Carbocyclization versus oxycyclization on the metal-catalyzed reactions of oxyallenyl C3-linked indoles

Article abstract of DOI:10.1021/jo401013d

The preparation of previously unknown (indol-3-yl)-α-allenols and -allenones was accomplished from indole-3-carbaldehydes, through indium-mediated Barbier allenylation reaction taking advantage of the N-(2-pyridyl)sulfonyl group. Metal-catalyzed cyclizations of oxyallenyl C3-linked indoles proceeded in two ways depending on the presence or absence of the N-(2-pyridyl)sulfonyl group. For allenols, gold-catalyzed oxycyclization occurred in the presence of the protecting group; in the absence of the protecting group, palladium- and gold-catalyzed benzannulations operated. On the contrary, under gold catalysis furyl-indoles were obtained as exclusive products from NH-allenones, while 5-endo carbocyclization adducts were the major components starting from N-SO₂py-protected allenones. These cyclization reactions have been developed experimentally, and their mechanisms have additionally been investigated by a computational study.

Full text of DOI:10.1021/jo401013d

Article
pubs.acs.org/joc
Carbocyclization versus Oxycyclization on the Metal-Catalyzed
Reactions of Oxyallenyl C3-Linked Indoles
Benito Alcaide,*,† Pedro Almendros,*,‡ Jose M. Alonso,† and Israel Fernandez§
́
́
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organ
Química, Universidad Complutense de Madrid, 28040 Madrid, Spain
́
ica I, Unidad Asociada al CSIC, Facultad de
‡Instituto de Química Organ
§Departamento de Química Organ
́
ica General, IQOG, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
ica I, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain
́
S
* Supporting Information
ABSTRACT: The preparation of previously unknown (indol-3-yl)-α-allenols and -allenones was accomplished from indole-3-
carbaldehydes, through indium-mediated Barbier allenylation reaction taking advantage of the N-(2-pyridyl)sulfonyl group.
Metal-catalyzed cyclizations of oxyallenyl C3-linked indoles proceeded in two ways depending on the presence or absence of the
N-(2-pyridyl)sulfonyl group. For allenols, gold-catalyzed oxycyclization occurred in the presence of the protecting group; in the
absence of the protecting group, palladium- and gold-catalyzed benzannulations operated. On the contrary, under gold catalysis
furyl-indoles were obtained as exclusive products from NH-allenones, while 5-endo carbocyclization adducts were the major
components starting from N-SO2py-protected allenones. These cyclization reactions have been developed experimentally, and
their mechanisms have additionally been investigated by a computational study.
cyclization reactions have been developed experimentally, and
their mechanisms have additionally been investigated by a
computational study.
INTRODUCTION
■
Allenes have metamorphosed from a laboratory curiosity to a
versatile and uniquely reactive functional group,1 allowing
chemists to prepare a variety of compounds of chemical and
biological interest.2 Arguably, the indole scaffold is one of the
most common heterocyclic nuclei in natural and synthetic
products of biological significance.3 Consequently, methods for
the synthesis of new indole derivatives are highly appreciated.
Because of the fact that the C3-position of an indole is the most
reactive site for electrophilic functionalization, annulation of 2-
allenyl derivatives to the C3 indole position has been explored
in recent years.4 However, carbocyclization of indole-tethered
allenes to the C2 indole position is considerably less studied,5
with the metal-catalyzed C3−C2 cyclization being missed at the
outset of this study.6
Following up on our combined interest in the area of
heterocycles and allenes,7 we wish to report here a method
using gold- or palladium-based salts that enables catalytic
benzannulation8 at the C2 position of allenyl C3-linked indoles
to afford substituted carbazoles.9 Besides, a divergent reactivity
(oxycyclization versus carbocyclization) has also been encoun-
tered for N-SO2py-protected allenols and allenones. These
RESULTS AND DISCUSSION
■
The preparation of key starting materials, for example, NH-C3-
(α-hydroxyallenyl) indoles, required for our study was an initial
challenge. Starting allenyl C3-linked indoles were planned to be
prepared from indole-3-carbaldehydes. Disappointingly, the
widely utilized Sakurai-, Grignard-, and Barbier-type allenyla-
tions of carbonyls failed in NH- and N-alkyl-indole-3-
carbaldehydes. Fortunately, it was found that the indium-
mediated Barbier carbonyl-allenylation reaction in aqueous
media could be achieved for indole-3-carbaldehydes possessing
electron-withdrawing substituents directly attached to the
nitrogen atom. The 1-Boc-, 1-SO2Ar-, and 1-SO2py-substituted
indoles 1c−e were more effective than 1-H-, or 1-alkyl-
substituted substrates 1a and 1b, and the yields of C3-allenyl
indoles 2c−e were good (Scheme 1).
Received: May 8, 2013
© XXXX American Chemical Society
A
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a
Scheme 1. Regiocontrolled Preparation of Indole-C3-Tethered α-Hydroxyallenes 2c−e
a
Boc = tert-butoxycarbonyl. Ar = (2,4,6-triisopropyl)phenyl. SO2py = (2-pyridyl)sulfonyl.
a
Scheme 2. Preparation of NH-Indole-C3-Tethered α-Hydroxyallenes 3
a
SO2py = (2-pyridyl)sulfonyl.
Next, we focused on finding a cleavage procedure for the
above N-protecting groups that could be compatible with the
sensitive allenol moiety. This task was not trivial for N-Boc
derivative 2c and N-SO2Ar derivative 2d, because the allene
functionality was not able to survive under conventional
protective group removal conditions.10 Although methods for
N−S bond cleavage of pyridyl-2-sulfonamides are known, and
recent examples pertaining to indole derivatives have been
reported,11 no methodology exists for the removal in
synthetically useful allene derivatives. Nicely, after considerable
experimentation it was found that the desulfonylation of N-
SO2py-indoles efficiently occurred using inexpensive magne-
sium in methanol. Of note, the allene functionality at C3
remained intact despite its inherent reactivity. Removal of the
(2-pyridyl)sulfonamide from N1-protected indoles 2 utilizing
Mg-promoted conditions provided the corresponding NH-
indoles 3. Differently substituted indoles 2 at the benzene ring
were well tolerated, and the yields of C3-allenyl indoles 3 were
good (Scheme 2).
Table 1. Selective Oxycyclization Reaction of Allenylindole
2e under Modified Acid-Catalyzed Conditions
a
entry
catalyst
time (h)
yield (%)
b
1
2
3
4
5
6
HOTf
AuCl3
AuCl
2
2
59
67
73
75
83
1.5
1
[AuClPPh3]/AgOTf
[AuClPPh3]/AgBF4
[(Ph3P)AuNTf2]
1
1
a
Yield of pure, isolated product with correct analytical and spectral
b
data. A very complicated mixture was observed.
Indole-C3-tethered α-hydroxyallenes 2 and 3 have diverse
reactive sites, at which two different transformations (C-
cyclization versus O-cyclization) can take place. Our inves-
tigation began with allenol 2e as model substrate. The reaction
of 2e in the presence of 5 mol % of HOTf gave rise to a very
complicated mixture (Table 1, entry 1). We next investigated
gold-based catalysts. Optimization of the gold salt revealed that
Gagosz catalyst was the best election (Table 1, entry 6). The
use of other gold(I) or gold(III) catalysts gave inferior results
(Table 1, entries 2−5). Under the optimized conditions,
treatment of (indol-3-yl)-α-allenol 2e with a catalytic amount of
[(Ph3P)AuNTf2] gave dihydrofuran-attached indole 4e in 83%
yield (Scheme 3). 1,2-Dichloroethane was the solvent of choice
in terms of short reaction times and yield. Similar oxy-
cyclization results were encountered for C3-allenyl N-SO2py-
indoles 2f and 2h−k, to afford dihydrofuranyl-indoles 4f−k.
These results clearly show that the gold-catalyzed cyclo-
etherification is preferred over carbocyclization for N-SO2py-
protected substrates. We then investigated the reactions of
substrates without having an N-protecting group, NH-indole-
C3-tethered α-hydroxyallenes 3, to determine whether they
gave oxycyclization or carbocyclization. Our initial studies
concentrated on the gold-catalyzed cyclization reaction of
allenyl C3-linked indole 3e. On the basis of reaction time and
yield, [(Ph3P)AuNTf2] proved to be the most efficient catalyst,
providing the desired N-unprotected carbazole 5e in 77% yield
after 16 h at room temperature in toluene or DCE. Substrates
3f and 3j with additional aromatic substitutents showed no loss
B
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Scheme 3. Metal-Catalyzed Synthesis of (2,5-Dihydrofuran-2-yl)-indoles 4, 3-Methyl-9H-carbazoles 5, and 2-Allyl-3-methyl-9H-
a
carbazoles 6
a
SO2py = (2-pyridyl)sulfonyl. NTf2 = bis(trifluoromethanesulfonyl)imide. DCE = 1,2-dichloroethane.
of selectivity during the formation of carbazoles 5f and 5j
(Scheme 3). In addition, carbocyclization−functionalization
reactions of the allene subunit can be realized when allyl
bromide is added in the palladium-catalyzed transformation of
substrate 3e to generate 2,3-disubstituted-9H-carbazole deriv-
ative 6e. To evaluate the general applicability of this
benzannulation−functionalization protocol, a series of allenyl
C3-linked indole derivates were converted under the same
reaction conditions. All of the reactions delivered the
substituted NH-carbazoles 6f, 6g, 6i, and 6j in good yields
within acceptable reaction times (Scheme 3). Notably, despite
that metal-based catalysts are well-known for their ability to
promote the cycloetherification of α-allenols,12 no traces of
dihydrofurans were detected. In our case the 6-endo
carbocyclization reaction (carbazole formation) is favored
over the 5-endo oxycyclization (dihydrofuran formation).
In addition to C3-(α-hydroxyallenyl) indoles, substrates with
an α-ketone functionality at the allene position were also
investigated. The synthesis of the indole-C3-tethered allenones
was not an easy task because of the sensitivity of indolic
compounds under oxidative conditions. Thus, the reaction with
the reported reagent for the conversion of α-allenols into α-
allenones,13 i.e., Dess−Martin periodinane, resulted in a
complicated mixture. Fortunately, treatment of (α-hydroxyal-
lenyl) C3-linked indoles 2 or 3 with activated manganese(IV)
oxide resulted in the formation of the corresponding α-
allenones 7 and 8 (Scheme 4). These species are highly
sensitive and polymerize easily.
Scheme 4. Preparation of Indole-C3-Tethered α-Allenones 7
and 8
a
a
SO2py = (2-pyridyl)sulfonyl.
ring in allenones 8 is directly conjugated to a carbonyl moiety,
it is more electron-deficient than indole ring in allenols 3.
Hence, the cyclization takes place first at the oxygenated moiety
to form furyl-indoles 10. Besides, the fixed geometry of the
incorporated CO bond in allenones 8, which led to a lower
degree of conformational freedom compared with the indoles 3
with allenol side chains helps furan formation.
As for substrates 7 bearing an N-SO2py-protective group, the
reactions proceeded smoothly under the established conditions.
Interestingly, under gold catalysis α-allenones 7 delivered fused
tricycles 12 in addition to furyl-indoles 11 that were easily
separable by flash column chromatography (Scheme 5).16 In
comparison with α-allenone C3-linked NH-indoles 8, the
oxycyclization reaction of N-SO2py allenones 7 may be partially
hindered by the deactivating effect imparted by the (2-
Taking cues from the reaction of NH-indole-C3-tethered α-
hydroxyallenes 3, we expected that the reaction of NH-indole-
C3-tethered α-allenones 8 in the presence of a gold(I) catalyst
would initially produce a carbazolone 9. However, NH-indoles
8 displayed different reactivity, and furyl-indoles 10 were
obtained as exclusive products in reasonable yields (Scheme
5).14,15 The high reactivity toward oxycyclization of the
allenone system in 8 in comparison with allenols 3 probably
resulted from the presence of the carbonyl group. As indole
C
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a
Scheme 5. Gold-Catalyzed Synthesis of (Furan-2-yl)-indoles 10 and 11, and 2,3-Dihydrocyclopenta[b]indolones 12
a
NTf2 = bis(trifluoromethanesulfonyl)imide. SO2py = (2-pyridyl)sulfonyl. DCE = 1,2-dichloroethane.
pyridyl)sulfonyl group. The formation of adducts 12 can be
explained invoking a gold-catalyzed 5-endo-dig carbocyclization
toward the central allene carbon (see below). Besides, an
appealing temperature effect next emerged from the observa-
tion that performing the reaction under otherwise identical
conditions but at −20 °C resulted in the exclusive formation of
furyl-indoles 11 in good yields (Scheme 5). Interestingly, when
N-SO2py allenone 7e was treated with [(Ph3P)AuNTf2] in 1,2-
dichloroethane at 145 °C under microwave irradiation for 20
min,17 furyl-indole 11e and cyclopentaindolone 12e were
isolated in 27 and 58% yields, respectively (Scheme 5).
Similarly, the gold-catalyzed reactions of allenones 7f and 7g at
145 °C under microwave irradiation furnished mixtures of
furyl-indoles 11f and 11g and fused tricycles 12f and 12g
(Scheme 5). Cyclopentaindolones 12 (major component) are
easily separable by column chromatography from furyl-indoles
11 (minor component). The observed chemoselectivity
dependence on the reaction temperature is apparently the
result of kinetic and thermodynamic control in the cyclization
process. In the reaction at low temperature, it is expected that
the oxycyclization occurs, which would be more favorable than
carbocyclization, leading to 11 as the kinetic product.
Scheme 6. Mechanistic Explanation for the Gold-Catalyzed
Synthesis of Furyl-indoles 10 and 11
It is believed that the formation of compounds 4−6 proceeds
through expected cyclization mechanisms,18−20 following
known reactivity of allenes.1,2
carbon−gold bond of furan 21 yields adducts 10 and 11 and
eventually reforms the Au(I) catalytic species (Scheme 6).
A tentative proposal for the gold-catalyzed carbocyclization
of α-allenones 7 to fused tricycles 12 is presented in Scheme 7.
It is assumed that the mechanism starts with the coordination
of the gold salt to the proximal allenic double bond of allenes 7
to give the corresponding complex 7-Au-prox. Then the 5-
endo-dig carbocyclization toward the central allene carbon takes
place with formation of carbocation 22. This is followed by loss
of HNTf2 to produce neutral species 23. The required fused
Scheme 6 describes a putative mechanism for generating
furyl-indoles 10 and 11 from the cycloisomerization of indole-
C3-tethered α-allenones 7 and 8. Initially, [(Ph3P)AuNTf2]
coordinates to the distal allenic double bond of allenones 7 and
8 to produce 7-Au and 8-Au. The chemo- and regioselective 5-
endo oxycyclization reaction of the thus generated gold
complexes gives intermediates 20. The loss of proton in
oxonium 20 furnishes neutral species 21. Protonolysis of the
D
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steps deliberate tricycles 12, thereby facilitating the regener-
ation of the gold catalyst.
Scheme 7. Mechanistic Explanation for the Gold-Catalyzed
Synthesis of Fused Tricycles 12
Density functional theory (DFT) calculations have been
carried out to gain more insight into the reaction mechanisms
involving the formation of furyl-indoles 11 and tricycles 12
from α-allenones 7. The corresponding computed reaction
profiles of the reaction of allenone 7e with the model
[(Me3P)AuNTf2] as catalyst are depicted in Figure 1, which
shows the corresponding free energies (at 298 K) in DCE
solution (PCM-M06/def2-SVP// B3LYP/def2-SVP level).21
As proposed in Scheme 6, our calculations suggest that the
formation of furyl-derivates 11 starts with the exergonic
+
coordination of the AuPMe3 catalyst to the distal double
bond of the allenic moiety of 7e to form 7e-Au (ΔG298 = −10.8
kcal/mol). Then, the 5-endo oxyauration reaction occurs to
produce the cationic intermediate 20-Au through the transition
state TS1. This saddle point is associated with the nucleophilic
addition of the carbonyl group to the electrophilic gold-
complexed distal carbon atom of the allene moiety. This
process proceeds with a low activation barrier (ΔGa,298 = 8.9
kcal/mol) in a highly exergonic transformation ((ΔGR,298
=
−15.0 kcal/mol), which reflects the easiness of the reaction. 20-
Au complex is then transformed into the final furyl-indole 11e
by subsequent proton loss and protonolysis of the C−Au bond
as previously reported by us.22
cyclopentenones 12 are generated from 23 by subsequent
Au(I)/proton exchange and dehydration. These consecutive
Figure 1. Computed reaction profiles for the reaction of α-allenone 7e and [(PMe3)AuNTf2] catalyst to produce compounds 11e and 12e. Relative
free energies (ΔG, at 298 K) are given in kcal/mol and bond distances in the transition states in angstroms. Atoms are represented as spheres: C,
gray; H, white; N, blue; O, red; P, orange, S, yellow; Au, dark yellow. All data have been computed at the PCM(DCE)-M06/def2-SVP//B3LYP/
def2-SVP level.
E
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Figure 2. Computed Nazarov-type cyclization of α-allenone 7e and [(PMe3)AuNTf2] catalyst to produce 12e. See caption of Figure 1 for additional
details.
Scheme 7 suggests that the formation of tricyclic species 12
involves the initial proximal coordination of the gold(I)-catalyst
to the allene moiety. However, our calculations indicate that
this coordination mode, which leads to complex 7e-Au-prox, is
less exergonic (ΔG298 = −6.5 kcal/mol) than the distal
coordination (Figure 1). Despite that, we were able to locate
on the potential energy sufarce a transition state (TS3), which
connects 7e-Au-prox with the cationic tricyclic intermediate
22-Au. The computed high activation barrier (ΔGa,298 = 25.3
kcal/mol) and endergonicity (ΔGR,298 = 5.2 kcal/mol) make
this 5-endo-dig carbocyclization reaction not feasible at −20 °C
or at room temperature. Nevertheless, tricyclic compounds 12
are formed, although as a minor component, when the reaction
is conducted at room temperature (see above). This
experimental finding necessarily means that a more feasible
reaction pathway leading to these species should exist. Indeed, a
new saddle point TS2, associated with the formation of the C−
C bond from the distal complex 7e-Au, was located. This
process leads to the tricyclic cationic species 24-Au with a lower
activation barrier (ΔGa,298 = 20.7 kcal/mol) in a less endergonic
pathway from both kinetic and thermodynamic points of
view. For this reason, furyl-indoles 11 are exclusively formed
when the reaction is conducted at −20 °C. Similarly,
compounds 11 are the major reaction products when the
reaction is conducted at room temperature (see Scheme 5).
However, within these conditions the available thermal energy
seems to be enough to overcome, at least in part, the barriers
associated with TS2 and TS4 that lead to tricyclic compounds
12 as minor reaction products. Both barriers and also that
involving TS3 (in the proximal reaction pathway) are easily
overcome at 140 °C (and microwave irradiation conditions). As
a consequence, a significant amount of compounds 12 is
produced together with the most favored furyl-indoles 11.
Given that from the computational data in Figure 1 furyl-
indole 11 is both the product of kinetic and thermodynamic
control, we subjected the kinetic product 11 to reaction
conditions to discard that the purported thermodynamic
product 12 is formed. Indeed, the treatment of 11e under
microwave irradiation at 145 °C in the presence of the gold salt
did not result in formation of tricycle 12e.
−
transformation (ΔGR,298 = 4.1 kcal/mol). NTf2 -mediated
Alternatively, the observed indolones 12 may be formed
following a Nazarov-type cyclization mechanism.23 As shown in
Figure 2, coordination of the gold(I)-catalyst to the oxygen
atom of the carbonyl group of 7e instead of the allenyl moiety
proton loss transforms 24-Au into the neutral species 25-Au,
which is subsequently converted in complex 23-Au through the
transition state TS4. This saddle point is associated with the
1,3-migration of the gold(I)-fragment through the π-allyl
moiety of 25-Au. The gold(I)-migration is also feasible at
room temperature in view of the computed activation barrier
(ΔGa,298 = 15.1 kcal/mol) and exergonicity (ΔGR,298 = −4.6
kcal/mol). Please note that 23-Au can be also formed in the
proximal reaction pathway by proton-loss from intermediate
22-Au, which connects both reaction pathways. Again,
protonolysis of the C−Au bond in 23-Au will produce the
final tricyclic compounds 12.
leads to the exergonic formation of complex 7e-Au-O (ΔG298
=
−11.7 kcal/mol). This species evolves to the stabilized allylic
carbocation 26-Au via TS5, a transition state associated with
the C−C bond formation in a Nazarov-type cyclization
reaction. This process proceeds with an activation barrier of
ΔGa,298 = 20.4 kcal/mol, which indicates that it is competitive
over the processes described above involving TS2 or TS3.
Complex 26-Au will be finally converted into the final indolone
12e after 1,3-proton migration and decoordination of the
catalyst.
From the data in Figure 1, it becomes obvious that the
oxycyclization process via TS1 is the preferred reaction
F
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DCE as solvent) on the B3LYP/def2-SVP optimized geometries. This
level is denoted PCM(DCE)-M06/def2-SVP//B3LYP/def2-SVP.
Preparation of 1c and 1d. N-Boc derivative 1c and N-SO2Ar
derivative 1d were prepared according to previously reported
procedures.32,33
In addition, since at high temperature the gold catalyst may
decompose to give acid, it can be suggested that the in situ
generated protons may also catalyze the Nazarov-type
cyclization reaction of allenones 7. To check this hypothesis,
7e was reacted with 5 mol % of HOTf as the catalyst (under
otherwise identical conditions) and tricyclic product 12e was
formed in 90% yield (Scheme 8).24 Therefore, it can be
General Procedure for the Synthesis of 1-SO2py-Substituted
Indoles 1e−k. Over a solution of the corresponding NH-indole in
anhydrous THF (13 mL/mmol) at 0 °C, NaH (1.5 equiv) was added
in portions. After 1.5 h of stirring, 2-pyridinsulfonyl chloride was
slowly added, and the mixture was warmed to room temperature and
left stirring overnight. After completion (TLC), the reaction was
quenched with water and extracted with AcOEt. The organic phases
were combined, washed with brine, and dried on MgSO4. The solvent
was evaporated under reduced pressure, and the mixture was purified
on column chromatography, yielding analytically pure compounds.
Spectroscopic and analytical data for pure forms of 1e−k follow.
1-SO2py-Substituted Indole 1e. Starting from the corresponding
aldehyde (200 mg, 1.38 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 3:1), 340 mg (86%) of the
N-protected compound were obtained as a colorless solid: mp 189−
Scheme 8. Controlled Preparation of 2,3-
Dihydrocyclopenta[b]indolone 12e through Proton-
a
Catalyzed Carbocyclization of Allenone 7e
1
a
191 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.41 (2H, m), 7.56
SO2py = (2-pyridyl)sulfonyl. DCE = 1,2-dichloroethane.
(1H, ddd, J = 7.6, 4.7, 0.9 Hz), 8.00 (2H, m), 8.29 (2H, m), 8.38 (1H,
s), 8.65 (1H, m), 10.17 (1H, s); 13C NMR (75 MHz, CDCl3) δ 185.5,
154.6, 150.8, 138.4, 137.8, 135.5, 128.2, 126.3, 126.2, 125.1, 122.7,
122.6, 122.4, 113.4; IR (CHCl3) ν = 1677, 1383, 1162, 1121 cm−1;
HRMS (ES) calcd for C14H11N2O3S [M + H]+ 287.0490, found
287.0485.
concluded that the formation of these tricycles 12 may be the
result of this proton-mediated Nazarov reaction or, alter-
natively, of the above commented gold(I)-catalyzed process via
TS5.
1-SO2py-Substituted Indole 1f. Starting from the corresponding
aldehyde (250 mg, 1.57 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 3:1), 423 mg (90%) of the
N-protected compound were obtained as a colorless solid: mp 194−
195 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.46 (3H, s), 7.21 (1H,
m), 7.54 (1H, m), 7.85 (1H, d, J = 8.5 Hz), 7.99 (1H, td, J = 7.7, 1.6
Hz), 8.10 (1H, s), 8.26 (1H, d, J = 7.9 Hz), 8.34 (1H, s), 8.65 (1H,
m), 10.14 (1H, s); 13C NMR (75 MHz, CDCl3) δ 185.8, 154.6, 150.9,
144.9, 138.4, 138.2, 135.3, 128.2, 127.6, 126.6, 127.7, 122.5, 122.3,
113.1, 21.4; IR (CHCl3) ν = 1679, 1390, 1177, 1122 cm−1; HRMS
(ES) calcd for C15H13N2O3S [M + H]+ 301.0647, found 301.0631.
1-SO2py-Substituted Indole 1g. Starting from the corresponding
aldehyde (250 mg, 1.06 mmol), after purification on column
chromatography (dichloromethane/ethyl acetate, 2:1), 395 mg
(99%) of the N-protected compound were obtained as a colorless
CONCLUSION
■
In conclusion, the chemo- and regiocontrolled cyclization of
oxyallenyl C3-linked indoles into different heterocycles has
been realized by using various catalysts, such as Pd(II)- and
Au(I)-based salts. The scope of these protocols has been
investigated and clearly demonstrates their utility for the
selective preparation of furyl-indoles, carbazoles, and cyclo-
pentaindolones from structurally related substrates. These
cyclization reactions have been developed experimentally, and
their mechanisms have additionally been investigated by a
computational study. At present time, the application of this
methodology into the selective preparation of other types of
indole-based compounds is ongoing in our group.
1
solid: mp 201−202 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 2.42
(3H, s), 7.29 (2H, m), 7.61 (3H, m), 8.01 (2H, m), 8.29 (1H, dt, J =
7.9, 1.0 Hz), 8.39 (1H, s), 8.50 (1H, m), 8.66 (1H, m), 10.18 (1H, s);
13C NMR (75 MHz, CDCl3) δ 185.6, 154.6, 151.0, 138.7, 138.5, 138.4,
137.7, 137.3, 134.7, 129.6 (2C), 128.3, 127.3 (2C), 127.0, 125.7, 122.8,
122.6, 120.7, 113.7, 21.1; IR (CHCl3) ν = 1678, 1384, 1163, 1120
cm−1; HRMS (ES) calcd for C21H17N2O3S [M + H]+ 377.0960, found
377.0943.
EXPERIMENTAL SECTION
■
General Methods. 1H NMR and 13C NMR spectra were recorded
on 700, 500, 300, or 200 MHz spectrometers. NMR spectra were
recorded in CDCl3 solutions, except when otherwise stated. Chemical
shifts are given in ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C,
76.9 ppm). Low and high resolution mass spectra were taken on a
QTOF LC−MS spectrometer using the electronic impact (EI) or
electrospray modes (ES) unless otherwise stated. Specific rotation
[α]D is given in 10−1 deg cm2 g−1 at 20 °C, and the concentration (c)
is expressed in g per 100 mL. All commercially available compounds
were used without further purification.
1-SO2py-Substituted Indole 1h. Starting from the corresponding
aldehyde (350 mg, 1.846 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 1:1), 500 mg (82%) of the
N-protected compound were obtained as a pale yellow solid: mp 166−
168 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.69 (3H, s), 3.88 (3H,
s), 6.99 (1H, d, J = 0.1 Hz), 7.54 (1H, ddd, J = 7.7, 4.7, 0.9 Hz), 7.80
(1H, d, J = 9.1 Hz), 7.98 (1H, td, J = 7.7, 1.6 Hz), 8.23 (1H, d, J = 7.9
Hz), 8.39 (1H, s), 8.64 (1H, m), 10.17 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 184.9, 155.2, 154.6, 150.9, 139.7, 138.4, 130.9, 128.2, 127.4,
124.5, 127.7, 120.9, 111.3, 110.5, 56.7, 14.4; IR (CHCl3) ν = 1689,
1391, 1165, 1119 cm−1; HRMS (ES) calcd for C16H15N2O4S [M +
H]+ 331.0753, found 331.0747.
Computational Details. All the calculations reported in this paper
were obtained with the Gaussian 09 suite of programs.25 Geometry
optimizations were performed using the B3LYP26 hybrid functional in
combination with the double-ζ quality plus polarization def2-SVP27
basis set for all atoms. Reactants and products were characterized by
frequency calculations28 and have positive definite Hessian matrices.
Transition structures (TS) show only one negative eigenvalue in their
diagonalized force constant matrices, and their associated eigenvectors
were confirmed to correspond to the motion along the reaction
coordinate under consideration using the intrinsic reaction coordinate
(IRC) method.29 Single point energy calculations were computed
using the dispersion-corrected meta-hybrid M06 functional, which has
been recommended for transition-metal-containing species30 in
combination with the polarizable continuum model31 (PCM, using
1-SO2py-Substituted Indole 1i. Starting from the corresponding
aldehyde (350 mg, 1.815 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 1:1), 683 mg (97%) of the
N-protected compound were obtained as a colorless solid: mp 190−
1
191 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 1.16 (6H, d, J = 6.8
Hz), 2.92 (1H, sept, J = 6.8 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.42 (1H,
dd, J = 7.8, 4.7 Hz), 7.72 (1H, s), 7.87 (1H, td, J = 7.7, 1.4 Hz), 8.06
(1H, d, J = 8.2 Hz), 8.13 (1H, d, J = 7.9 Hz), 8.21 (1H, s), 8.52 (1H,
G
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m), 10.00 (1H, s); 13C NMR (75 MHz, CDCl3) δ 185.7, 154.5, 150.9,
147.9, 138.5, 137.6, 135.9, 128.3, 124.4, 124.2, 127.7, 122.4, 122.3,
111.1, 34.6, 24.3 (2C); IR (CHCl3) ν = 1672, 1399, 1192, 1122 cm−1;
HRMS (ES) calcd for C17H17N2O3S [M + H]+ 329.0960, found
329.0954.
1-SO2py-Substituted Indole 1j. Starting from the corresponding
aldehyde (200 mg, 1.26 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 2:1), 290 mg (77%) of the
N-protected compound were obtained as a colorless solid: mp 194−
195 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 2.54 (3H, s), 7.14 (1H,
d, J = 7.29 Hz), 7.29 (1H, m), 7.58 (1H, ddd, J = 7.7, 4.7, 1.2 Hz), 8.04
(1H, td, J = 7.9, 1.8 Hz), 8.20 (1H, dt, J = 7.9, 0.9 Hz), 8.26 (1H, m),
8.55 (1H, s), 8.64 (1H, m), 10.18 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 185.7, 156.2, 150.7, 141.2, 138.6, 135.7, 129.8, 128.3, 128.1,
125.4, 124.1, 122.3, 121.6, 120.5, 21.7; IR (CHCl3) ν = 1680, 1394,
1187, 1127 cm−1; HRMS (ES) calcd for C15H13N2O3S [M + H]+
301.0647, found 301.0641.
1-SO2py-Substituted Indole 1k. Starting from the corresponding
aldehyde (250 mg, 1.712 mmol), after purification on column
chromatography (hexanes/ethyl acetate, 2:1), 428 mg (87%) of the
N-protected compound were obtained as a pale yellow solid: mp 194−
195 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 7.22 (1H, dd, J = 7.9,
4.8 Hz), 7.47 (1H, ddd, J = 7.8, 4.7, 1.1 Hz), 7.95 (1H, td, J = 7.7, 1.6
Hz), 8.31 (1H, dd, J = 4.8, 1.6 Hz), 8.43 (1H, s), 8.48 (1H, m), 8.52
(1H, m), 10.02 (1H, s); 13C NMR (75 MHz, CDCl3) δ 185.4, 154.5,
150.6, 147.7, 146.7, 138.4, 137.4, 131.6, 128.4, 124.7, 120.8, 119.8,
119.1; IR (CHCl3) ν = 1686; 1396; 1190; 1137 cm−1; HRMS (ES)
calcd for C13H10N3O3S [M + H]+ 288.0443, found 288.0437.
Indium-Promoted Reaction between 1-Bromo-2-butyne
and Indole-3-carbaldehydes 1. General Procedure for the
Synthesis of α-Allenic Alcohols 2. 1-Bromo-2-butyne (3.0 mmol)
was added to a well stirred suspension of the appropriate aldehyde 1
(1.0 mmol) and indium powder (6.0 mmol) in THF/NH4Cl (aq. sat.)
(1:5, 5 mL) at 0 °C. The reaction was stirred at rt for 16 h. After
disappearance of the starting material (TLC), the mixture was
extracted with ethyl acetate (3 × 5 mL). The organic extract was
washed with brine, dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/hexanes
or dichloromethane/ethyl acetate mixtures gave analytically pure
compounds. Spectroscopic and analytical data for pure forms of 2
follow.
α-Allenic Alcohol 2c. Starting from aldehyde 1c (120 mg, 0.49
mmol), 108 mg (77%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
5:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.58 (12H, s), 4.84 (2H,
m), 5.32 (1H, s), 7.13 (1H, m), 7.23 (1H, td, J = 7.6, 1.3 Hz), 7.52
(2H, m), 8.05 (1H, d, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3) δ
205.2, 149.8, 136.0, 128.6, 124.5, 123.6, 122.6, 121.4, 120.1, 115.3,
101.5, 83.8, 77.7, 69.2, 28.2 (3C), 14.4; IR (CHCl3) ν = 3508−3350,
1540, 1019 cm−1; HRMS (ES) calcd for C18H22NO3 [M + H]+
300.1600, found 300.1594.
m); 13C NMR (75 MHz, CDCl3) δ 205.2, 155.4, 150.4, 138.1, 135.9,
129.0, 127.5, 125.1, 124.8, 123.4, 123.1, 122.3, 120.7, 113.9, 101.3,
77.9, 69.1, 14.3; IR (CHCl3) ν = 3509−3352, 1542, 1038 cm−1;
HRMS (ES) calcd for C18H17N2O3S [M + H]+ 341.0960, found
341.0954.
α-Allenic Alcohol 2f. Starting from aldehyde 1f (500 mg, 1.660
mmol), 501 mg (85%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
3:2): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.63 (3H, t, J = 3.0 Hz),
2.41 (3H, s), 4.94 (2H, m), 5.36 (1H, s), 7.13 (1H, d, J = 8.5 Hz), 7.38
(1H, s), 7.44 (1H, ddd, J = 7.7, 4.7, 1.1 Hz), 7.64 (1H, m), 7.86 (2H,
m), 8.08 (1H, d, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 205.5,
155.7, 150.8, 138.5, 134.4, 133.5, 129.7, 127.9, 126.6, 125.6, 123.3,
122.7, 120.9, 114.0, 101.6, 78.8, 69.3, 21.9, 14.8; IR (CHCl3) ν =
3512−3353, 1540, 1038 cm−1; HRMS (ES) calcd for C19H18N2O3S
[M + H]+ 355.1116, found 355.1111.
α-Allenic Alcohol 2g. Starting from aldehyde 1g (320 mg, 0.851
mmol), 280 mg (76%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
2:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.67 (3H, t, J = 3.2 Hz),
2.43 (3H, s), 4.96 (2H, m), 5.45 (1H, s), 7.29 (2H, m), 7.52 (4H, m),
7.73 (1H, s), 7.81 (1H, d, J = 1.3 Hz), 7.93 (1H, td, J = 7.4, 1.6 Hz),
8.07 (1H, dd, J = 8.6, 0.4 Hz), 8.17 (1H, d, J = 7.9 Hz), 8.63 (1H, m);
13C NMR (75 MHz, CDCl3) δ 205.1, 155.3, 150.5, 138.4, 138.3, 138.2,
136.9, 136.8, 135.1, 129.6 (2C), 127.7, 127.2 (2C), 125.5, 124.3, 123.2,
118.9, 114.1, 101.3, 78.0, 69.1, 21.1, 14.3; IR (CHCl3) ν = 3512−3342,
1544, 1032 cm−1; HRMS (ES) calcd for C25H23N2O3S [M + H]+
431.1429, found 431.1424.
α-Allenic Alcohol 2h. Starting from aldehyde 1h (500 mg, 1.515
mmol), 470 mg (80%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
2:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.64 (3H, t, J = 3.1 Hz),
2.39 (3H, s), 3.74 (3H, s), 4.73 (2H, m), 5.42 (1H, s), 6.80 (1H, d, J =
9.1 Hz), 7.33 (1H, ddd, J = 7.6, 4.7, 1.0 Hz), 7.59 (1H, s), 7.70 (1H, d,
J = 9.1 Hz), 7.77 (1H, td, J = 7.7, 1.7 Hz), 7.97 (1H, d, J = 8.0 Hz),
8.47 (1H, m); 13C NMR (75 MHz, CDCl3) δ 205.8, 155.2, 154.2,
150.4, 138.1, 130.9, 129.7, 127.5, 127.0, 124.4, 122.3, 119.2, 111.5,
109.7, 101.9, 78.1, 60.7, 56.8, 15.5, 12.0; IR (CHCl3) ν = 3512−3342,
1544, 1023 cm−1; HRMS (ES) calcd for C20H20N2O4SNa [M + Na]+
407.1041, found 407.1036.
α-Allenic Alcohol 2i. Starting from aldehyde 1i (633 mg, 1.930
mmol), 787 mg (99%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
2:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.20 (6H, d, J = 6.9 Hz),
1.53 (3H, t, J = 3.03 Hz), 2.93 (1H, sept, J = 6.8 Hz), 4.85 (2H, m),
5.27 (1H, s), 7.03 (1H, dd, J = 8.3, 1.5 Hz), 7.36 (1H, ddd, J = 7.6, 4.7,
1.0), 7.43 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 0.9 Hz), 7.81 (2H, m),
8.02 (1H, d, J = 8.0 Hz), 8.51 (1H, m); 13C NMR (75 MHz, CDCl3) δ
205.0, 155.3, 150.4, 146.3, 138.0, 136.1, 127.6, 127.1, 124.6, 123.00,
122.4, 122.3, 120.3, 111.6, 101.3, 77.9, 69.0, 34.5, 24.4 (2C), 14.3; IR
(CHCl3) ν = 3512−3351, 1533, 1039 cm−1; HRMS (ES) calcd for
C21H23N2O3S [M + H]+ 383.1429, found 383.1424.
α-Allenic Alcohol 2j. Starting from aldehyde 1j (160 mg, 0.533
mmol), 170 mg (90%) of the allenol were obtained as a brown oil,
after purification on column chromatography (hexanes/ethyl acetate,
5:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.68 (3H, t, J = 3.1 Hz),
2.61 (3H, s), 4.97 (2H, m), 5.43 (1H, s), 7.07 (1H, d, J = 7.3 Hz), 7.17
(1H, t, J = 7.4 Hz), 7.50 (2H, m), 7.84 (1H, s), 7.93 (1H, td, J = 7.6,
1.7 Hz), 8.02 (1H, d, J = 7.9 Hz), 8.62 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 205.3, 150.3, 138.2, 135.8, 131.0, 128.5, 127.9, 127.4, 125.0,
123.85, 122.4, 122.0, 118.3, 115.3), 101.2, 77.8, 69.0, 22.0, 14.4; IR
(CHCl3) ν = 3508−3343, 1544, 1029 cm−1; HRMS (ES) calcd for
C19H19N2O3S [M + H]+ 355.1116, found 355.1111.
α-Allenic Alcohol 2d. Starting from aldehyde 1d (190 mg, 0.46
mmol), 120 mg (51%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
8:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.02 (12H, d, J = 6.7 Hz,
4Me), 1.17 (6H, d, J = 7.0 Hz), 1.65 (3H, t, J = 3.1 Hz), 2.83 (1H,
sept, J = 6.9 Hz), 4.11 (2H, sept, J = 6.7 Hz), 4.84 (2H, m), 5.32 (1H,
s), 7.11 (4H, m), 7.33 (1H, m), 7.45 (1H, s), 7.54 (1H, m); 13C NMR
(75 MHz, CDCl3) δ 205.6, 155.0, 151.8, 136.1, 131.9, 131.9, 128.5,
124.7, 124.7 (2C), 123.6, 122.9, 121.8, 120.9, 113.1, 101.7, 77.6, 69.5,
34.6, 28.9 (2C), 24.9 (4C), 23.9 (2C), 14.8; IR (CHCl3) ν = 3501−
3344, 1542, 1022 cm−1; HRMS (ES) calcd for C28H36NO3S [M + H]+
466.2416, found 466.2410.
α-Allenic Alcohol 2e. Starting from aldehyde 1e (60 mg, 0.209
mmol), 66 mg (93%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
2:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.65 (3H, t, J = 3.1 Hz),
4.95 (2H, m), 5.41 (1H, s), 7.28 (2H, m); 7.47 (1H, ddd, J = 7.7, 4.7,
1.0 Hz), 7.63 (1H, d, J = 7.4 Hz), 7.71 (1H, s), 7.91 (1H, td, J = 7.4,
1.8 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.13 (1H, d, J = 8.1 Hz), 8.61 (1H,
α-Allenic Alcohol 2k. Starting from aldehyde 1k (428 mg, 1.491
mmol), 400 mg (78%) of the allenol were obtained as a pale yellow oil,
after purification on column chromatography (hexanes/ethyl acetate,
1:1): 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.69 (3H, t, J = 3.2 Hz),
4.96 (2H, m), 5.40 (1H, s), 7.17 (1H, dd, J = 7.9, 4.8 Hz), 7.50 (1H,
ddd, J = 7.6, 4.7, 1.6 Hz), 7.9 (1H, s), 7.97 (2H, m), 8.35 (1H, dd, J =
4.8, 1.6 Hz), 8.49 (1H, d, J = 7.9 Hz), 8.61 (1H, m); 13C NMR (75
H
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MHz, CDCl3) δ 204.9, 155.4, 150.2, 148.0, 145.1, 138.1, 129.5, 127.7,
125.0, 124.1, 121.5, 120.0, 119.0, 101.3, 78.2, 69.1, 14.5; IR (CHCl3) ν
= 3508−3337, 1542, 1039 cm−1; HRMS (ES) calcd for C17H16N3O3S
[M + H]+ 342.0912, found 342.0907.
purification: 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.68 (3H, t, J = 3.2
Hz), 4.98 (2H, m), 5.45 (1H, s), 7.12 (1H, dd, J = 7.9, 4.8 Hz), 7.38
(1H, s), 8.07 (1H, dd, J = 8.0, 1.5 Hz), 8.33 (1H, m), 10.67 (1H, s);
13C NMR (75 MHz, CDCl3) δ 204.7, 149.2, 142.9, 128.7, 123.2, 118.6,
Magnesium-Promoted Desulfonylation of Allenic N-SO2py-
Indoles 2. General Procedure for the Synthesis of Allenic NH-
Indoles 3. Over a solution of the corresponding allenol 2 (1 mmol) in
MeOH (8 mL) at 0 °C, Mg powder was added in one portion (10
equiv). The mixture was stirred and left to warm up to room
temperature. After completion (TLC, usually 2−3 h), NH4Cl (aq. sat.)
(8 mL) and Et2O (8 mL) were added. The mixture was stirred for 1 h
and then extracted with AcOEt. The organic extract was washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate/hexanes mixtures
gave analytically pure compounds. Spectroscopic and analytical data
for pure forms of 3 follow.
α-Allenic Alcohol 3e. Starting from N-SO2py-protected allenol 2e
(60 mg, 0.176 mmol), 30 mg (86%) of the NH adduct were obtained
as a pale yellow oil, and used in the next step without further
purification: 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.66 (3H, t, J = 3.2
Hz), 4.97 (2H, m), 5.46 (1H, s), 7.20 (3H, m), 7.38 (1H, dd, J = 8.0,
1.0 Hz), 7.72 (1H, d, J = 7.3 Hz), 8.16 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 204.8, 136.7, 125.8, 122.7, 122.3, 119.8, 119.8, 117.0, 111.3,
102.5, 77.7, 69.1, 15.0; IR (CHCl3) ν = 3524−3300, 3418, 1567 cm−1;
HRMS (ES) calcd for C13H14NO [M + H]+ 200.1075, found
200.1070.
α-Allenic Alcohol 3f. Starting from N-SO2py-protected allenol 2f
(500 mg, 1.412 mmol), 200 mg (67%) of the NH adduct were
obtained as a pale yellow oil, and used in the next step without further
purification: 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.57 (3H, t, J = 3.1
Hz), 2.37 (3H, s), 4.89 (2H, m), 5.32 (1H, s), 6.96 (1H, d, J = 9.2
Hz), 7.07 (1H, d, J = 2.3, 1.0 Hz), 7.16 (2H, m), 7.41 (1H, s), 7.95
(1H, s); 13C NMR (75 MHz, CDCl3) δ 204.8, 135.0, 129.0, 126.1,
124.0, 127.8, 119.5, 116.6, 110.9, 102.5, 77.8, 69.0, 21.6, 15.0; IR
(CHCl3) ν = 3524−3291, 3418, 1567 cm−1; HRMS (ES) calcd for
C14H16NO [M + H]+ 214.1232, found 214.1226.
115.8, 115.5, 102.4, 77.8, 69.2, 14.9; IR (CHCl3) ν = 3508−3337,
1560, 1039 cm−1; HRMS (ES) calcd for C12H13N2O [M + H]+
201.1028, found 201.1022.
Manganese-Promoted Oxidation of Allenol-Tehered Indoles
2 and 3. General Procedure for the Synthesis of Indole-C3-
Tethered α-Allenones 7 and 8. Over a solution of the
corresponding allenol (1 mmol) in anhydrous MeCN (11 mL) at 0
°C, previously activated MnO2 was added in one portion (10 equiv).
The mixture was warmed up to room temperature and stirred
overnight. After completion (TLC), the crude was filtered through a
pad of Celite, and the solvent was evaporated under reduced pressure.
The resulting mixture was immediately used in the next step, as it
showed quick decomposition on solution in most of the cases.
α-Allenone 7e. Starting from allenol 2e (235 mg, 0.680 mmol), 180
mg (45%) of the allenone were obtained as a dark gum, after
purification on column chromatography (deactivated silica gel,
1
hexanes/ethyl acetate, 2:1): H NMR (300 MHz, CDCl3, 25 °C) δ
1.95 (3H, t, J = 2.9 Hz), 5.16 (2H, q, J = 2.9 Hz), 7.24 (2H, m), 7.41
(1H, m), 7.85 (2H, m), 8.11 (2H, m), 8.32 (1H, s), 8.51 (1H, m); 13C
NMR (75 MHz, acetone-d6) δ 216.9, 188.1, 155.4, 151.8, 140.1, 135.7,
134.6, 129.7, 129.4, 126.4, 125.5, 123.8, 123.4, 120.3, 114.2, 103.4,
79.7, 14.8; IR (CHCl3) ν = 1933, 1635, 1381, 1186 cm−1; HRMS (ES)
calcd for C18H15N2O3S [M + H]+ 339.0803, found 339.0798.
α-Allenone 7f. Starting from allenol 2f (235 mg, 0.680 mmol), 216
mg (54%) of the allenone were obtained as a brown oil, and used
immediately in the next step, as it showed quick decomposition on
1
solution: H NMR (300 MHz, acetone-d6, 25 °C) δ 1.94 (3H, t, J =
2.9 Hz), 2.35 (3H, s), 5.16 (2H, q, J = 3.1 Hz), 7.05 (1H, dd, J = 8.5,
1.0 Hz), 7.40 (1H, ddd, J = 7.8, 4.7, 1.0 Hz), 7.73 (1H, d, J = 8.4 Hz),
7.84 (1H, td, J = 7.7, 1.8 Hz), 7.92 (1H, m), 8.08 (1H, d, J = 7.9 Hz),
8.3 (3H, m), 8.51 (1H, m); IR (CHCl3) ν = 1942, 1658, 1381, 1188
cm−1; HRMS (ES) calcd for C19H17N2O3S [M + H]+ 353.0960, found
353.0954.
α-Allenone 7g. Starting from allenol 2g (200 mg, 0.466 mmol), 120
mg (60%) of the allenone were obtained as a brown oil, after
purification on column chromatography (deactivated silica gel,
hexanes/ethyl acetate, 2:1): 1H NMR (300 MHz, acetone-d6, 25
°C) δ 1.82 (3H, t, J = 2.9 Hz), 2.19 (3H, s), 5.26 (2H, q, J = 2.9 Hz),
7.10 (2H, m), 7.39 (2H, m), 7.47 (1H, dd, J = 8.5, 1.9 Hz), 7.54 (1H,
ddd, J = 7.7, 4.5, 1.0 Hz), 7.88 (1H, dd, J = 8.8, 0.5 Hz), 8.03 (1H, td, J
= 7.8, 1.6 Hz), 8.21 (2H, m), 8.36 (1H, s), 8.50 (1H, m); 13C NMR
(75 MHz, acetone-d6) δ 216.9, 188.1, 155.4, 151.9, 140.1, 138.9, 137.8,
135.2, 130.5 (2C), 129.7, 129.2, 127.9 (2C), 125.9, 125.6, 123.8, 121.3,
120.5, 116.2, 114.6, 103.4, 79.8, 21.1, 14.9; IR (CHCl3) ν = 1939,
1632, 1364, 1188 cm−1; HRMS (ES) calcd for C25H21N2O3S [M +
H]+ 429.1273, found 429.1267.
α-Allenone 7k. Starting from allenol 2k (215 mg, 0.630 mmol), 86
mg (40%) of the allenone were obtained as an orange oil, after
purification on column chromatography (deactivated silica gel,
hexanes/ethyl acetate, 2:1): 1H NMR (300 MHz, acetone-d6, 25
°C) δ 1.85 (3H, t, J = 2.9 Hz), 5.34 (2H, q, J = 2.9 Hz), 7.23 (1H, dd, J
= 7.9, 4.7 Hz), 7.58 (1H, ddd, J = 7.7, 4.7, 1.0 Hz), 8.09 (1H, td, J =
7.7, 1.6 Hz), 8.14 (1H, dd, J = 4.7, 1.6 Hz), 8.34 (1H, m), 8.37 (1H,
m), 8.45 (1H, m), 8.53 (1H, s); 13C NMR (75 MHz, acetone-d6) δ
216.8, 187.5, 155.6, 151.5, 147.9, 146.6, 139.7, 134.2, 132.2, 129.7,
125.3, 121.9, 121.4, 117.8, 103.0, 80.0, 14.9; IR (CHCl3) ν = 1957,
1633, 1379, 1188 cm−1; HRMS (ES) calcd for C17H14N3O3S [M +
H]+ 340.0756, found 340.0750.
α-Allenone 8a. Starting from allenol 3e (255 mg, 1.280 mmol), 108
mg (45%) of the allenone were obtained as an orange oil, after
purification on column chromatography (deactivated silica gel,
hexanes/ethyl acetate, 3:1): 1H NMR (300 MHz, acetone-d6, 25
°C) δ 1.81 (3H, t, J = 3.1 Hz), 5.04 (2H, q, J = 3.1 Hz), 7.08 (2H, m),
7.35 (1H, m), 8.15 (2H, m); 13C NMR (75 MHz, acetone-d6) δ 213.7,
186.2, 133.0, 132.8, 126.2, 122.4, 122.1, 121.4, 121.2, 111.2, 101.3,
α-Allenic Alcohol 3g. Starting from N-SO2py-protected allenol 2g
(280 mg, 0.653 mmol), 140 mg (75%) of the NH adduct were
obtained as a pale yellow oil, after purification on column
1
chromatography (hexanes/ethyl acetate, 2:1): H NMR (300 MHz,
CDCl3, 25 °C) δ 1.71 (3H, t, J = 3.1 Hz), 2.44 (3H, s), 5.07 (2H, m),
5.51 (1H, s), 7.29 (4H, m), 7.52 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 204.8, 150.5, 139.7, 138.2, 136.1, 133.3, 129.4 (2C), 127.3
(2C), 123.21, 122.2, 118.2, 117.4, 111.4, 102.5, 77.8, 69.1, 21.1, 15.0;
IR (CHCl3) ν = 3535−3301, 3422, 1566 cm−1; HRMS (ES) calcd for
C20H20NO [M + H]+ 290.1545, found 290.1539.
α-Allenic Alcohol 3i. Starting from N-SO2py-protected allenol 2i
(350 mg, 0.916 mmol), 160 mg (73%) of the NH adduct were
obtained as a pale yellow oil, and used in the next step without further
1
purification: H NMR (300 MHz, CDCl3, 25 °C) δ 1.22 (6H, d, J =
7.0 Hz), 1.56 (3H, t, J = 3.0 Hz), 2.93 (1H, sept, J = 7.0 Hz), 4.87 (2H,
m), 5.33 (1H, s), 6.96 (1H, dd, J = 8.4, 1.5 Hz), 7.06 (1H, d, J = 2.3),
7.13 (1H, m), 7.55 (1H, d, J = 8.3 Hz), 7.96 (1H, s); 13C NMR (75
MHz, CDCl3) δ 205.2, 144.0, 137.5, 124.3, 122.5, 119.9, 119.6, 117.4,
108.8, 78.0, 69.6, 34.7, 24.9 (2C), 15.4; IR (CHCl3) ν = 3510−3349,
1533, 1039 cm−1; HRMS (ES) calcd for C16H20NO [M + H]+
242.1545, found 242.1539.
α-Allenic Alcohol 3j. Starting from N-SO2py-protected allenol 2j
(160 mg, 0.452 mmol), 100 mg (99%) of the NH adduct were
obtained as a pale yellow oil, and used in the next step without further
purification: 1H NMR (300 MHz, CDCl3, 25 °C) δ 1.57 (3H, t, J = 3.0
Hz), 2.41 (3H, s), 4.87 (2H, m), 5.36 (1H, s), 6.98 (2H, m), 7.14 (1H,
d, J = 2.5 Hz), 7.47 (1H, m), 7.96 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 205.2, 136.7, 125.7, 123.3, 122.6, 120.8, 120.4, 118.0, 117.9,
102.8, 78.1, 69.6, 17.0, 15.3; IR (CHCl3) ν = 3530−3299, 3422, 1567
cm−1; HRMS (ES) calcd for C14H16NO [M + H]+ 214.1232, found
214.1226.
α-Allenic Alcohol 3k. Starting from N-SO2py-protected allenol 2k
(100 mg, 0.293 mmol), 57 mg (98%) of the NH adduct were obtained
as a pale yellow oil, and used in the next step without further
I
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Article
76.7, 14.0; IR (CHCl3) ν = 1935, 1641, 1381, 1186 cm−1; HRMS (ES)
calcd for C13H12NO [M + H]+ 198.0919, found 198.0913.
α-Allenone 8b. Starting from allenol 3f (277 mg, 1.300 mmol), 158
mg (57%) of the allenone were obtained as a brown oil, and used
immediately in the next step, as it showed quick decomposition on
solution.
td, J = 7.9, 1.8 Hz), 7.69 (1H, s), 7.35 (2H, m), 7.01 (2H, m), 5.67
(2H, m), 4.71 (2H, m), 2.49 (3H, s), 1.55 (3H, s); 13C NMR (75
MHz, CDCl3, 25 °C) δ 156.8, 150.3, 138.2, 137.2, 135.9, 131.2, 128.8,
128.5, 124.9, 123.9, 122.0, 121.6, 121.0, 118.0, 83.5, 75.2, 22.0, 12.6; IR
(CHCl3, cm−1) ν 2849, 1386, 1188, 590; HRMS (ES) calcd for
C19H19N2O3S [M + H]+ 355.1116, found 355.1111.
α-Allenone 8c. Starting from allenol 3j (125 mg, 0.587 mmol), 85
mg (68%) of the allenone were obtained as a brown oil, and used
immediately in the next step, as it showed quick decomposition on
solution.
Dihydrofuran 4k. From 70 mg (0.205 mmol) of allene 2k, and after
chromatography of the residue using hexanes/ethyl acetate (1:1) as
eluent gave compound 4k (68 mg, 94%) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.58 (1H, m), 8.48 (1H, d, J = 7.9 Hz),
8.34 (1H, dd, J = 4.8, 1.4 Hz), 7.96 (1H, td, J = 7.7, 1.6 Hz), 7.84 (2H,
m), 7.47 (1H, ddd, J = 7.7, 4.7, 1.0 Hz), 7.15 (1H, dd, J = 8.0, 4.0 Hz),
4.80 (2H, m), 5.57 (2H, m), 1.63 (3H, s); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 155.2, 150.3, 148.1, 145.1, 138.1, 136.8, 128.9, 127.8,
125.7, 124.1, 121.8, 121.5, 119.1, 118.8, 83.6, 75.3, 12.5; IR (CHCl3,
cm−1) ν 2844, 1382, 1176, 603; HRMS (ES) calcd for C17H16N3O3S
[M + H]+ 342.0912, found 342.0907.
General Procedure for the Au-Catalyzed Benzannulation of
C3-Allenyl NH-Indoles 3. Preparation of 3-Methyl-9H-carba-
zoles 5. [(Ph3P)AuNTf2] (0.005 mmol) was added to a stirred
solution of the corresponding allene 3 (0.1 mmol) in toluene (1.3 mL)
under argon. The resulting mixture was stirred at room temperature
until disappearance of the starting material (TLC). After filtration
through a pad of Celite, the mixture was extracted with ethyl acetate (3
× 5 mL), and the combined extracts were washed twice with brine.
The organic layer was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl acetate/
hexanes mixtures gave analytically pure adducts 5.
General Procedure for the Au-Catalyzed Oxycyclization of
C3-Allenyl N-SO2py-Indoles 2. Preparation of (2,5-Dihydrofur-
an-2-yl)-indoles 4. [(Ph3P)AuNTf2] (0.005 mmol) was added to a
stirred solution of the corresponding allene 2 (0.1 mmol) in 1,2-
dichloroethane (1.3 mL) under argon. The resulting mixture was
stirred at room temperature until disappearance of the starting material
(TLC). After filtration through a pad of Celite, the mixture was
extracted with ethyl acetate (3 × 5 mL), and the combined extracts
were washed twice with brine. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes mixtures gave analytically
pure adducts 4.
Dihydrofuran 4e. From 56 mg (0.164 mmol) of allene 2e, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent gave compound 4e (46 mg, 83%) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.50 (1H, m), 8.02 (1H, d, J = 7.9 Hz),
7.92 (1H, d, J = 8.2 Hz), 7.78 (1H, td, J = 7.7, 1.7 Hz), 7.57 (1H, s),
7.45 (1H, d, J = 7.6 Hz), 7.36 (1H, ddd, J = 7.7, 4.7, 1.0 Hz), 7.18 (2H,
m), 5.66 (2H, m), 4.70 (2H, m), 1.52 (3H, s); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 155.3, 150.5, 138.1, 137.1, 136.0, 129.1, 127.6, 125.8,
124.8, 123.5, 122.3, 121.8, 121.6, 120.2, 113.9, 83.5, 75.2, 15.5; IR
(CHCl3, cm−1) ν 2850, 1377, 1188, 599; HRMS (ES) calcd for
C18H17N2O3S [M + H]+ 341.0960, found 341.0954.
Carbazole 5e. From 60 mg (0.302 mmol) of allene 3e, and after
chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent gave compound 5e (41 mg, 77%) as a colorless solid: mp 208−
1
209 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.96 (1H, m), 7.89
(1H, m), 7.80 (1H, s), 7.33 (2H, m), 7.26 (1H, d, J = 8.1 Hz), 7.15
(2H, m), 2.46 (3H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 139.8,
137.7, 128.8, 127.2, 125.7, 125.3, 120.3, 120.3, 120.0, 119.2, 110.6,
110.2, 21.5; IR (CHCl3, cm−1) ν 3426, 1456, 1176, 715; HRMS (ES)
calcd for C13H12N [M + H]+ 182.0970, found 182.0964.
Dihydrofuran 4f. From 110 mg (0.320 mmol) of allene 2f, and
after chromatography of the residue using hexanes/ethyl acetate (2:1)
1
as eluent gave compound 4f (64 mg, 57%) as a pale yellow oil: H
NMR (300 MHz, CDCl3, 25 °C) δ 8.5 (1H, m), 7.99 (1H, d, J = 7.9
Hz), 7.79 (1H, d, J = 9.1 Hz), 7.51 (1H, s), 7.35 (1H, m), 7.20 (2H,
m), 7.04 (1H, dd, J = 8.5, 1.5 Hz), 5.66 (2H, m), 4.69 (2H, m), 2.30
(3H, s), 1.53 (3H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 155.6,
150.8, 138.5, 137.5, 134.5, 133.5, 129.6, 127.9, 126.6, 126.3, 122.7,
121.9, 120.4, 113.9, 83.8, 77.6, 75.5, 21.8, 13.0; IR (CHCl3, cm−1) ν
2850, 1381, 1178, 536; HRMS (ES) calcd for C19H19N2O3S [M + H]+
355.1116, found 355.1111.
Carbazole 5f. From 70 mg (0.328 mmol) of allene 3f, and after
chromatography of the residue using hexanes/ethyl acetate (8:1) as
eluent gave compound 5f (44 mg, 70%) as a colorless solid: mp 214−
1
215 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.76 (2H, m), 7.21
(4H, m), 2.45 (6H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 138.1
(2C), 135.8 (2C), 128.5 (2C), 127.0 (2C), 123.4 (2C), 110.2 (2C),
21.5 (2C); IR (CHCl3, cm−1) ν 3425, 1456, 1176, 720; HRMS (ES)
calcd for C14H14N [M + H]+ 196.1126, found 196.1121.
Dihydrofuran 4h. From 140 mg (0.364 mmol) of allene 2h, and
after chromatography of the residue using hexanes/ethyl acetate (2:1)
Carbazole 5j. From 80 mg (0.376 mmol) of allene 3j, and after
chromatography of the residue using hexanes/ethyl acetate (9:1) as
eluent gave compound 5j (48 mg, 67%) as a colorless solid: mp 175−
1
as eluent gave compound 4h (112 mg, 68%) as a pale orange oil: H
NMR (300 MHz, CDCl3, 25 °C) δ 8.49 (1H, m), 7.97 (1H, dd, J =
7.9, 0.9 Hz), 7.77 (2H, m), 7.35 (2H, m), 6.83 (1H, d, J = 9.1 Hz),
5.91 (1H, m), 5.70 (1H; s), 4.56 (2H, m), 3.74 (3H, m), 2.45 (3H, s),
1.74 (3H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 155.2, 154.3,
150.4, 138.0, 136.9, 130.8, 130.2, 127.5, 127.2, 123.3, 122.5, 122.3,
119.4), 111.4, 109.9, 82.4, 73.9, 57.0, 13.5, 11.9; IR (CHCl3, cm−1) ν
2851, 1377, 1189, 568; HRMS (ES) calcd for C20H21N2O4S [M + H]+
385.1222, found 385.1217.
Dihydrofuran 4i. From 120 mg (0.312 mmol) of allene 2i, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent gave compound 4i (40 mg, 55%) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.52 (1H, m), 7.99 (1H, dt, J = 7.9, 1.0
Hz), 7.77 (2H, m), 7.51 (1H, s), 7.36 (2H, m), 7.03 (1H, dd, J = 8.2,
1.5 Hz), 5.64 (2H, m), 4.69 (2H, m), 2.92 (1H, sept, J = 7.0 Hz), 1.52
(3H, s), 1.20 (6H, d, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3, 25 °C)
δ 155.2, 150.5, 146.3, 138.1, 137.1, 136.3, 127.6, 127.2, 125.3, 122.5,
122.3, 121.7, 121.5, 119.9, 111.6, 83.5, 75.2, 34.5, 24.4 (2C), 12.6; IR
(CHCl3, cm−1) ν 2850, 1379, 1190, 599; HRMS (ES) calcd for
C21H21N2O3S [M + H]+ 381.1273, found 381.1267.
1
176 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.96 (1H, d, J = 7.7
Hz), 7.93 (1H, s), 7.81 (2H, m), 7.26 (1H, m), 7.06 (2H, m), 2.80
(3H, s), 2.51 (3H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 136.0,
133.7, 129.2, 127.4, 126.6, 125.9, 120.8, 119.9, 119.7, 118.3, 110.7,
108.6, 21.9, 21.5; IR (CHCl3, cm−1) ν 3426, 1456, 1176, 715; HRMS
(ES) calcd for C14H14N [M + H]+ 196.1126, found 196.1121.
General Procedure for the Pd(II)-Catalyzed Carbocyclization
of C3-Allenyl NH-Indoles 3 in Presence of Allyl Bromide.
Preparation of 2-Allyl-3-methyl-9H-carbazoles 6. Palladium(II)
chloride (0.005 mmol) was added to a stirred solution of the
corresponding allene 3 (0.10 mmol) and allyl bromide (0.50 mmol) in
N,N-dimethylformamide (0.6 mL). The reaction was stirred under
argon atmosphere until disappearance of the starting material (TLC).
Water (0.5 mL) was added before being extracted with ethyl acetate (3
× 4 mL). The organic phase was washed with water (2 × 2 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromatography
of the residue eluting with hexanes/ethyl acetate mixtures gave
analytically pure adducts 6.
Dihydrofuran 4j. From 60 mg (0.169 mmol) of allene 2j, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent gave compound 4j (39 mg, 65%) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.52 (1H, m), 7.86 (1H, m), 7.84 (1H,
Carbazole 6e. From 60 mg (0.302 mmol) of allene 3e, and after
chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent gave compound 6e (46 mg, 85%) as a colorless solid: mp 128−
1
129 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.94 (1H, d, J = 7.7
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Hz), 7.81 (1H, s), 7.75 (1H, s), 7.31 (2H, m), 7.14 (2H, m), 5.98 (1H,
m), 4.98 (2H, m), 3.46 (2H, m), 2.37 (3H, s); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 139.6, 138.6, 137.6, 134.9, 129.7, 125.2, 121.7, 121.2,
120.6, 120.0, 119.2, 115.4, 111.7, 110.5, 37.9, 20.3; IR (CHCl3, cm−1)
ν 3413, 1469, 1241; HRMS (ES) calcd for C16H16N [M + H]+
222,1283, found 222.1277.
Furan 10b. From 75 mg (0.356 mmol) of allenone 8b, and after
chromatography of the residue using hexanes/ethyl acetate (4:1) as
eluent gave compound 10b (46 mg, 62%) as a colorless solid: mp 91−
93 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 8.07 (1H, s), 7.77 (1H,
s), 7.37 (1H, d, J = 1.8 Hz), 7.19 (2H, m), 6.98 (1H, dd, J = 8.3, 1.4
Hz), 6.28 (1H, d, J = 1.8 Hz), 2.40 (3H, s), 2.11 (3H, s); 13C NMR
(75 MHz, CDCl3, 25 °C) δ 146.7, 139.9, 134.2, 129.8, 125.9, 124.4,
121.6, 120.9, 113.9, 113.9, 110.7, 108.5, 21.6, 11.3; IR (CHCl3, cm−1)
ν 3400, 2929, 1386, 756; HRMS (ES) calcd for C14H14NO [M + H]+
212.1075, found 212.1070.
Carbazole 6f. From 50 mg (0.235 mmol) of allene 3f, and after
chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent gave compound 6f (42 mg, 78%) as a colorless solid: mp 132−
1
133 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.71 (2H, m), 7.21
(2H, m), 7.11 (2H, m), 5.96 (1H, m), 4.98 (2H, m), 3.44 (2H, m),
2.43 (3H, s), 2.36 (3H, s); 13C NMR (75 MHz, CDCl3, 25 °C) δ
139.3, 138.2, 138.0, 135.0, 129.9, 128.9, 126.9, 124.0, 121.9, 120.8,
120.4, 115.7, 112.0, 110.5, 38.3, 21.8, 20.7; IR (CHCl3, cm−1) ν 3411,
1473, 1241; HRMS (ES) calcd for C17H18N [M + H]+ 236.1439,
found 236.1433.
Carbazole 6g. From 70 mg (0.244 mmol) of allene 3g, and after
chromatography of the residue using hexanes/ethyl acetate (9:1) as
eluent gave compound 6g (44 mg, 59%) as a colorless solid: mp 113−
114 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 8.13 (1H, s), 7.84 (1H,
s), 7.79 (1H, s), 7.54 (4H, m), 7.37 (1H, m), 7.16 (2H, m), 5.99 (1H,
m), 5.00 (2H, m), 3.46 (2H, m) 2.38 (3H s), 2.34 (3H, s); 13C NMR
(75 MHz, CDCl3, 25 °C) δ 139.4, 139.1, 137.6, 136.0, 135.1, 132.8,
129.9, 129.5 (2C), 127.4, 127.1 (2C), 124.7, 124.0, 121.8, 120.6, 118.4,
115.4, 111.8, 110.6, 37.9, 21.1, 20.4; IR (CHCl3, cm−1) ν 3413, 1477,
1241; HRMS (ES) calcd for C23H21N [M + H]+ 311.1674, found
311.1665.
Furan 10f. From 100 mg (0.474 mmol) of allenone 8f, and after
chromatography of the residue using hexanes/ethyl acetate (5:1) as
1
eluent gave compound 10f (61 mg, 61%) as a pale yellow gum: H
NMR (300 MHz, CDCl3, 25 °C) δ 8.08 (1H, s), 7.84 (1H, d, J = 7.9
Hz), 7.36 (1H, d,, J = 1.8 Hz), 7.23 (1H, d, J = 2.6 Hz), 7.02 (2H, m),
6.28 (1H, d, J = 1.6 Hz), 2.42 (3H, s), 2.12 (3H, s); 13C NMR (75
MHz, CDCl3, 25 °C) δ 146.6, 140.0, 134.4, 125.2, 123.2, 121.2, 120.6,
120.2, 119.1, 114.0, 114.0, 109.5, 16.6, 11.3; IR (CHCl3, cm−1) ν 3409,
2924, 1379, 747; HRMS (ES) calcd for C14H14NO [M + H]+
212.1075, found 212.1070.
General Procedure for the Au-Catalyzed Oxycyclization of
C3-Allenyl N-SO2py-Indoles 7 at Low Temperature. Prepara-
tion of 3-(Furan-2-yl)-indoles 11. [(Ph3P)AuNTf2] (0.005 mmol)
was added to a stirred light-protected solution of the corresponding
allenone 7 (0.1 mmol) in 1,2-dichloroethane (1.3 mL) under argon at
−20 °C. The resulting mixture was stirred at −20 °C until
disappearance of the starting material (TLC). After filtration through
a pad of Celite, the mixture was extracted with ethyl acetate (3 × 5
mL), and the combined extracts were washed twice with brine. The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl acetate/
hexanes mixtures gave analytically pure adducts 11.
Carbazole 6i. From 72 mg (0.301 mmol) of allene 3i, and after
chromatography of the residue using hexanes/ethyl acetate (12:1) as
eluent gave compound 6i (53 mg, 67%) as a colorless solid: mp 126−
1
127 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.84 (1H, d, J = 8.04
Hz), 7.71 (1H, m), 7.15 (1H, s), 7.10 (1H, s), 7.01 (1H, dd, J = 8.2,
1.0 Hz), 5.97 (1H, m), 4.96 (2H, m), 3.45 (2H, m), 2.98 (1H, sept, J =
7.0 Hz), 2.36 (3H, s), 1.26 (6H, d, J = 7.0 Hz); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 146.7, 140.0, 138.7, 137.7, 137.1, 134.2, 129.5, 120.3,
119.8, 118.4, 115.3, 111.6, 110.7, 108.0, 37.9, 34.6, 24.5 (2C), 20.3; IR
(CHCl3, cm−1) ν 3407, 1484, 1240; HRMS (ES) calcd for C19H22N
[M + H]+ 264.1752, found 264.1747.
Furan 11e. From 70 mg (0.207 mmol) of allenone 7e, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
1
eluent gave compound 11e (57 mg, 85%) as a pale yellow gum: H
NMR (300 MHz, CDCl3, 25 °C) δ 8.50 (1H, m), 8.05 (1H, d, J = 7.9
Hz), 7.95 (1H, m), 7.78 (1H, td, J = 7.7, 1.8 Hz), 7.67 (1H, m), 7.37
(2H, m), 7.23 (2H, m), 6.30 (1H, d; J = 1.7 Hz), 2.18 (3H, s); 13C
NMR (75 MHz, CDCl3, 25 °C) δ 155.2, 150.6, 144.3, 141.1, 138.2,
135.0, 129.0, 127.7, 125.2, 123.9, 122.9, 122.3, 122.3, 117.3, 114.3,
114.3, 113.7, 11.5; IR (CHCl3, cm−1) ν 3143, 1446, 1375, 1185, 1128,
745; HRMS (ES) calcd for C18H15N2O3S [M + H]+ 339.0803, found
339.0798.
Furan 11f. From 100 mg (0.284 mmol) of allenone 7f, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
eluent gave compound 11f (60 mg, 80%) as a colorless gum: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.51 (1H, m), 8.01 (1H, d, J = 7.9 Hz),
7.82 (2H, m), 7.64 (1H, s), 7.39 (3H, m), 7.08 (1H, dd, J = 8.5, 1.5
Hz), 6.31 (1H, d, J = 1.8 Hz), 2.35 (2H, s), 2.18 (3H, s); 13C NMR
(75 MHz, CDCl3, 25 °C) δ 155.2, 150.5, 144.4, 141.1, 138.1, 134.3,
134.1, 133.6, 132.0, 127.6, 126.5, 123.1, 122.3, 122.0, 117.2, 114.3,
113.3, 21.5, 11.5; IR (CHCl3, cm−1) ν 3141, 1475, 1429, 1375, 1186,
1128, 601; HRMS (ES) calcd for C19H17N2O3S [M + H]+ 353.0960,
found 353.0954.
Furan 11g. From 80 mg (0.187 mmol) of allenone 7g, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
eluent gave compound 11g (49 mg, 63%) as a colorless gum: 1H NMR
(300 MHz, CDCl3, 25 °C) δ 8.52 (1H, m), 8.13 (1H, d, J = 1.8 Hz),
8.01 (2H, m), 7.81 (1H, m), 7.69 (1H, s), 7.41 (5H, m), 7.18 (2H, m),
6.32 (1H, d; J = 1.8 Hz), 2.31 (2H, s), 2.20 (3H, s); 13C NMR (75
MHz, CDCl3, 25 °C) δ 155.2, 150.6, 144.2, 141.2, 138.5, 138.3, 138.2,
137.4, 136.9, 129.5 (2C), 127.7, 127.3 (2C), 124.6, 123.4, 122.3, 120.5,
117.4, 115.2, 114.6, 114.3, 113.8, 21.1, 11.5; IR (CHCl3, cm−1) ν 3144,
1440, 1375, 1184, 1128, 746; HRMS (ES) calcd for C25H21N2O3S [M
+ H]+ 429.1273, found 429.1267.
Furan 11k. From 80 mg (0.234 mmol) of allenone 7k, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent gave compound 11k (74 mg, 94%) as a colorless solid: mp 86−
87 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 8.48 (1H, m), 8.41 (1H,
d, J = 7.9 Hz), 8.28 (2H, m), 7.88 (1H, td, J = 7.9, 1.8 Hz), 7.84 (1H,
Carbazole 6j. From 80 mg (0.376 mmol) of allene 3j, and after
chromatography of the residue using hexanes/ethyl acetate (6:1) as
eluent gave compound 6j (63 mg, 73%) as a colorless solid: mp 128−
1
129 °C; H NMR (300 MHz, CDCl3, 25 °C) δ 7.79 (1H, d, J = 7.7
Hz), 7.41 (1H, s), 7.07 (3H, m), 5.99 (1H, m), 4.97 (2H, m), 3.46
(2H, m), 2.47 (3H, s), 2.38 (3H, s); 13C NMR (75 MHz, CDCl3, 25
°C) δ 150.8, 137.6, 134.7, 132.6, 129.8, 128.9, 125.9, 120.7, 119.4,
117.7, 115.3, 111.8, 105.0, 102.9, 37.9, 20.3, 16.91; IR (CHCl3, cm−1)
ν 3408, 1489, 1240; HRMS (ES) calcd for C17H18N [M + H]+
236.1439, found 236.1434.
General Procedure for the Au-Catalyzed Oxycyclization of
C3-Allenyl NH-Indoles 8. Preparation of 3-(Furan-2-yl)-indoles
10. [(Ph3P)AuNTf2] (0.005 mmol) was added to a stirred light-
protected solution of the corresponding allenone 8 (0.1 mmol) in 1,2-
dichloroethane (1.3 mL) under argon. The resulting mixture was
stirred at room temperature until disappearance of the starting material
(TLC). After filtration through a pad of Celite, the mixture was
extracted with ethyl acetate (3 × 5 mL), and the combined extracts
were washed twice with brine. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes mixtures gave analytically
pure adducts 10.
Furan 10a. From 60 mg (0.305 mmol) of allenone 8a, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
eluent gave compound 10a (48 mg, 80%) as a colorless solid: mp 91−
92 °C; 1H NMR (300 MHz, CDCl3, 25 °C) δ 8.14 (1H, s), 7.97 (1H,
d, J = 7.7 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J = 7.4 Hz), 7.22
(1H, d, J = 2.5 Hz), 7.14 (2H, m), 6.29 (1H, d, J = 1.6 Hz), 2.12 (3H,
s); 13C NMR (75 MHz, CDCl3, 25 °C) δ 146.6, 140.0, 135.8, 129.4,
125.7, 122.8, 121.5, 121.4, 120.4, 114.0, 111.1, 109.0, 11.3; IR (CHCl3,
cm−1) ν 3401, 2932, 1373, 749; HRMS (ES) calcd for C13H12NO [M
+ H]+ 198.0919, found 198.0913.
K
dx.doi.org/10.1021/jo401013d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
s), 7.41 (2H, m), 7.14 (2H, m), 6.31 (1H, d, J = 1.7 Hz), 2.21 (3H, s);
13C NMR (75 MHz, CDCl3, 25 °C) δ 155.2, 150.3, 147.2, 145.4,
ASSOCIATED CONTENT
* Supporting Information
■
S
144.0, 141.2, 138.1, 131.1, 127.8, 124.2, 122.1, 121.3, 119.4, 117.3,
114.5, 111.6, 11.4; IR (CHCl3, cm−1) ν 2928, 1370, 757; HRMS (ES)
calcd for C17H14N3O3S [M + H]+ 340.0756, found 340.0750.
General Procedure for the Au-Catalyzed Carbocyclization of
C3-Allenyl N-SO2py-Indoles 7 under Microwave Heating.
Preparation of 2,3-Dihydrocyclopenta[b]indolones 12.
[(Ph3P)AuNTf2] (0.005 mmol) was added to a stirred light-protected
solution of the corresponding allenone 7 (0.1 mmol) in 1,2-
dichloroethane (1.3 mL). The resulting mixture was stirred at 145
°C under microwave irradiation until disappearance of the starting
material (TLC). After filtration through a pad of Celite, the mixture
was extracted with ethyl acetate (3 × 5 mL), and the combined
extracts were washed twice with brine. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. Chromatography
of the residue eluting with ethyl acetate/hexanes mixtures gave
analytically pure adducts 11 and 12.
Reaction of Allenone 7e. From 70 mg (0.207 mmol) of allenone
7e, and after chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent, 19 mg (27%) of the less polar compound 11e
and 38 mg (58%) of the more polar compound 12e were obtained.
Cyclopentaindolone 12e. Orange solid: mp 199−200 °C; 1H
NMR (300 MHz, CDCl3, 25 °C) δ 8.47 (1H, m), 8.10 (2H, m), 7.86
(2H, m), 7.43 (1H, ddd, J = 7.6, 4.7, 1.027 Hz), 7.31 (2H, m), 6.51
(1H, d, J = 1.2 Hz), 5.39 (1H, d, J = 1.2 Hz), 3.35 (1H, m) 1.34 (3H,
d, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3, 25 °C) δ 196.7, 158.9,
155.3, 150.7, 143.0, 138.3, 137.8, 128.4, 128.2, 127.0, 125.4, 122.3,
122.1, 121.7, 115.6, 114.3, 52.0, 15.4; IR (CHCl3, cm−1) ν 2923, 1700,
1452, 1192; HRMS (ES) calcd for C18H15N2O3S [M + H]+ 339.0803,
found 339.0798.
Reaction of Allenone 7f. From 100 mg (0.284 mmol) of allenone
7f, and after chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent, 19 mg (27%) of the less polar compound 11f
and 18 mg (23%) of the more polar compound 12f were obtained.
Cyclopentaindolone 12f. Orange gum: 1H NMR (300 MHz,
CDCl3, 25 °C) δ 8.47 (1H, m), 7.99 (2H, m), 7.84 (H, td, J = 7.7, 1.7
Hz), 7.42 (2H, m), 7.12 (1H, m), 6.48 (1H, d, J = 1.2 Hz), 5.37 (1H,
d, J = 1.2 Hz), 3.35 (1H, m), 2.34 (3H, s), 1.32 (3H, d, J = 7.4 Hz);
13C NMR (75 MHz, CDCl3, 25 °C) δ 196.9, 158.1, 150.6, 138.2,
137.8, 134.3, 134.1, 129.4, 129.2, 128.3, 128.1, 122.3, 121.6, 118.0,
115.2, 114.0, 52.0, 21.2, 15.4; IR (CHCl3, cm−1) ν 2931, 1703, 1447,
1188; HRMS (ES) calcd for C19H17N2O3S [M + H]+ 353.0960, found
353.0954.
Reaction of Allenone 7g. From 80 mg (0.187 mmol) of allenone
7g, and after chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent, 14 mg (19%) of the less polar compound 11g
and 34 mg (43%) of the more polar compound 12g were obtained.
Cyclopentaindolone 12g. Orange gum: 1H NMR (300 MHz,
CDCl3, 25 °C) δ 8.50 (1H, m), 8.15 (1H, d, J = 8.9 Hz), 8.04 (2H, m),
7.87 (1H, td, J = 7.9, 1.6 Hz), 7.55 (H, dd, J = 8.8, 1.9 Hz), 7.43 (4H,
m), 7.16 (1H, s), 6.51 (1H, d, J = 0.9 Hz), 5.40 (1H, d, J = 0.9 Hz),
3.37 (1H, m), 2.32 (3H, s), 1.35 (3H, d, J = 7.6 Hz); 13C NMR (75
MHz, CDCl3, 25 °C) δ 197.1, 158.8, 155.7, 151.1, 142.6, 139.1, 138.7,
138.2, 137.8, 137.7, 130.0, 128.8, 128.6 127.6 (2C), 126.6, 123.0,
122.7, 120.0, 116.1, 114.7, 52.4, 21.5, 15.8; IR (CHCl3, cm−1) ν 2931,
1703, 1447, 1188; HRMS (ES) calcd for C25H21N2O3S [M + H]+
429.1273, found 429.1267.
Procedure for the Proton-Catalyzed Carbocyclization of
Allenone 7e. Preparation of 2,3-Dihydrocyclopenta[b]-
indolone 12e. HOTf (0.005 mmol) was added to a stirred light-
protected solution of allenone 7e (34 mg, 0.10 mmol) in 1,2-
dichloroethane (1.3 mL). The resulting mixture was stirred at room
temperature for 2 h. Saturated aqueous sodium hydrogen carbonate (1
mL) was added, and the mixture was extracted with ethyl acetate (3 ×
5 mL). The organic extract was washed twice with brine. The organic
layer was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with hexanes/ethyl acetate
(3:1) gave 29 mg (90%) of analytically pure adduct 12e.
1
Schemes S1−S3, computational details and copies of the H
NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the MINECO [Projects CTQ2012-
33664-C02-01, CTQ2012-33664-C02-02, CTQ2010-20714-
C02-01, and Consolider-Ingenio 2010 (CSD2007-00006)],
and Comunidad Auton
1752 and S2009/PPQ-1634) is gratefully acknowledged. J.M.A.
thanks Comunidad Autonoma de Madrid and Fondo Social
́
oma de Madrid (Projects S2009/PPQ-
́
Europeo for a postdoctoral contract.
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double bond of allenes 2. Next, chemo- and regioselective 5-endo
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neutral species 14. Protonolysis of the carbon−gold bond of 14
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species following a similar reaction mechanism as previously
reported12d (see Supporting Information, Scheme S1).
(19) Scheme S2 (Supporting Information) comprises a mechanistic
rationale for the [(Ph3P)AuNTf2]-catalyzed conversion of NH-indole-
C3-tethered α-hydroxyallenes 3 into carbazoles 5. First, gold
precatalyst formed complex 3-Au through coordination of the cationic
gold to the distal allenic double bond. Next, chemo- and regioselective
attack from the 2-position of the indole occurs through 6-endo
carboauration to form carbocation 15. Loss of HNTf2 generates
neutral species 16, which followed by protonolysis of the carbon−gold
bond and dehydration afforded carbazoles 5 with concomitant
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cyclization leads to a spiro intermediate that undergoes 1,2-migration
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Scheme S3 (Supporting Information). Initial Pd(II)-coordination to
the 1,2-diene moiety gave an allenepalladium complex 3-Pd, which
suffers a chemo- and regioselective 6-endo carbopalladation reaction to
give the zwitterionic species 17. Palladadihydrocarbazole 17 reacted
with allyl bromide via 18 to form intermediate 19, which after a trans
β-heteroatom elimination with concurrent dehydration under the
reaction conditions forms carbazoles 6 with concurrent regeneration of
the palladium(II) catalyst.
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