Gold(I)-Catalyzed Dearomative [2+2]-Cycloaddition of Indoles with Activated Allenes: A Combined Experimental-Computational Study

Article abstract of DOI:10.1002/chem.201503598

The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is pres

Full text of DOI:10.1002/chem.201503598

DOI: 10.1002/chem.201503598
Full Paper
&
Gold Catalysis
Gold(I)-Catalyzed Dearomative [2+2]-Cycloaddition of Indoles
with Activated Allenes: A Combined Experimental–Computational
Study
Riccardo Ocello,[a] Assunta De Nisi,[a] Minqiang Jia,[b] Qing-Qing Yang,[a] Magda Monari,[a]
Pietro Giacinto,[a] Andrea Bottoni,[a] Gian Pietro Miscione,*[a, c] and Marco Bandini*[a]
Abstract: The gold-catalyzed synthesis of methylidene 2,3-
cyclobutane-indoles is documented through a combined ex-
perimental/computational investigation. Besides optimizing
the racemic synthesis of the tricyclic indole compounds, the
enantioselective variant is presented to its full extent. In par-
ticular, the scope of the reaction encompasses both arylox-
yallenes and allenamides as electrophilic partners providing
high yields and excellent stereochemical controls in the de-
sired cycloadducts. The computational (DFT) investigation
has fully elucidated the reaction mechanism providing clear
evidence for a two-step reaction. Two parallel reaction path-
ways explain the regioisomeric products obtained under ki-
netic and thermodynamic conditions. In both cases, the
dearomative CÀC bond-forming event turned out to be the
rate-determining step.
Introduction
Achieving chemical complexity in indolyl-based alkaloid
chemistry is currently attracting much interest in synthetic or-
ganic chemistry.[1] In particular, the intrinsic molecular diversity
of synthetic and natural occurring compounds belonging to
this family continues to inspire developments in organic syn-
thesis. To this aim, catalysis is the ultimate forefront in this
area with a large portfolio of reliable metal- and metal-free
methodologies available.[2]
Partially dearomatized C(2),C(3)-polycyclic fused indoline and
indolenine motifs are widely diffused molecular architectures
in indole alkaloids, featuring stereochemically defined all-
carbon quaternary stereocenters at the C(3)-position.[3] A col-
lection of titled compounds is shown in Figure 1.
Figure 1. Collection of natural products featuring polycyclic C(2),(3)-fused in-
doline and indolenine scaffolds.
Among the numerous catalytic methodologies available, the
enantioselective C(2),C(3)-annulation of indoles by cycloaddi-
tion reactions is gaining growing credit in terms of chemical
efficiency. Based on these methodologies, densely functional-
ized C(2),C(3)-fused cyclopropa-([2+1]),[4a] cyclopenta-([3+2])[4b]
and cyclohexa-indoline cores ([3+3])[4c] have been prepared in
a stereochemically defined manner.
[a] R. Ocello,+ A. De Nisi,+ Q.-Q. Yang, Prof. M. Monari, P. Giacinto,
Prof. A. Bottoni, Dr. G. P. Miscione, Prof. M. Bandini
Department of Chemistry “G. Ciamician”
Alma Mater Studiorum - University of Bologna
Via Selmi 2, 40126 Bologna (Italy)
Intriguingly, C(2),C(3)-indolincyclobutanes[5] have found less
attention in the literature. More precisely, besides the elegant
intramolecular approach reported by Zhang,[6a] the cyclobutyl-
fused indole species was isolated in low yields through con-
densation of allenamides with indoles by LopØz and Mascare-
Ças.[6b] Additionally, Xie and co-workers very recently docu-
mented the dearomative [2+2]-cycloaddition between o-car-
boryne and N-silylated indoles under thermal conditions.[7]
In this context, gold catalysis[8] offers unique opportunities
due to the peculiar characteristics of this coinage metal in pro-
E-mail: gianpietro.miscione@unibo.it
marco.bandini@unibo.it
[b] Dr. M. Jia
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (China)
[c] Dr. G. P. Miscione
Department of Chemistry, Universidad de los Andes
Carrera 1 N8 18A 10, Bogotµ (Colombia)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503598.
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moting cycloaddition transformations through electrophilic ac-
tivation of p-systems.[9,10] Recently, we exploited the potential
of gold-based catalysis and we documented the first enantio-
selective gold-catalyzed synthesis of C(2),C(3)-indolincyclobu-
tanes by formal [2+2]-cycloaddition reactions between N-pro-
tected indoles and allenamides (Scheme 1).[11]
reaction conditions showed DCM to be the best reaction
medium.[13] Initial attempts afforded the partially dearomatized
indolenine 5a and the nitrogen-allylated indole 6a as main by-
products of the process.
From the collection of results summarized on Table 1, [John-
[14]
PhosAu(NCMe)]SbF6 clearly emerged as a suitable catalyst in
promoting the cycloaddition, providing the [2+2]-adduct 4a
as the major product (entry 6, yield 49%) under mild reaction
conditions (CH2Cl2, RT, 16 h).
Table 1. Optimization of the reaction conditions for the racemic variant
of the formal [2+2]-cycloaddition reaction.[a]
Scheme 1. Preliminary results on the gold-catalyzed asymmetric condensa-
tion of indoles and allenamides.
In conjunction with our research interests focused on gold-
assisted manipulation of indole rings,[12] we present here a com-
prehensive investigation on the dearomative formal [2+2]-cy-
cloaddition reaction between 2,3-disubtituted indoles and alle-
namides, to give densely functionalized 2,3-cyclobutyl-indo-
lines. In particular, the gold-catalyzed racemic and enantiose-
lective condensations of allenamide/aryloxyallenes with
a range of N-substituted indoles 1 will be discussed. Moreover,
a detailed computational investigation at the density function-
al theory (DFT) level is carried out to obtain a mechanistic in-
sight on the high regioselectivity experimentally observed.
The complete range of indoles (1) and allenyl-derivatives (2
and 3) herein employed is shown below.
Run
[Au] (5 mol%)
Yield [%] 4[b]
Yield [%][b]
5a/6a
1
2
3
4
5
6
7
JackiePhosAuNTf2
Ph3PAuNTf2
XPhosAuNTf2
JohnPhosAuTFA
XPhosAuTFA
[JohnPhosAu(NCMe)]SbF6
[JohnPhosAu(NCMe)]SbF6
[JohnPhosAu(NCMe)]SbF6
[JohnPhosAu(NCMe)]SbF6
<5 (4a)
6 (4a)
19 (4a)
<5 (4a)
8 (4a)
49 (4a)
60 (4b)
73 (4b)
89 (4b)
22/33
18/75
–/–
77/<5
70/<5
5/–
–/–
–/–
–/–
8[c]
9[d]
[a] All the reactions were carried out under nitrogen atmosphere (1/2/
[Au]=1.2:1:0.05). [b] Isolated yields after flash chromatography. [c] T=
À208C, t=5 h. [d] T=À408C, t=16 h.
Based on these promising results we inferred that the intro-
duction of an electron-withdrawing group at the N-(1)-position
of the indole could have significant effects on the reaction
mechanism and its energetics by preventing the undesired N-
alkylation (6a) and by increasing the electrophilic character of
the intermediate immonium derivative (vide infra for further
mechanistic details).[15] We proved that, N-(Boc)-2,3-(Me)2-
indole 1b is a competent reaction partner providing the de-
sired diastereomerically pure cyclobutyl derivative 4b in 60, 73
and 89% yield at room temperature, À20 and À408C, respec-
tively (entries 7–9 of Table 1).[16] The increase of isolated yields
at lower temperatures can be rationalized in terms of minimi-
zation of gold-promoted self-condensation of 2 (i.e., dimeriza-
tion or polymerization).[10f]
Results and Discussion
Concerning the stereochemical aspects, optimal conditions
provided the cis-C(2),C(3)-fused tricyclic compounds in high di-
asteoreomeric ratio (d.r.=20:1). Furthermore, the exo-carbon=
carbon double bond was exclusively obtained in the Z configu-
ration.
Gold-catalyzed dearomatization reaction: the racemic ver-
sion (allenamides)
To optimize the synthesis of indolyl-2,3-cyclobutyl derivatives
by cycloaddition reaction between electron-rich allenes and in-
doles, we examined initially a range of cationic [AuI] complexes
in the model reaction involving the nitrogen-free 2,3(Me)2-
indole 1a and the allenamide 2. At the same time, a survey of
The scope of the reaction was then examined by treating
a range of N-protected-2,3-disubstitued indoles (1c–u) under
the chosen conditions and the obtained results are collected in
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Table 2. Interestingly, the cycloadducts 4c–k were obtained in
high yield from indoles carrying acyclic C(2),C(3) substituents
(1c–k). Similarly, the presence of C5- and C7-membered cycles
fused at the C(2),C(3)-positions of the pyrrolyl ring were ade-
quately tolerated, providing the corresponding tetra- and pen-
tacyclic compounds 4l–u from moderate to excellent yields
(41–95%). This screening addressed also the tolerance towards
substituents on the benzene ring. In particular, electron-donat-
ing (i.e., Me, OMe) and moderately electron-withdrawing
groups (i.e., Br) were found to be effective in the process. On
the contrary, strong EWG NO2 group (C(5), 1d) completely sup-
pressed the kinetics of the transformation (entry 2). Finally, the
Boc-protecting group was also successfully replaced by Cbz
(1c) with an untouched isolated yield (95%).
It is worth mentioning that, the 2,3-disubstitution pattern at
the indole core was mandatory for the reaction. More precisely,
while with N-Boc-indole and N-Boc-3-Me-indole the dimeriza-
tion products of 2 were the main outcomes, N-Boc-2-Me-
indole furnished the desired [2+2]-cycloadduct only in 18%
yield.
Table 2. Indole scope of the dearomative [2+2]-cycloaddition.[a]
Run
1
Product
Yield
[%][b]
(4)
1
2
3
4
5
1c
1d
1e
1 f
1j
95
n.r.
76
85
64
Gold-catalyzed dearomatization reaction: the racemic ver-
sion (aryloxyallene)
6
1k
62
Aryloxyallenes are an important class of electron-rich p-system
that have found extensive application in organic chemistry,
particularly with respect to cycloaddition reactions and site-se-
lective condensation with nucleophilic agents.[17] Analogously
to the afore-described allenamides, the nucleophilic addition
to the g-carbon would lead to a formal allylation reaction with
the simultaneous insertion of a synthetically versatile enol
ether moiety.
7
1l
78
75
80
60
8
1m
1n
1o
Despite their undoubted synthetic interest, to the best of
our knowledge, this family of unsaturated compounds has not
been employed in dearomative processes to date.
9
To assess the possibility of extending this synthetic method-
ology to aryloxyallenes, a range of allenyl derivatives (3a–f)[18]
was synthesized through a conventional two-step procedure
(i.e., propargylation of the corresponding phenol followed by
base-assisted isomerization) and subjected to the dearomative
cyclization in the presence of 1b and [JohnPhosAu(NCMe)]SbF6
(1–5 mol%).
10
11
12
13
14
1q
1r
1s
1t
81
70
70
41
The synthetic procedure turned out to be extraordinarily
adaptable to a variety of aryloxyallenes. Accordingly, a range of
racemic methylene cyclobutanes 7 (Table 3) was isolated as
a single stereoisomer in good to excellent yields (75–96%)
under mild reaction conditions ([Au]: 1–5 mol%, DCM, 08C,
4 h).
Subsequently, the substrate scope was further investigated
by condensing differently substituted N-Boc-indoles and al-
lenes 3b and 3d. The results reported in Scheme 2 emphasize
the efficiency of the above-described gold-catalyzed methodol-
ogy in providing densely functionalized tricyclic fused indolinyl
scaffolds 7.
In particular, we found that the reaction proved to be not
significantly affected by the presence of substituents (including
either carbon- or heteroatom-based groups) at the indole N(1),
C(2), C(3) and C(5) positions. The isolated yields ranged be-
tween 50 and 94% and the decrease of the catalyst loading to
1 mol% did not at all affect the chemical outcome. Both mo-
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lecular skeleton and stereochemical aspects were finally sub-
stantialized by obtaining the X-ray structure of (+/À)-7hd by
slow evaporation from a solution of AcOEt.
Table 2. (Continued)
Gold-catalyzed dearomatization reaction: mechanistic study
Run
15
1
Product
(4)
Yield
[%][b]
Interesting and unexpected experimental evidence was ob-
tained on the classic cycloaddition reaction between allena-
mide 2 and NBoc-indole 1b. In particular, we observed that,
when the condensation was carried out at temperatures
higher than 08C (i.e., room temperature or 408C), we detected
a second product that became predominant in the latter case
(yield 35%). Crystallographic analysis showed that this product
has the structure of the regioisomeric indoline-cyclobutyl ring
4b’, corresponding to a reverse approaching orientation (with
respect to 4b) of the two reaction partners (Scheme 3). Fur-
thermore, when 4b was treated in the presence of the gold
complex in hot DCM (408C), 4b’ was again isolated along with
some decomposition products. This experimental finding sug-
gests the existence of a kinetic (4b) and thermodynamic (4b’)
product that can interconvert.
1u
95
[a] All the reactions were carried out under nitrogen atmosphere [Au]:
[JohnPhosAu(NCMe)]SbF6 (5 mol%). [b] Isolated yields after flash chroma-
tography. Each compound was isolated as a single diastereoisomer. n.r.=
no reaction.
Table 3. Gold-catalyzed dearomative [2+2]-cycloaddition between 1a
and aryloxyallenes 3.[a]
Run
[Au] (x mol%)
3 (Ar)
Yield 7 [%][b]
1
2
3
4
5
6
5
1
5
5
5
5
3a (Ph)
75 (7ba)
83 (7bb)
96 (7bc)
81 (7bd)
83 (7be)
95 (7bf)
3b (b-naphth)
3c (pBrC6H4)
3d (pNO2C6H4)
3e (pF,o-BrC6H3)
3 f (p,o-Cl2C6H3)
[a] All the reactions were carried out under nitrogen atmosphere (1b/3=
1.2:1).[b] Isolated yields after flash chromatography. d.r.>20:1.
Scheme 3. Regiodivergent outcome of the [2+2]-cycloaddition when per-
formed in refluxing DCM. Proving the interconversion of 4b into 4b’ in hot
DCM.
These intriguing experimental results stressed the impor-
tance of elucidating the reaction mechanism to answer impor-
tant and unsolved questions, such as: 1) What is the coordina-
tion/activation mode of the gold catalyst with the allena-
mides?[18] 2) Is the mechanism concerted or step-wise? 3) What
is the rationale for the recorded regio- and stereochemistry? In
particular, why does the ring closure occur without affecting
the stereochemistry of the exocyclic double bond (Scheme 4)?
4) Are the “kinetic” and “thermodynamic” adducts the results
of two separate reaction channels coexisting on the reaction
surface?
To answer these questions we carried out a computational
investigation of the reaction surface. We used a DFT approach
and a model system formed by 1b and 2 activated by the
[AuI] cation bonded to the JohnPhos ligand ([JohnPhosAu+]).
First we examined how the cationic gold complex governs
the electrophilic activation of allenamide 2.[19] We found that
the interaction of the metal with the cumulated diene involves
Scheme 2. Formal [2+2]-cycloaddition between N-Boc-indoles and aryloxyal-
lenes (1/3/([JohnPhosAu(NCMe)]SbF6 =1:2:0.05, DCM, 08C, 16 h). *: 1 mol%
of catalyst was used. All the compounds were obtained in racemic manner.
7xb: Ar=2-naphth; 7xd: Ar=pNO2C6H4.
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more stable than reactants), where the indole ring plane and
the plane of the metal allyl cation are facing each other, the
C(3)ÀCg and C(2)ÀCg distances being 2.87 and 3.00 Š, respec-
tively. Interestingly, in the encounter complex the preferred co-
ordination of the gold cation is h1 and not h2 as found in the
isolated allenamide-[JhonPhosAu+] species. The higher stability
of the s type complex (h1) can be reasonably ascribed to the
stabilizing interaction between the electron-rich indole p-
system and the positive charge localized on the a allenamide
carbon (0.3 is the net computed charge on Ca).
Two reaction paths (both consisting of two steps) originate
from M0 and lead to different regioisomers corresponding to
opposite approaching orientations of the reacting species (see
above). These regioisomers should correspond to the hypothe-
sized thermodynamic and kinetic products 4b’ and 4b (the
former being 3.5 kcalmolÀ1 more stable than the latter). We
denote the two paths leading to 4b’ and 4b as Path(T) and
Path(K), respectively.
Scheme 4. Hypothetical mechanisms for the ring-closing step.
an equilibrium between three different complexes M1(p),
M2(s), M3(p) showing h2, h1 and h2 coordination to [AuI], re-
spectively. Both h2 complexes (M1(p) and M3(p)) are more
stable than M2(s) (2.9 and 3.4 kcalmolÀ1, respectively; a 3D
representation of the three complexes is given in Figure 2).
Along Path(K) (kinetic path-
way) the transition state TS1(K)
(6.3 kcalmolÀ1 above M0) corre-
sponding to the rate-determin-
ing step of the process, de-
scribes the attack of C(3) on Cg
and leads to the formation of
the indoleninic intermediate
M1(K), 13.6 kcalmolÀ1 more
stable than reactants. The newly
forming bond is 2.17 Š in TS1(K)
and becomes 1.57 Š in M1(K)
where the bond formation is
completed. Here the distance
C(2)ÀCb (that identifies the
second bond required to obtain
the final product) is 2.73 Š. The
s-coordination of the gold atom
as found in M0 is conserved in
TS1(K) and M1(K). The variation
of the NÀC(2) bond length along
Figure 2. A schematic 3D representation of the allenamide-[AuI] complexes. Total energy values [kcalmolÀ1] are
relative to M3(p). Bond lengths are given in Š.
the
transformation
M0!
TS1(K)!M1(K)
(1.41,
1.37,
1.32 Š, respectively) indicates
The perturbation of the p-system caused by the interaction
with the gold complex is evidenced by a slight increase of the
CÀC bond lengths in M1(p) and M3(p) and the increase of the
corresponding positive charge density on a and g carbons.
The reaction surface for the cycloaddition involving indole
1b and allenamide 2 complexed with [AuI] (reactants) is re-
ported in Figure 3 where two reaction channels are evidenced.
In the Figure a schematic representation of the corresponding
reaction patterns is also given. Additionally, two-dimensional
pictures of the structure of the various critical points located
along the two pathways are given in Figure 4. More detailed
3D representations for each point are reported in Figures S1–
S9 in the Supporting Information.
that the formation of the new C(3)ÀCg bond is brought about
by the indole nitrogen lone pair through an enaminic-type
electronic shift (see M1(K) structure in Figure 4).
A rather low activation barrier (2.8 kcalmolÀ1) must be over-
come (transition state TS2(K)) to close the ring. The structure
of TS2(K) is similar to that of the previous intermediate M1(K):
the most important difference is the decrease of the C(2)ÀCb
distance (the incipient CÀC bond), which becomes 2.26 Š.
Importantly, the CaÀCb bond length remains approximately
constant on passing from M1(K) to TS2(K) (1.34 and 1.36 Š, re-
spectively). This suggests that the formation of the C(2)ÀCb
bond involves the [Au]ÀCb heterolytic bond breakage (path B
in Scheme 4) rather than the enamidic fragment (NÀCaÀCb)
electrons (path A in Scheme 4). Thus, the ring-closing process
does not affect the nature of the CaÀCb exocyclic double
The approach of the two reacting species initially leads to
the formation of an encounter complex M0 (12.9 kcalmolÀ1
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The transition state for the
subsequent ring-closing step
(transition state TS2(T), 3.3 kcal
molÀ1 above TS2(K)) has an in-
trinsic activation energy of
6.1 kcalmolÀ1. The values of the
computed bond lengths again
indicate that the ring-closing
process involves the CbÀ[Au]
electrons. The stability of the re-
sulting product M2(T) (34.3 kcal
molÀ1 below reactants) can be
reasonably ascribed to the re-
storing of the aromaticity of the
indolinic ring. As observed for
M2(K) the coordination mode of
the gold cation [AuI] again be-
comes h2. It is reasonable to be-
lieve that the energetic gap
among these two adducts is due
to the steric hindrance between
the Boc and the oxazolinonic
groups. In M2(K) these two
groups are rather close, but this
steric hindrance is partially can-
celled in the thermodynamic
adduct M2(T) (compare Figur-
Figure 3. The two computed reaction profiles Path(K) and Path(T). The total energy values (E, kcalmolÀ1) include
ZPE corrections.
bond, which maintains its Z-configuration generated from the
initial outer-sphere nucleophilic attack of the indole on the
gold-activated allenamide.
es S5 and S9 in the Supporting Information).
Comparison of the two reaction profiles clearly indicates
that the two transition states for indole dearomatization (rate-
determining step in both cases) are close enough (the two ac-
tivation barriers differ by 1.3 kcalmolÀ1) to explain why, when
the reaction is performed at 08C, small amounts of the ther-
modynamic product are observed and only through a rigid ki-
netic control (À408C) it is possible to avoid the formation of
the regioisomer 4b’.
The energy difference between TS1(K) and TS1(T) can be
plausibly ascribed to the different indole dearomatization abili-
ty associated with the attack of C(3) and C(2) on the allenami-
dic carbon Cg. The energy cost is higher in the latter case
where a loss of aromaticity of the entire system (also involving
the benzene ring) occurs. Otherwise, when the attack proceeds
from C(3) the loss of aromaticity is confined to the heterocyclic
portion.
The final M2(K) product complex (the 4b regioisomer) is
30.8 kcalmolÀ1 more stable than reactants. In this complex the
gold atom gets away from Cb (CbÀAu distance=2.44 Š) and
moves much closer to Ca (2.37 Š), thus reactivating a h2 coor-
dination with the exocyclic double bond. Notably, the NÀC2
distance (indole moiety) increases from 1.32 to 1.47 Š along
the transformation M1(K)!M2(K).
This points out the disappearance of the formal charge on
the immonium ion (characterizing the indoleninic intermediate
M1(K)) and the repositioning of the lone-pair on the nitrogen
atom in M2(K).
Also, it demonstrates the importance of the protecting
group Boc that assists the cycloaddition process by displacing
electron density from N-C(2).
Along Path(T) (thermodynamic pathway) the first transition
state TS1(T) describes the nucleophilic attack of C2 on Cg (the
new incipient C2ÀCg bond is 2.14 Š) and corresponds again to
the rate determining step of the process. TS1(T) is 7.6 kcal
molÀ1 higher than M0 (1.3 kcalmolÀ1 above TS1(K)) and leads
to M1(T), the indoleninic dearomatizated intermediate, where
the new C2ÀCg bond formation is completed (1.57 Š).
The dearomatization process occurring in the passage M0!
M1(T) and involving the delocalization of the benzene p elec-
trons on indole is evidenced by the gradual increase in the
indole moiety of the C2ÀC3 (from 1.37 to 1.48 Š) and C4ÀC5
(from 1.41 to 1.44 Š) distances and a simultaneous shortening
of C3ÀC4 bond (from 1.44 to 1.38 Š).
Enantioselective gold-catalyzed [2+2]-cycloaddition be-
tween indoles and electron-rich allenes
The enantioselective cycloaddition reactions[20] involving in-
doles, represents a powerful tool for a direct access to stereo-
chemically defined dearomatized indolyl-based scaffolds.[21] As
a matter of fact, several metal- and metal-free stereoselective
methodologies have been developed with the site-selective
functionalization of the C(2)- and C(3)-positions of the indole
core.[3] Interestingly, despite the enormous interest towards the
development of efficient catalytic methodologies to polycyclic
fused indolines, enantioselective protocols to access C(2)/(3)-
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that the removal of the EWG
group from the nitrogen causes
a marked drop in the isolated
yield (8%) but with similar enan-
tiocontrol (91%, entry 1).
On the basis of these experi-
mental evidences, the efficiency
of the stereoselective gold-cata-
lyzed intermolecular [2+2]-cyclo-
addition between aryloxyallenes
and N-Boc indoles was investi-
gated. Among the screened
chiral ligands (see the Support-
ing Information), (R)-DTBM-seg-
phos furnished the highest
levels of chemical (61%) and op-
tical (85%) yields (CH2Cl2, 08C,
cat. loading=2.5 mol%) in the
model reaction (3a+1b) in
combination with AgNTf2 as the
gold-activator.[23] On the contra-
ry, lower performances were re-
corded with different C1- and
C2-symmetric chiral units.
Finally, the performances of
the catalytic system in the case
of aryloxyallenes were assessed
by condensing several indoles
with 3 under optimal conditions
(Table 5). Aryloxyallenes 3 were
generally found less reactive
than that allenamide 2 in the
enantioselective variant and
higher reaction temperatures
(i.e., 08C/À208C) were required
in order to access synthetically
acceptable reaction kinetics.
Figure 4. A schematic representation of the structures of the critical points located along Path(K) and Path(T). En-
ergies [kcalmolÀ1] are relative to reactants and include ZPE corrections. Bond lengths are given in Š.
The enantioselectivity ranges
from high (64%) to excellent
(95%) with moderate to good
cyclobutylindoline compounds were still unreported until our
recent contribution on the stereoselective gold-catalyzed
formal [2+2]-cycloaddition reaction.[11]
yield. Indoles featuring cyclic substituents at the C2/C3 carbon
atoms (1l,q) and trimethyl-substituted indole 1e (entry 5) were
proved to be particularly competent.
In particular, the use of in situ formed (R)-DTBM-seg
phos(AuOTf)2 (2.5–5.0 mol%) enabled the enantioselective
preparation of tricyclic indoline scaffolds in straightforward
manner by condensing a range of N-Boc-indoles and 2 (DCM,
À608C).[22]
Conclusions
A comprehensive investigation of the gold-catalyzed dearoma-
tive cycloaddition reaction of indoles with electron-rich allenes
is documented by means of experimental and computational
tools.
A collection of results is depicted in Table 4. Here, excellent
levels of regio-, diastereo- (d.r.>20:1) and enantioselection (ee
up to 98%) were obtained for differently substituted indoles.
In particular, 2,3-annulated indoles carrying C5 and C7-mem-
bered rings worked particularly well providing methylenecyclo-
buta-indolines 1l–t in enantiomeric excesses up to 99% (en-
tries 7–14). Also, it appears that alkyl substituents were also
tolerated at the C(2)/C(3)-sites (1b–1j), as well as EDGs and
EWGs in the benzene ring C(5)-position. It is worth mentioning,
Commercially available ([JohnPhosAu(NCMe)]SbF6 showed
competence in performing the chemo-, regio- and diastereose-
lective formal [2+2]-cycloaddition between a wide range of
substrates under mild conditions. A portfolio of densely func-
tionalized C(2),C(3)-fused cyclobutylindolines (4/7) is accessible
in a straightforward manner. Additionally, the use of chiral
C(2)-symmetric DTBM-segphos enabled the control of the ste-
Chem. Eur. J. 2015, 21, 18445 – 18453
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18451
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determining and corresponds to a dearomatization process.
The ring closure occurring in the second step involves the het-
erolytic rupture of the s [Au]ÀCb bond and not the electrons
of the exocyclic Ca=Cb double bond, which maintains its origi-
nal Z-configuration in agreement with the experiments.
The energy cost for the dearomatization process is higher
along the thermodynamic pathway (attack from the C(2)-
indole position) where the loss of aromaticity involves the
entire system (indole and benzene ring). This cost decreases
when the attack proceeds from C(3)- and the dearomatization
is confined to the indole moiety. The energy difference be-
tween the two dearomatization transition states is not very
large (about 1.3 kcalmolÀ1). This explains why at 08C small
amounts of the thermodynamic product 4b’ are observed and
only under severe kinetic conditions (À408C) it is possible to
avoid the formation of this regioisomer.
Table 4. Enantioselective dearomative cycloaddition between indoles
and 2.[a]
Run
R/R1/R2/X (1)
Yield 4 [%][b]
ee 4 [%][c]
1
2
3
4d
5d
6
7
8
9
10
11
12
13
14
Me/Me/H/H (1a)
8
91
93
96
81
86
92
94
93
95
94
98
98
94
99
Me/Me/H/Boc (1b)
Me/Me/H/Cbz (1c)
Me/Me/Me/Boc (1e)
Me/Me/OMe/Boc (1 f)
Me/Et/H/Boc (1j)
-(CH2)3-/H/Boc (1l)
-(CH2)3-/Me/Boc (1m)
-(CH2)3-/OMe/Boc (1n)
-(CH2)3-/Br/Boc (1o)
-(CH2)5-/H/Boc (1q)
-(CH2)5-/Me/Boc (1r)
-(CH2)5-/OMe/Boc (1s)
-(CH2)5-/Br/Boc (1t)
95
60
90
90
72
96
96
94
55
95
96
92
41
Studies addressing the exploitation of the gold-catalyzed
condensation of allenes with different aromatic compounds
are currently under investigation in our laboratory.
[a] All the reactions were carried out under nitrogen atmosphere (1/2=
1.2:1). [b] Isolated yields after flash chromatography. [c] Determined by
HPLC analysis with chiral column. Absolute configuration as reported in
the Scheme of Table 4 (see ref. [11]). [d] Catalyst loading=2.5 mol%.
Acknowledgements
University of Bologna and MIUR Rome are acknowledged for
the financial support. Q.Q.Y. thanks the China Scholarship
Council for financial support.
Table 5. Gold-catalyzed enantioselective cycloaddition between indoles
and 3.[a]
Keywords: allenamide
·
asymmetric catalysis
·
density
functional calculations · gold · indole
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Me/Me/H (1b)
Me/Me/H (1b)
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Received: September 8, 2015
Published online on October 30, 2015
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www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim