presence
of various nucleophiles. The collection of examples presented
in Scheme 5 reflect the diversity of products that can be
produced and the tolerance for a variety of common func-
tional groups (halogen, ester, et0her, amide, imide, alkene,
azole) present either on the aromatic ring, on the alkyne
substituent, or on the nucleophile.[25]
In conclusion, we have developed a new gold(I)-catalyzed
reaction that converts 2-alkynyl arylazides into indolin-3-ones
and 3-substituted indoles. The reaction, which is performed
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Table 3: Formation of 3-substituted indoles.
various oxygen and carbon nucleophiles to furnish hetero-
cyclic motifs that are frequently found in the structure of
biologically active compounds or natural products. The
possibility of producing indolin-3-ones possessing two vicinal
asymmetric quaternary carbon centers is also noteworthy
given its potential applicability to the synthesis of pseudoin-
doxyl alkaloids. Further studies on this new process and its
application to the synthesis of natural products are in
progress.
Entry
NuH
t
Product
Yield
[%][a]
[h]
ROH
1
2
EtOH
1
2
16a
16b
99
80
Received: April 19, 2011
Published online: June 24, 2011
3
4
tBuOH
H2O
ArOH
6
2
16c
16d
41
Keywords: azides · Claisen rearrangement · gold ·
homogeneous catalysis · nitrogen heterocycles
89[b]
.
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Scheme 5. Generation of molecular diversity. Bn=benzyl, Ts=p-tolue-
nesulfonyl.
[10] No example of such a Claisen rearrangement has been reported
in the literature.
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Communications
[11] For
a
review on the Claisen rearrangement, see: A. M.
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[19] Intermediate 19 could also be produced from iminium 18.
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[18] Compound 16e was isolated with a small amount of the ortho-
substituted phenol regioisomer (9:1 ratio; see the Supporting
À
À
[20] For examples of gold-carbene insertions into O H, N H, and
À
C H bonds, see: M. R. Fructos, T. R. Belderrain, P. de Frꢁmont,
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[21] No cyclopropanation products were formed when 8 was treated
with 8 mol% of gold complex 13 and 10 equiv of styrene.
[22] The carbene reactivity is not supported by the selectivity
observed in the formation of the 3-arylated indoles 16e–g
(Table 3, entries 5 and 6).
[23] The moderate selectivity observed in the Claisen products is
possibly due to steric effects that do not favor a chairlike over a
boatlike transition-state intermediate.
[24] When the reaction of azide 8 with allylic alcohol was monitored
1
by H NMR spectroscopy (CDCl3 as solvent), the postulated 3-
allyloxyindole intermediate 10 could not be observed. This result
tends to support a reaction pathway involving a rapid Claisen
rearrangement via gold complex 21 or a reaction pathway
involving the iminium species 23.
[25] The use of the sterically congested nucleophile (À)-myrtenol did
not result in the Claisen rearrangement, and only compound 29
could be obtained.
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