back-to-Front Indole Synthesis Using Silver(I) Catalysis: Unexpected C-3 Pyrrole Activation Mode Supported by DFT

Article abstract of DOI:10.1021/acscatal.8b00745

An efficient silver(I)-catalyzed method is reported for the synthesis of substituted indoles, most notably 5-hydroxy-derivatives, via π-acidic alkyne activation. Most methods for the preparation of indoles involve annulation of a benzene precursor, but the method reported herein is unusual in that pyrrole precursors are used. Density Functional Theory (DFT) studies suggest that these reactions proceed via initial activation of the pyrrole C-3 position before undergoing subsequent rearrangement, contradicting the conventional wisdom that pyrroles are more nucleophilic through C-2.

Full text of DOI:10.1021/acscatal.8b00745

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Article
"Back-to-Front" Indole Synthesis using Silver(I) Catalysis:
Unexpected C-3 Pyrrole Activation Mode Supported by DFT
Aimee K. Clarke, Jason M. Lynam, Richard John Kenneth Taylor, and William Paul Unsworth
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00745 • Publication Date (Web): 13 Jun 2018
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"Back-to-Front" Indole Synthesis using Silver(I) Catalysis: Unex-
pected C-3 Pyrrole Activation Mode Supported by DFT
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Aimee K. Clarke, Jason M. Lynam,* Richard J. K. Taylor* and William P Unsworth*
University of York, Heslington, York, YO10 5DD (UK)
KEYWORDS: Indoles, alkynes, silver(I), cyclisation, spirocycles
ABSTRACT: An efficient silver(I)-catalysed method is reported for the synthesis of substituted indoles, most notably 5-
hydroxy-derivatives, via π-acidic alkyne activation. Most methods for the preparation of indoles involve annulation of a
benzene precursor, but the method reported herein is unusual in that pyrrole precursors are used. Density Functional
Theory (DFT) studies suggest that these reactions proceed via initial activation of the pyrrole C-3 position before under-
going subsequent rearrangement, contradicting the conventional wisdom that pyrroles are more nucleophilic through C-
2.
and arbidol (8, influenza).1,2 Furthermore, many more
Introduction
indoles with high pharmaceutical potential are in the
Indole derivatives are crucial in human biology (Figure
pipeline, e.g. evodiamine 93 and dragmacidin D.4
1); for example, tryptophan 1 is an essential amino acid
and serotonin 2 and melatonin are neurotransmitters.1,2
The range of applications of indole derivatives has
stimulated much research into the search for efficient
methods for their synthesis.1,5,6 As can be seen from Figure
1, versatile synthetic approaches are needed in terms of
substituent variation. Such a synthetic challenge, with
such valuable targets, ensures that novel approaches to
indole synthesis are continually being reported.1,5,6,7 Of
course the Fischer indole synthesis,6 in which a phenyl-
hydrazine is treated with an aldehyde or ketone, is still
enormously important both in small scale and industrial
procedures. The vast majority of subsequently developed
procedures also employ arylhydrazines, anilines, nitro-
benzenes or related benzene derivatives - and we have
termed these the "standard" (or "front-to-back") ap-
proaches, with many being named reactions (Scheme 1a).
Indoles are also ubiquitous in the plant world, and they
are important components of agrochemicals, functional
polymers/sensors, fragrances and dyes. However, the
significance of indole derivatives (especially 5-hydroxy
indoles) is best highlighted by their biomedical applica-
tions (Figure 1).
CO2H
HO
NH2
N
O
NH2
H
OH
N
N
H
N
H
3
Pindolol
(Antiꢀhypertensive)
Me
N
2
Serotonin
1
Tryptophan
H
O
N
HN
NMe2
S
O2
Ondansetron 4
(Antiꢀemetic)
N
H
NPh
N
N
Sumatriptan 5
(Migraine)
Me
CO2H
Scheme 1. Standard (a) and back-to-front (b) ap-
proaches to substituted indoles6-9
MeO
MeO
MeO
Me
N
Me
N
H
a) "Standard" (frontꢀtoꢀback) benzeneꢀbased approaches to indoles
O
Indomethacin 6
(Arthritis)
Oxypertine 7
(Schizophrenia)
O
or
(R)n
(R)n
Cl
NMe2
CO2Et
SPh
NXY
NHNH2
e.g. Bartoli, Fukuyama,
Gassman, Larock,
N
Fischer
(R)n
HO
(R)n
LeimgruberꢀBatcho,
Reissert, Bischler–Möhlau
MeN
Evodiamine 9
(Traditional Chinese Medicine)
N
H
N
Br
(R)n
Me
Arbidol 8 (Influenza)
N
H
Figure 1. Biologically important indole derivatives
b) Less common "backꢀtoꢀfront"
pyrroleꢀbased approaches
N
H
As well as well-known natural products such as the an-
ti-cancer vinca alkaloids (vincristine/vinblastine) and
tranquillising reserpine alkaloids, major indole-based
drugs include pindolol (3, anti-hypertensive), on-
dansetron (4, anti-emetic), sumatriptan (5, migraine),
indomethacin (6, arthritis), oxypertine (7, schizophrenia),
In contrast, there are far fewer indole syntheses which
commence from pyrrole or substituted pyrroles (Scheme
1b), and those that are known often afford little scope for
substituent variation.8,9 The Muratake–Natsume indole
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synthesis (a Friedel–Crafts-type approach) is perhaps the
mation of disubstituted indoles 12e and 12f (just 28% and
19% conversion respectively under the same conditions).
However, using a silica-supported AgNO3 catalyst (Ag-
NO3·SiO2), which was developed as part of our earlier
work on alkyne activation,10d the desired products were
isolated in 43% and 99% yield respectively. The role of
Ag2O in these reactions is not entirely clear; Ag2O has
been shown to improve reaction turnover when included
as an additive in related Ag(I)-mediated cyclisation reac-
tions10b (as observed in this study) but it is not catalytical-
ly active in its own right; for example, ynol 11c did not
react when treated with 15 mol% Ag2O under the stand-
ard reaction conditions. Thus, the role of this basic addi-
tive may instead be to modulate the acidity of the reac-
tion (e.g. by quenching any adventitious protic acids pre-
sent in the reaction) which may help prevent unwanted
side reactions and/or catalyst degradation.10b Alternative-
ly, its basicity may help to drive the dehydration step.
only established named reaction of this type,8a although a
few other more recent procedures have also been report-
ed.9
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8
The research described herein concerns the develop-
ment of new silver(I)-catalysed, pyrrole-based routes to
indoles, of the rare "back-to-front" type, as outlined above
in Scheme 1b. We have recently developed a number of
efficient metal-catalysed ynone and ynol cyclisation pro-
cedures for the synthesis of various cyclic scaffolds, in-
cluding spirocyclic indolenines,10,11 other spirocycles,10a,10d,12
carbazoles,10b,10c quinolines1ob,10e and quinolizidines.13 In
this manuscript, two new silver(I)-catalysed procedures
for the conversion of ynols 11 into indoles 12, and ynones
13 into 5-hydroxy-indoles 14 are reported (Scheme 2).
Both approaches can be used to prepare indoles with a
range of substitution patterns from closely related start-
ing materials. Furthermore, they are simple to perform
and use mild reaction conditions, and hence represent a
practical and versatile new approach to these important
scaffolds. The reactions were also studied using Density
Functional Theory (DFT), and intriguingly, these studies
suggest that the reactions proceed via initial cyclisation
via the pyrrole C-3 position before undergoing subse-
quent rearrangement, contradicting the conventional
wisdom that pyrroles are more nucleophilic through C-2.
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Scheme 3. Ynol cyclisation to indoles 12a-f
HO
R1
R1
A
(
) AgNO3 (10 mol%) and Ag2O (5 mol%)
(B) AgNO3—SiO2 (10 mol%)
N
H
R2
12aꢀf
N
R2
H
CH2Cl2, RT
11aꢀf
Monosubstituted
Unsubstituted
Scheme 2. "Back-to-front" ynol/ynone cyclisation ap-
proaches to substituted indoles
N
H
N
H
N
H
HO
R1
R1
12a
(A) 24h, 63%
12b
(A) 19 h, 94%
12c
) 5 h, 94%
Ag(I)
A
(
F
N
H
N
Disubstituted
Ph
R2
Me
R2
R2
11
13
H
12
Me
O
R2
N
H
HO
N
H
R3
N
H
Ag(I)
Ph
N
R3
12e
12d
(A) 21 h, 86%
12f
N
R4
R4
R1
R1
(A) 48 h, 28% conv.
(B) 48 h, 43%
(A) 24 h, 19% conv.
(B) 24 h, 99%
14
Next, attention turned to the reactions of ynone deriva-
tives of the form 13 (Scheme 4). These cyclisation reac-
tions are arguably of greater importance due to the fact
that a 5-hydroxy substituent is produced in the product
14; 5-hydroxylated indoles are ubiquitous in nature (e.g.
serotonin 2/indomethacin 6), and this method could be
used to generate analogues of these important com-
pounds.15 The hydroxy group may also serve as a reactive
handle to enable further chemical modifications, e.g. al-
kylation, cross-coupling, etc. First, simple 5-hydroxy in-
dole 14a was formed in 64% yield using 10 mol% AgNO3
as catalyst, again upon stirring for 1.5 hours at RT in
CH2Cl2, with the Ag2O additive not being necessary in this
case. The Ag2O additive was also not needed during the
formation of disubstituted indoles 14b–i, and the catalyst
loading of AgNO3 could also be lowered to 5 mol%. The
yields were consistently high across this series, with ali-
phatic and electron-rich/electron-poor aromatic groups
Results and Discussion
We started by examining the cyclisations of ynol deriv-
atives 11a–f (Scheme 3). The requisite starting materials
(as well as ynones 13a–o discussed later) were all prepared
by standard literature procedures or minor variations
thereof,14 with full experimental and characterisation de-
tails included in the Supporting Information (SI). First, it
was found that pyrrole 11a (R1 = R2 = H) could be convert-
ed into unsubstituted indole 12a in reasonable yield upon
stirring with 10 mol% AgNO3 and 5 mol% Ag2O for 24
hours at RT in CH2Cl2; these conditions were chosen as
they had been shown to be effective for the cyclisation of
indole-tethered ynols in our earlier work.10b Monosubsti-
tuted indoles 12b and 12c were also formed in high yield
using the same AgNO3/Ag2O conditions. Disubstituted
indole 12d was also formed in high yield in the same way,
but these conditions were less successful for the for-
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being well tolerated, as were tethered alkyl chloride and
proceeds via C-3 (route B) to form a spirocyclic interme-
diate of the form 17, before undergoing 1,2-migration (17
→ 16), followed by protodemetallation and tautomerisa-
tion as in route A. For the ynol series, the same mecha-
nism is likely to operate, except that the tautomerisation
step is replaced by the elimination of water (not shown).
1
2
3
4
5
6
7
8
protected amine substituents. In the case of indole 14h,
its structural assignment is supported by X-ray crystallo-
graphic data.16 Finally, four trisubstituted indoles 14j–m
were also generated; these substrates generally reacted
more slowly than their disubstituted analogues and some
required the addition of Ag2O to proceed to completion,
but nonetheless, each was formed in high yield under
these modified conditions.
Scheme 5. Mechanistic possibilities
9
R1
O
R1
10
11
12
13
14
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O
(R)n
Scheme 4. Ynone cyclisation to indoles 14a-m
3
[Ag]
A) via Cꢀ2
(R)n
2
N
Ag
H
N
R2
R2
16
15
H
protodemetallation
and tautomerisation
n
o
B) via Cꢀ3
i
t
a
r
g
i
m
ꢀ
2
,
O
1
R1
R1
HO
(R)n
Ag
(R)n
R2
17
N
N
H
H
R2
14
However, subsequent examples led us to question our
notion that C-2 cyclisation is the more favourable path-
way. Thus, when each of ynones 13n and 13o were reacted
with 10 mol% AgNO3 and 5 mol% Ag2O at RT in CH2Cl2
none of the expected indole products 14n and 14o were
formed, and instead spirocycles 18n and 18o were isolated
(Scheme 6). These results were surprising, not only be-
cause dearomatising spirocyclisation reactions through
pyrrole C-3 positions are rare,19,20 but also because spiro-
cyclisation had taken place in preference to C-2 annula-
tion. Re-subjecting the spirocyclic products 18n and 18o
to the reaction conditions led to no discernible reaction
(when 1,2-migration to convert them into 14n and 14o
respectively might have been expected), even when heat-
ed to reflux, attesting to their surprising stability.
Scheme 6. Dearomatising spirocyclisation reactions
of ynones 13m and 13n
a
Double the standard catalyst loading was required to
achieve full conversion in this case.
Bu-n
HO
In terms of the mechanism for these cyclisation reac-
tions, two main pathways were considered, illustrated in
Scheme 5 for the ynone series. First, coordination of the
alkyne to the active π-acidic silver species17,18 increases its
electrophilicity and activates it towards attack from the
electron-rich pyrrole ring, either via the pyrrole C-2 posi-
tion (15 → 16) or its C-3 position (15 → 17). Cyclisation via
C-2 (route A) was considered to be the most likely at the
outset of this study, in view of the well-accepted wisdom
that pyrroles are more nucleophilic through C-2 than C-3,
and the fact that this was judged to be the less sterically
encumbered of the two alternative pathways. Attack via
C-2 is also the most direct route to the product, and thus
from intermediate 16, protodemetallation and tautomeri-
sation completes the reaction to form indole 14. A second
possibility, which was considered less likely in view of the
above, but could not be ruled out, was that cyclisation
O
Bu-n
Ph
14n
N
R
H
, R = Ph, 0%
14o, R = Bu-n, 0%
AgNO3 (10 mol%)
Ag2O (5 mol%)
O
Ph
N
R
Bu-n
H
CH2Cl2, RT
13n
, R = Ph
13o, R = Bu-n
R
Ph
N
18n
, R = Ph, 69%, 2 h
18o, R = Bu-n, 52%, 1.5 h
In order to gain a better understanding of the potential
mechanistic pathways underpinning the silver-catalysed
reactions, a number of possible pathways for C–C bond
formation were probed with Density Functional Theory
(DFT, see SI for details of the computational methodology
employed).21 Thus, one example from the ‘normal’ indole-
forming series (13e to 14e) was examined, and compared
with another (13n) in which the spirocycle 18n was
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netic product (ꢀG298 = –58 kJ mol-1). Although employing
the substituted pyrrole 13n changed the outcome of the
experimental reaction, it did not significantly alter this
picture with 14n being more stable than 18n indicating
that this reaction is under kinetic control.
formed unexpectedly. The calculations indicated that the
1
2
3
4
Gibbs energies for the transformation of 13e to 14e and
(putative) 18e (Scheme 7a) were both exergonic, but that
indole 14e is the thermodynamic product of the reaction
(ꢀG298 = –223 kJ mol-1) and spirocycle 18e would be a ki-
5
6
7
8
9
Scheme 7 DFT-calculated energies for (a) formation of compounds 14e/n and 18e/n from 13e/n and (b) silver-
catalysed C-C bond formation from alkyne complex A. Energies are Gibbs energies at 298 K at the D3-PBE0/def2-
TZVPP//BP86/SVP(P) level with COSMO solvent correction in CH2Cl2 in kJ mol-1.
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Silver(I) complexes are kinetically labile and in the case
of simple salts such as AgNO3 the precise nature of the
active species is unclear. However, the reaction of AgOTf
with one equivalent of PPh3 results in the formation of
known complex Ag(OTf)(PPh3).22 It was anticipated that
the ynone substrate would displace the weakly bound OTf
ligand in this complex to give a cationic silver(I) phos-
phine species that (1) would promote C-C bond formation
and (2) could be effectively modelled by DFT. To demon-
strate the feasibility of this approach AgOTf (10 mol%)
was mixed with PPh3 (10 mol%) in CH2Cl2 solution to gen-
erate Ag(OTf)(PPh3). Subsequent reaction with 13e for 3
hours resulted in the formation of 14e in 77% isolated
yield, demonstrating that this was indeed a viable catalyst
system.
The silver complex A, in which the alkyne is bound
through the ynone oxygen atom was taken as the refer-
ence state for the calculations (Scheme 7b). In the case of
the cyclisation reaction from 13e, the η2-(CC) bound al-
kyne complex Be lies at +2 kJ mol-1, but C-C bond for-
mation takes places from the slipped alkyne complex Ce,
which may be viewed as being a formal carbocation. Two
transition states for C-C bond formation were located.
Transition state tsCD is best viewed as nucleophilic attack
by the C-3 atom of the pyrrole at the carbocation of C and
leads to the silver-coordinated spirocycle De. A second
transition state, tsCE was also located which corresponds
to C-C bond formation between the C-2 position of the
pyrrole with the carbocation leading to Ee and subse-
quent keto-enol tautomerisation would then give Fe.
Therefore, the cyclisation of ynones 13e and 13n were
On the basis of these calculations the potential energy
surface is almost flat, with tsCDe and tsCEe at +18 and +28
modelled by DFT using [Ag(PPh3)]+ as the catalyst system.
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kJ mol-1 respectively. Although the formation of De will
1
2
3
4
occur more rapidly than Ee based on these data, the equi-
librium position between Ae, Be, Ce and De is expected
to favor Ae. Therefore, as Ee is significantly lower energy
(-32 kJ mol-1) this would be the expected product from the
reaction, as long as protodemetallation is slow. All at-
5
6
7
tempts to find a transition state connecting De and Ee
23
(i.e. a formal 1,2-migration) resulted in tsCD
.
8
9
In the case of 13n the situation is somewhat different,
the corresponding complex Dn is now lower in energy
than An, Bn24 and Cn. This may provide an explanation
for the different reaction outcome in this case as, in con-
trast to 13e, the complex Dn will dominate the equilibri-
um between the states A–D (i.e. it will be the major rest-
ing state prior to the slower formation of En) and hence
should be more prone to protodemetallation to give the
spirocyclic product 18n. This is consistent with 18n being
a kinetic product formed from the lower lying transition
state (tsCD).
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Examination of the predicted structure of De revealed
that there are no elemental intramolecular steps that
could lead to protodemetallation. Therefore, this step
Interestingly, the DFT results suggest that dearomatisa-
tion through the pyrrole C-3 position (C to D) is lower in
energy than dearomatisation through the pyrrole C-2 po-
sition (C to E) in both ynone systems 13e and 13n (and
indeed, this is likely to be the case for most/all of the re-
lated ynones 13 in this study), but spirocyclic products are
generally not isolated due to slow protodemetallation of
the vinyl silver intermediate D. Based on this hypothesis,
we reasoned that if the rate of protodemetallation of D
could be increased relative to isomerisation to E, this
might enable C-3 spirocyclic products to be prepared by
trapping intermediate D. To test this, we first attempted
the reaction of ynone 13e at lower temperature (0 °C) but
this resulted in no reaction. Instead, the same reaction
was then attempted using 5 mol% of the silica supported
catalyst (AgNO3·SiO2) in place of AgNO3 at RT; Ag-
NO3·SiO2 was found to accelerate protodemetallation in
our earlier work on related indole spirocyclisation reac-
tions, hence we predicted that the use of this catalyst
might enable spirocyclic vinyl silver intermediate De to
be trapped out prior to rearrangement.10d Pleasingly, this
experiment worked well; although the use of AgNO3·SiO2
did not lead to a complete switch in chemoselectivity,
spirocycle 18e was indeed formed, and isolated in 28%
yield, alongside indole 14e which was formed in 38% yield
(Scheme 9).27 These results add strong support to those
obtained in the DFT study that spirocyclic vinyl silver
species De is an intermediate in the synthesis of indole
14e, and also show that under appropriate conditions, this
intermediate can be intercepted, enabling synthetically
challenging C-3 spirocyclic pyrrole derivatives to be pre-
pared.
must
involve
an
intermolecular
deprotona-
tion/protonation pathway, however, modelling such steps
is fraught with difficulty as the precise nature of the base
is unclear. In order to obtain at least an indicative picture
of this process, triflate was used as a model base. The neu-
tral metallated spirocycle Ge and triflic acid were used as
the reference point for the calculation (Scheme 8). Pro-
todemetallation proceeds via an initial encounter com-
plex He in which the HOTf has a weak interaction with
the M–C bond. Proton transfer through TSHIe is essential-
ly barrierless25 implying that protonation of the Ag-C
bond by HOTf is rapid. Protonation ultimately leads to Ie,
which has a T-shaped geometry with the silver coordinat-
ed to PPh3, a triflate anion and an O-bound spirocycle.
A further state, Ke, was also located which corresponds
to De with a hydrogen bonded triflate anion. This is sig-
nificantly lower in energy than both the reference state
and those involved in proton transfer. These data imply
that the rate of the proton transfer reaction would be con-
trolled by the deprotonation of De rather than the proto-
nation of the M–C bond, at least in the case of HOTf.26
Scheme 8. Scheme 8 DFT-calculated energies for pro-
ton transfer reactions for metallated spirocycle. En-
er-gies are Gibbs energies at 298 K at the D3-
PBE0/def2-TZVPP//BP86/SVP(P) level with COSMO
solvent correction in CH2Cl2 in kJ mol-1.
Scheme 9. Synthesis of Spirocycle 18e
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Imine Acylation of Ortho-Substituted Benzoic Acid Derivatives:
the Total Synthesis (±)-Cavidine. Tetrahedron 2014, 70, 7172–7180
and references therein.
(4) Zhang, F.; Wang, B.; Prasad, P.; Capon, R. J.; Jia, Y., Asym-
metric Total Synthesis of (+)-Dragmacidin D Reveals Unex-
pected Stereocomplexity. Org. Lett. 2015, 17, 1529–1532 and refer-
ences therein.
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In summary, a new "back-to-front" method to generate
substituted indoles from pyrrole ynol and ynone precur-
sors has been developed. The synthetic procedures are
promoted by relatively mild silver(I) catalysts, proceed at
room temperature and are insensitive to air and moisture.
DFT studies conducted on the pyrrole-tethered ynone
series (13) suggest that these reactions proceed via nucle-
ophilic attack onto the activated alkyne via the pyrrole C-
3 position, going against the generally accepted view that
pyrroles are most nucleophilic through C-2. Formal C-2
annulation products are still formed in most cases (likely
via ring opening and re-closing) but this discovery could
be highly significant in the design of new dearomatising
spirocyclisation methods for pyrrole precursors; methods
to prepare C-3 spirocycles from pyrroles are very rare, but
the knowledge that they are transiently formed en route
to C-2 annulated products should help to inform new
strategies by which the spirocycles can be intercepted
prior to rearrangement.
6
7
8
9
(5) (a) Indole Ring Synthesis: From Natural Products to Drug
Discovery, Gribble, G. W. Wiley, 2016; (b) Gribble, G. W. J., Re-
cent developments in indole ring synthesis—methodology and
applications. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075; (c)
Inman, M.; Moody, C. J., Indole Synthesis – Something Old,
Something New. Chem. Sci., 2013, 4, 29–41
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17
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(6) The Fischer Indole Synthesis, Robinson, B. Wiley, 1982.
(7) For recent approaches, see: (a) Zhang, Z.-Z.; Liu, B.; Xu, J.-
W.; Yan, S-Y.; Shi, B.-F., Indole Synthesis via Cobalt(III)-
Catalyzed Oxidative Coupling of N-Arylureas and Internal Al-
kynes. Org. Lett. 2016, 18, 1776–1779; (b) Wu, C.-J.; Meng, Q.-Y.;
Lei, T.; Zhong, J.-J.; Liu, W.-Q.; Zhao, L.-M.; Li, Z.-J.; Chen, B.;
Tung, C.-H.; Wu, L.-Z., An Oxidant-Free Strategy for Indole Syn-
thesis via Intramolecular C–C Bond Construction under Visible
Light Irradiation: Cross-Coupling Hydrogen Evolution Reaction.
ACS Catal. 2016, 6, 4635–4639; (c) Hermann, G. N.; Jungab, C. L.;
Bolm, C., Mechanochemical Indole Synthesis by Rhodium-
Catalysed Oxidative Coupling of Acetanilides and Alkynes under
Solventless Conditions in a Ball Mill. Green Chem. 2017, 19, 2520–
2523; (d) Tussing, S.; Ohland, M.; Wicker, G.; Flörkeb G.;
Paradies, J., Borane-Catalyzed Indole Synthesis through Intramo-
lecular Hydroamination. Dalton Trans., 2017, 46, 1539–1545; (e)
Ilies, L.; Isomura, M.; Yamauchi, S.-I.; Nakamura, T.; Nakamura,
E., Indole Synthesis via Cyclative Formation of 2,3-
Dizincioindoles and Regioselective Electrophilic Trapping. J. Am.
Chem. Soc. 2017, 139, 23–26; (f) Agasti, S.; Deya, A.; Maiti, D.,
Palladium-Catalyzed Benzofuran and Indole Synthesis by Multi-
ple C–H Functionalizations. Chem. Commun. 2017, 53, 6544–
6556.
(8) (a) Muratake, H.; Mikawa, A.; Natsume, M., Total synthe-
sis of (+)-Herbindole A, (+)-Herbindole B, and (+)-Herbindole C.
Determination of the Absolute Configuration of the Natural
Herbindoles. Tetrahedron Lett. 1992, 33, 4595–4598; (b)
Kozikowski, A. P.; Sato, K.; Basu, A.; Lazo, J. S., Synthesis and
Biological Studies of Simplified Analogs of Lyngbyatoxin A; use
of an Isoxazoline-based Indole Synthesis. Quest for Protein Ki-
nase C modulators. J. Am. Chem. Soc. 1989, 111, 6228–6234, and
references therein. See also reference 5a, Section 10.
(9) (a) Jackson, P. M.; Moody, C. J., Diels-Alder Reactions of
2,3-Dimethylenepyrrole Analogues; a New Synthesis of lndoles. J.
Chem. Soc. Perkin Trans. 1 1990, 2156–2158; (b) Jackson, P. M.;
Moody, C. J., Diels-Alder Reactions of 1,5-Dihydropyrano[3,4-
b]pyrrol-5(1H)-ones, Pyrrole-2,3-quinodimethane Analogues; a
New Synthesis of Indoles. Tetrahedron 1992, 48, 7447–7466; (c)
Andrews, J. F. P.; Jackson, P. M.; Moody, C. J., Pyrrole-2,3-
quinodimethane Analogues in the Synthesis of Indoles. Part 2.1
Synthesis and Diels-Alder Reactions of 1,6-Dihydropyrano[4,3-
b]pyrrol-6(1H)-ones. Tetrahedron 1993, 49, 7353–7372; (d) Hash-
mi, A. S. K.; Yang, W.; Rominger, F., Gold(I)-Catalyzed Rear-
rangement of 3-Silyloxy-1,5-enynes: An Efficient Synthesis of
Benzo[b]thiophenes, Dibenzothiophenes, Dibenzofurans, and
Indole Derivatives. Chem. Eur. J. 2012, 18, 6576–6580; (e) Mar-
tins, G. M.; Zeni, G.; Back, D. F.; Kaufman, T. S.; Silveira, C. C.,
Expedient Iodocyclization Approach Toward Polysubstituted
3H-Benzo[e]indoles. Adv. Synth. Catal. 2015, 357, 3255–3261; (f)
Li., Y.; Waser, J., Platinum-Catalyzed Domino Reaction with
Benziodoxole Reagents for Accessing Benzene-Alkynylated In-
doles. Angew. Chem. Int. Ed. 2015, 54, 5438–5442; (g) Kanchupal-
li, Joseph, D.; Katukojvala, S., Pyridazine N-Oxides as Precursors
ASSOCIATED CONTENT
Supporting Information. Full characterisation data, images
of NMR spectra and experimental and computational details
for all of the materials produced in this study, as well as a
link to the raw data, can be found in the Supporting Infor-
mation. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* jason.lynam@york.ac.uk; richard.taylor@york.ac.uk; wil-
liam.unsworth@york.ac.uk
ACKNOWLEDGMENT
The authors would like to thank the EPSRC (A.K.C.
EP/R013748/1), the University of York (A.K.C., W.P.U.) and
the Leverhulme Trust (for an Early Career Fellowship, ECF-
2015-013, W.P.U.) for financial support. We also thank the
EPSRC (grants EP/H011455/1 and EP/K031589/1) for funding
the computational resources used in this study.
REFERENCES
(1) For a comprehensive overview, see: Comprehensive Hetero-
cyclic Chemistry III; Katritzky, A. R.; Ramsden, C. A.; Scriven, E.
F. V.; Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008, and references
therein (especially Volume 3, Ed. Ramsden, C. A.; Jones, G.).
(2) For a review of the biomedical applications of indole deriv-
atives see: Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim,
C. H.; Verma, A. K.; Choi, E. H., Biomedical Importance of In-
doles. Molecules 2013, 18, 6620–6662.
(3) (a) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K., Direct
Imine Acylation: Rapid Access to Diverse Heterocyclic Scaffolds.
Org. Lett. 2013, 15, 258–262; (b) Kitsiou, C.; Unsworth, W. P.;
Coulthard, G.; Taylor, R. J. K., Substrate Scope in the Direct
ACS Paragon Plus Environment

Page 7 of 9
ACS Catalysis
of Metallocarbenes: Rhodium-Catalyzed Transannulation with
Pyrroles. Org. Lett. 2015, 17, 5878–5881.
Dorado, M.; Rodríguez-García, I., Silver-Mediated Synthesis of
Heterocycles. Chem. Rev. 2008, 108, 3174–3198.
1
2
3
4
5
6
7
8
(10) (a) James, M. J.; Cuthbertson, J. D.; O’Brien, P.; Taylor, R.
J. K.; Unsworth, W. P., Silver(I)- or Copper(II)-Mediated
Dearomatization of Aromatic Ynones: Direct Access to Spirocy-
clic Scaffolds. Angew. Chem. Int. Ed. 2015, 54, 7640–7643; (b)
James, M. J.; Clubley, R. E.; Palate, K. Y.; Procter, T. J.; Wyton, A.
C.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P., Silver(I)-
Catalyzed Dearomatization of Alkyne-Tethered Indoles: Diver-
gent Synthesis of Spirocyclic Indolenines and Carbazoles. Org.
Lett. 2015, 17, 4372–4375; (c) Liddon, J. T. R.; James, M. J.; Clarke,
A. K.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P., Catalyst-
Driven Scaffold Diversity: Selective Synthesis of Spirocycles,
Carbazoles and Quinolines from Indolyl Ynones. Chem. Eur. J.
2016, 22, 8777–8780; (d) Clarke, A. K.; James, M. J.; O’Brien, P.;
Taylor, R. J. K.; Unsworth, W. P., Silica-Supported Silver Nitrate
as a Highly Active Dearomatising Spirocyclisation Catalyst: Syn-
ergistic Alkyne Activation by Silver Nanoparticles and Silica.
Angew. Chem. Int. Ed. 2016, 55, 13798–13802; (e) Liddon, J. T. R.;
Clarke, A. K.; Taylor, R. J. K.; Unsworth, W. P., Preparation and
Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of
Spirocyclic Indole Derivatives. Org. Lett. 2016, 18, 6328−6331
(11) For a review of spirocyclic indolenine synthesis, see:
James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P., Syn-
thesis of Spirocyclic Indolenines. Chem. Eur. J. 2016, 22, 2856–
2881.
(12) (a) Unsworth, W. P.; Cuthbertson, J. D.; Taylor, R. J. K.,
Total Synthesis of Spirobacillene A. Org. Lett. 2013, 15, 3306–
3309; (b) Clarke, A. K.; Liddon, J. T. R.; Cuthbertson, J. D.; Tay-
lor, R. J. K.; Unsworth, W. P., Dearomatisation Approaches to
Spirocyclic Dienones via the Electrophilic Activation of Alkynes.
Org. Biomol. Chem., 2017, 15, 233–245.
(13) (a) James, M. J.; Grant, N. D.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P., Catalytic Dearomatization Approach to Quino-
lizidine Alkaloids: Five Step Total Synthesis of (±)-Lasubine II.
Org. Lett. 2016, 18, 6256−6259; (b) Ho, H. E.; James, M. J.;
O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P., Ag(I)-Catalyzed
Synthesis of Azabicyclic Alkaloid Frameworks from Ketimine-
Tethered Ynones: Total Synthesis of Indolizidine 209D. Org.
Lett. 2018, 20, 1439–1443.
(14) (a) Trost, B. M.; Lumb J.-P.; Azzarelli, J. M., An Atom-
Economic Synthesis of Nitrogen Heterocycles from Alkynes. J.
Am. Chem. Soc., 2011, 133, 740–743; (b) Yasuhara, A.; Takeda, Y.;
Suzuki, N.; Sakamoto, T., Synthesis of 2,3-Disubstituted Indole
Using Palladium(II)-Catalyzed Cyclization with Alkenylation
Reaction. Chem. Pharm. Bull., 2002, 50, 235–238; (c) Ravinder, K.;
Reddy, A. V.; Mahesh, K. C.; Narasimhulu, M.; Venkateswarlu,
Y., Simple and Selective Removal of the t-Butyloxycarbonyl (Boc)
Protecting Group on Indoles, Pyrroles, Indazoles, and Car-
bolines. Synth. Commun., 2007, 37, 281–287; (d) Yadav, J. S.;
Reddy, B. V. S.; Satheesh, G., InBr3/Cu(OTf)2-Catalyzed C-
Alkylation of Pyrroles and Indoles with α-Diazocarbonyl Com-
pounds. Tetrahedron Lett., 2003, 44, 8331–8334; (e) Bray, B. L.;
Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis, D. R.;
Muchowski, J. M., N-(Triisopropylsilyl)pyrrole. A Progenitor "Par
Excellence" of 3-Substituted Pyrroles. J. Org. Chem., 1990, 55,
6317–6328.
(15) LaPorte, M.; Hong, K. B.; Xu, J.; Wipf, P., 5-
Hydroxyindoles by Intramolecular Alkynol–Furan Diels–Alder
Cycloaddition. J. Org. Chem., 2013, 78, 167–174 and references
therein.
(16) CCDC 1554901 contains the crystallographic data for com-
pound 14h, see: www.ccdc.cam.ac.uk/data_request/cif (data of
access: 9th June 2017).
(18) For related processes involving alkyne activation with
other π-acidic catalysts, see: (a) Loh, C. C. J.; Badorrek, J.; Raabe,
G.; Enders, D., Merging Organocatalysis and Gold Catalysis:
Enantioselective Synthesis of Tetracyclic Indole Derivatives
through a Sequential Double Friedel–Crafts Type Reaction.
Chem. Eur. J. 2011, 17, 13409–13414; (b) Peshkov, V. A.; Pereshivko,
O. P.; Van der Eycken, E. V., Synthesis of Azocino[5,4-b]indoles
via Gold-Catalyzed Intramolecular Alkyne Hydroarylation. Adv.
Synth.
Catal.
9
2012, 354, 2841–2848; (c) Heffernan, S. J.; Tellam, J. P.; Queru, M.
E.; Silvanus, A. C.; Benito, D.; Mahon, M. F.; Hennessy, A. J.;
Andrews, B. I.; Carbery, D. R., Double Gold-Catalysed Annula-
tion of Indoles by Enynones. Adv. Synth. Catal. 2013, 355, 1149–
1159; (d) Corkey, B. K.; Heller, S. T.; Wang, Y.-M.; Toste, F. D.,
Enantioselective Cyclization of Enamide-ynes and Application to
the Synthesis of the Kopsifoline Core. Tetrahedron 2013, 69,
5640–5646; (e) Gronnier, C.; Faudot dit Bel, P.; Henrion, G.;
Kramer, S.; Gagosz, F., Divergent Product Selectivity in Gold-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
versus
Silver-Catalyzed
Reaction
of
2-Propynyloxy-6-
fluoropyridines with Arylamines. Org. Lett. 2014, 16, 2092–2095;
(f) Xu, W.; Wang, W.; Wang, X., Gold-Catalyzed Cyclization
Leads to a Bridged Tetracyclic Indolenine that Represses β-
Lactam Resistance. Angew. Chem., Int. Ed. 2015, 54, 9546–9549;
(g) Schroder. F.; Ojeda. M.; Erdmann. N.; Jacobs. J.; Luque. R.;
Noel. T.; Van Meervelt. L.; Van der Eycken. J.; Van der Eycken.
E., Supported Gold Nanoparticles as Efficient and Reusable Het-
erogeneous Catalyst for Cycloisomerization Reactions. Green
Chem. 2015, 17, 3314–3318.
(19) For general reviews on dearomatisation reactions, see ref-
erence 11, as well as: (a) Zheng, C.; You, S. L., Catalytic Asymmet-
ric Dearomatization by Transition-Metal Catalysis: A Method for
Transformations of Aromatic Compounds. Chem 2016, 1, 830–
857; (b) Roche, S. P.; Youte Tendoung, J. J.; Tréguier, B., Advanc-
es in Dearomatization Strategies of Indoles. Tetrahedron 2015, 71,
3549–3591. (c) Zhuo, C. X.; Zheng, C.; You, S. L., Transition-
Metal-Catalyzed Asymmetric Allylic Dearomatization Reactions.
Acc. Chem. Res. 2014, 47, 2558–2573. (d) Zhuo, C.-X.; Zhang, W.;
You, S. L., Catalytic Asymmetric Dearomatization Reactions.
Angew. Chem., Int. Ed. 2012, 51, 12662–12686.
(20) For rare exceptions of C-3 pyrrole dearomatising spirocy-
clisation processes, see reference 10d, as well as: (a) Shabalina, D.
A.; Dvorkoa, M. Y.; Schmidt, E. Y.; Ushakov, I. A.; Protsuk, N. I.;
Kobychev, V. B.; Soshnikov, D. Y.; Trofimov, A. B.; Vitkovskaya,
N. M.; Mikhaleva, A. I.; Trofimov, B. A., 3H-Pyrroles from Ketox-
imes and Acetylene: Synthesis, Stability and Quantum-Chemical
Insight. Tetrahedron 2015, 71, 3273–3281; (b) Chambers, S. J.;
Coulthard, G.; Unsworth, W. P.; O’Brien, P.; Taylor, R. J. K.,
From Heteroaromatic Acids and Imines to Azaspirocycles: Stere-
oselective Synthesis and 3D Shape Analysis. Chem. Eur. J. 2016,
22, 6496–6500.
(21) For related DFT studies, see: Alcaide, B.; Almerndros, P.;
Alonso, J. M.; Busto, E.; Fernández, I.; Ruiz, M. P.; Xiaokaiti, G.,
Versatile Synthesis of Polyfunctionalized Carbazoles from (3-
Iodoindol-2-yl)butynols via a Gold-Catalyzed Intramolecular
Iodine-Transfer Reaction. ACS Catal. 2015, 5, 3417–3421 and ref-
erence cited therein.
(22) (a) Bardajı
́
Structural Characterization
[Ag(O3SCF3)(L)] (L=PPh3, PPh2Me, SC4H8) and [AgLn](CF3SO3)
(n=2–4), (L=PPh3, PPh2Me). Inorg. Chim. Acta 2000, 304, 7; (b)
Lettko, L.; Wood, J. S.; Rausch, M. D., Synthesis of (Phos-
phine)silver(I) Trifluoromethanesulfonate Complexes and the
Molecular Structure of Di-μ-trifluoromethylsulfonate-(tetrakis-
triphenylphosphine)disilver(I). Inorg. Chim. Acta 2000, 308, 37.
(17) For silver(I) mediated alkyne activation, see references 10–
13 and citations therein, as well as: Álvarez-Corral, M.; Muñoz-
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(23) A similar stepwise rearrangement was described (with
plexes: Bonding and Reaction Pathways. Angew. Chem. Int. Ed.
2017, 56, 13861–13865.
DFT support) for the overall 1,2-migration of aza-
spiroindolenines, see: Wu, Q.-F.; Zheng, C.; Zhuo, C.-X.; You, S.-
L., Highly Efficient Synthesis and Stereoselective Migration Re-
actions of Chiral Five-membered aza-Spiroindolenines: Scope
and Mechanistic Understanding. Chem. Sci. 2016, 7, 4453–4459.
(24) (a) Ciano, L.; Fey, N.; Halliday, C. J. V.; Lynam, J. M.;
Milner, L. M.; Mistry, N. Pridmore, N. E.; Townsend, N. S.;
Whitwood, A. C., Dispersion, Solvent and Metal Effects in the
Binding of Gold Cations to Alkynyl Ligands: Implications for
Au(I) Catalysis. Chem. Commun., 2015, 51, 9702–9705; (b) Roc-
chigiani, L.; Fernandez-Cestau, J.; Agonigi, G.; Chambrier, I.;
Budzelaar, P. H. M.; Bochmann, M., Gold(III) Alkyne Com-
1
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3
4
5
6
7
8
(25) The difference in free energies of states He and TSHIe was
< 10 kJ mol-1 at all levels of theory employed. Therefore the ap-
parent artefact in Scheme 8 that TSHIe is lower in energy than
He may simply reflect the precision of the calculations.
(26) A transition state connecting Ke and De + HOTf could
not be located.
(27) As was found for spirocycles 18n and 180, spirocycle 18e
does not rearrange when re-subjected to the reaction conditions
(with both AgNO3 and AgNO3·SiO2) or upon reflux in CH2Cl2.
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19 examples
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