Intramolecular palladium-catalysed enolate arylation of 2- and 3-iodoindole derivatives for the synthesis of β-carbolines, γ-carbolines, and pyrrolo[3,4-b]indoles

Article abstract of DOI:10.1039/c1ob05087g

The palladium-catalysed intramolecular α-arylation of carbonyl compounds with amino-tethered 2- and 3-iodoindoles provides a useful methodology for the synthesis of indolo-b-fused nitrogen heterocycles. A variety of substituted tetrahydro β- and γ-carboli

Full text of DOI:10.1039/c1ob05087g

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PAPER
Intramolecular palladium-catalysed enolate arylation of 2- and 3-iodoindole
derivatives for the synthesis of b-carbolines, c-carbolines, and
pyrrolo[3,4-b]indoles†
Daniel Sole´,* M.-Llu¨ısa Bennasar and Iva´n Jime´nez
Received 17th January 2011, Accepted 25th March 2011
DOI: 10.1039/c1ob05087g
The palladium-catalysed intramolecular a-arylation of carbonyl compounds with amino-tethered 2-
and 3-iodoindoles provides a useful methodology for the synthesis of indolo-b-fused nitrogen
heterocycles. A variety of substituted tetrahydro b- and g-carbolines, and pyrrolo[3,4-b]indoles, have
been prepared by means of this palladium-catalysed annulation process.
Introduction
Indolo-b-fused nitrogen heterocycles are the structural basic
units of a variety of natural products and synthetic biologically
active compounds. Among b-annelated indoles, those containing
five- and six-membered nitrogen heterocycles are of particular
interest (Fig. 1). For example, the pyrido[3,4-b]indole framework
(b-carboline) is central to a number of pharmaceutical targets1
and is also present in diverse and more structurally complex
natural products,2 including for example the antihypertensive
agents reserpine3 and vincamine.4 The pyrido[4,3-b]indole system
(g-carboline) has also been extensively studied, despite being
present in only a few (very simple) naturally occurring products,5
since g-carbolines are precursors of the biologically active tetra-
and hexahydro derivatives.6 The pyrrolo[3,4-b]indole fragment
also shows a broad spectrum of pharmacological activity.7 More-
over, pyrrolo[3,4-b]indoles are valuable synthetic analogues of
indole-2,3-quinodimethanes, which have been used in cycload-
dition reactions leading to carbazoles, carbolines, and related
systems.8
Given the importance of b-annelated indoles,9 it is not surprising
that many methods exist for their formation and that the devel-
opment of new methodologies for their synthesis is a very active
area of research. In particular, palladium-catalysed annulation
processes have proven extremely useful for the construction of a
wide variety of fused heterocyclic systems.10
Fig. 1 Indolo-b-fused nitrogen heterocycles.
of palladium-catalysed intramolecular coupling of amino-tethered
aryl halides with enolates for the synthesis of heterocycles.12
Continuing our research on both these aspects of synthetic
chemistry, we were interested to see whether the palladium-
catalysed intramolecular a-arylation of carbonyl compounds
could be used for the preparation of diversely substituted indolo-
b-fused nitrogen heterocycles.
As part of our ongoing program on the synthesis of natural
products, we have been working in the development of efficient
methodologies for the preparation of indolo-b-fused medium-
sized nitrogen heterocycles.11 We have also been studying the use
During recent years, the palladium-catalysed arylation of
enolate-type nucleophiles has received a great deal of attention.13
In particular, the intramolecular version of these reactions14–18 has
found an increasing application in the synthesis of complex natural
products.19 Nevertheless, examples of these palladium-catalysed
annulation processes involving haloindole substrates20 are scarce
and only feature the reactions of 4-haloindoles.19f,19k,21
Herein we report the application of the Pd-catalysed intramolec-
ular a-arylation of carbonyl compounds to the construction
of tetrahydro b- and g-carbolines, and pyrrolo[3,4-b]indoles
(Scheme 1).
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, and Institut de
Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII s/n, 08028,
Barcelona, Spain. E-mail: dsole@ub.edu; Fax: +34 93 402 45 39; Tel: +34
93 402 45 40
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for the starting materials. See DOI:
10.1039/c1ob05087g
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On the other hand, reductive amination of 2 with glycine
methyl ester, followed by reaction with benzyl bromide led to a-
aminoester 7 (Scheme 3).
Scheme 1 Synthesis of indolo-b-fused nitrogen heterocycles by Pd(0)-
catalysed enolate arylation.
Scheme 3 Synthesis of 2-iodoindole 7.
Results and discussion
The 3-iodoindoles 11, 12, 13, and 14 were prepared using
similar reductive amination–alkylation sequences starting from
2-formyl-3-iodoindole 9, which in turn was obtained by methy-
lation of the known indole 823(Schemes 4 and 5); and N-
(phenylsulfonyl)indoles 17 and 18 were synthesized following the
same sequences starting from the known 3-iodoindole 15 (Scheme
4).23
Synthesis of the starting materials
To establish the feasibility of our proposal, we focused on the
palladium-catalysed reactions of 2- and 3-iodoindole substrates in
which the length of the chain joining the indole nucleus and the
carbonyl group, the position of the nitrogen in the tether, and the
type of carbonyl compound were variously modified. To this end,
2-iodoindoles 4–7 and 21, and 3-iodoindoles 11–14, 17, 18, and 22
were chosen (Schemes 2–7).
These starting materials were efficiently prepared by standard
methodologies. For the synthesis of ketones 4 and 6, and esters
5 and 7 a fast formylation–reductive amination sequence starting
from the known 2-iodoindole 122 was used. Thus, formylation of 1
under Vilsmeier conditions afforded 3-formylindole 2. Reductive
amination of 2 with methylamine, followed by reaction of the
resulting secondary amine 3 with methyl vinyl ketone, methyl
acrylate or chloroacetone afforded b-aminoketone 4, b-aminoester
5, and a-aminoketone 6, respectively (Scheme 2).
Scheme 4 Synthesis of 3-iodoindoles 11–13 and 17–18.
Scheme 5 Synthesis of 3-iodoindole 14.
Treatment of tryptophol 1924 with p-toluenesulfonylchloride
afforded sulfonic acid ester 20, which on reaction with
Scheme 2 Synthesis of 2-iodoindoles 4–6.
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methylamine, followed by alkylation of the resulting secondary
amine with chloroacetone, led to tryptamine 21 (Scheme 6).
Fig. 2 Ligands used in the a-arylation reactions.
the methyl group at the indole N and the reactive point at C-2 of
the indole. The best results with iodoindole 4 were obtained with
Buchwald’s monodentate ligand L2 (Table 1, entry 6) and with
diphosphine ligands with narrow natural bite angles (dppe and
BINAP, Table 1, entries 3 and 2, respectively).
In contrast, in the cyclization reactions of 3-iodoindoles 11 and
17, the best overall yields were obtained with the ferrocene-based
ligand L1, which has a wide bite angle (Table 1, entries 9 and 14).
The only other ligand that allowed us to obtain both 24 and 25,
although in inferior yields, was BINAP (Table 1, entries 7 and 13).
Interestingly, although the highest yield for the conversion of 17 to
25 was obtained using PPh3 as the ligand (Table 1, entry 12), under
the same reaction conditions 11 failed to undergo annulation and
only afforded degradation compounds (not in the table).
Scheme 6 Synthesis of 2-iodoindole 21.
Finally, amide 22 was synthesized from ester 14 by reaction
with the dimethylaluminium chloride dimethylamine complex25
(Scheme 7).
In marked contrast to the cyclization of 4, the ferrocene-based
phosphine L1 turned out to be the most effective ligand for the a-
arylation of a-aminoketone 21 to provide tetrahydro-b-carboline
26 (Table 1, entry 17). Far worse results were obtained using the
monodentate ligand L2 (Table 1, entry 18), BINAP (Table 1, entry
16), or PPh3 (Table 1, entry 15), while dppe in this instance resulted
in the recovery of the starting material (not in the table).
Scheme 7 Synthesis of amide 22.
a-Arylation reactions
The studies of the a-arylation reactions were initiated with
b-aminoketones 4, 11, and 17, and a-aminoketone 21, from
which the annulation would deliver tetrahydrocarboline deriva-
tives. Several ligands, bases, and solvents were evaluated for the
cyclization reaction, with the most significant results of these
studies summarized in Table 1.
The results of the ligand screening in the annulation reactions
of 4, 11, 17, and 21 show that the phosphine of choice for these
processes is highly substrate-dependent and suggest that there is
no correlation between the bite angle of the diphosphine ligand
and the efficiency of the catalyst. The possibility of monodentate
coordination for the diphosphines due to the ability of the
distal amino group to chelate the palladium atom12c,27,28 could
account for the lack of bite-angle effects in these reactions.29
On the other hand, the somewhat different behaviour between
2-iodoindoles 4 and 21 could be explained in part by the presence
in the latter of the phenylsulfonyl group, which would also
be able to weakly coordinate the initially formed indole–Pd(II)
intermediate,30 modifying both its stability and reactivity.
We extended the studies on the intramolecular a-arylation
reaction of iodoindoles to b-amino esters 5 and 12 to prepare
tetrahydrocarbolines 28 and 27, respectively. Knowing that 3-
iodoindoles behaved better in these cyclization reactions, we
initiated the studies with b-amino ester 12. As expected, the
higher pKa values of the esters made the a-arylation a more
challenging task. In fact, major amounts of the starting material
were recovered when the reaction was performed in the presence
of all the ligands except BINAP. After some experimentation, the
best results for the a-arylation of 12 to give b-carboline 27 were
As we had previously observed in the reactions of (2-
halobenzylamino) ketones,12c Cs2CO3 is, by far, the base of choice
for the a-arylation processes of amino-tethered iodoindoles with
ketones. When using K3PO4 as the base significant amounts of
t
the starting material were usually recovered. Using BuOK12a
or PhOK26 was not acceptable either, because only compounds
arising from the retro-Michael degradation of the b-amino ketone
moiety and hydrodehalogenation were isolated. Optimization of
the solvent revealed that the reaction could be carried out in either
toluene or THF, the latter usually giving inferior results.
From the plethora of ligands that have been used in Pd-catalysed
a-arylation of carbonyl compounds,13 we focused on six different
commercially available phosphines (Fig. 2).
As can be seen in Table 1, among the b-amino ketones, the 2-
iodoindole 4 afforded inferior results overall to the 3-iodoindoles
11 and 17. The behaviour of 4 could be due to a combination
of electronic factors together with the steric interaction between
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Table 1 a-Arylation of aminoketones: synthesis of tetrahydrocarbolinesa
Entry
Aminoketone
Catalyst (equiv.)
Temp./time
Products (yield)b
1
2
3
4
5
6
4
4
4
4
4
4
PdCl2(PPh3)2 (0.2)
110 ◦C/24 hc
110 ◦C/60 h
110 ◦C/72 hc
90 ◦C/24 h
90 ◦C/24 h
110 ◦C/72 h
23 (21%)d
23 (43%)e
23 (45%)
23 (18%)d
23 (17%)d
23 (51%)
Pd2(dba)3 (0.05), BINAP (0.1)
PdCl2(PPh3)2 (0.2), dppe (0.4)
Pd2(dba)3 (0.05), L1 (0.1)
Pd2(dba)3 (0.05), xantphos (0.1)
Pd2(dba)3 (0.05), L2 (0.1)
7
8
9
10
11
11
11
11
11
11
Pd2(dba)3 (0.05), BINAP (0.1)
Pd2(dba)3 (0.05), dppe (0.1)
Pd2(dba)3 (0.05), L1 (0.1)
Pd2(dba)3 (0.05), xantphos (0.1)
Pd2(dba)3 (0.05), L2 (0.1)
110 ◦C/48 h
110 ◦C/24 h
90 ◦C/24 h
90 ◦C/24 h
110 ◦C/24 h
24 (49%)f
24 (40%)g
24 (60%)
24 (41%)
24 (43%)h
12
13
14
17
17
17
Pd(PPh3)4 (0.1)
Pd2(dba)3 (0.05), BINAP (0.1)
Pd2(dba)3 (0.05), L1 (0.1)
110 ◦C/24 h
110 ◦C/48 h
90 ◦C/24 h
25 (65%)
25 (40%)i
25 (59%)
15
16
17
18
21
21
21
21
Pd(PPh3)4 (0.1)
110 ◦C/48 hc
110 ◦C/48 h
90 ◦C/30 h
110 ◦C/48 h
26 (30%)
26 (18%)
26 (70%)
26 (47%)
Pd2(dba)3 (0.1), BINAP (0.2)
Pd2(dba)3 (0.05), L1 (0.1)
Pd2(dba)3 (0.1), L2 (0.2)
a
a-Arylation reactions were run with the iodoindole (0.15–0.20 mmol), the catalyst, and Cs2CO3 (3 equiv.) in toluene in a sealed tube. b Yield refers
to pure isolated products. c THF was used as the solvent. d 4-Acetyl-4-hydroxy-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was also isolated
(5–10%). e When using K3PO4 (3 equiv.) as the base a 9 : 1 mixture of 4 and 23 was obtained. f When using THF as the solvent 24 was obtained in 35%
yield. g When using THF as the solvent a 9 : 1 mixture of 11 and 24 was obtained. h When using THF as the solvent a 1 : 1 mixture of 11 and 24 was
obtained. i Secondary amine 16 was also isolated (20%).
obtained using BINAP and Cs2CO3 as the base in THF at 110 ◦C
(Scheme 8).
together with a catalytic amount of phenol12e,31 in THF at 110 ◦C
(Scheme 9).
However, the application of these reaction conditions to 2-
iodoindole 5 also resulted in the recovery of the starting material.
The a-arylation was finally accomplished, although in a modest
23% yield, by a lengthy treatment of 5 with Pd(PPh3)4 and K3PO4
The reluctance of esters 5 and 12, which were mainly recovered
unchanged, to undergo the a-arylation reaction could be due to
a combination of the high stability of the initially formed Pd(II)
chelates30 together with the lower acidity of the ester, which would
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the only apparent reaction, alcohol 31 being isolated in 48% yield
(Table 2, entry 5). We have previously observed the competition
between a-arylation and the nucleophilic attack on the carbonyl
in the Pd-catalysed reactions of b-(2-haloanilino) ketones.12c,33
Computational studies have shown that the delocalisation of the
LP in the p-system of the aniline increases the nucleophilicity of the
reactive arylic carbon atom, favouring the attack on the carbonyl
group.34 As a similar delocalisation operates in 13, we realized that
by significantly decreasing the nucleophilicity of the indole C-3
position we could favour the a-arylation process instead. In fact,
the nucleophilic addition to the ketone carbonyl was not observed
in any of the Pd-catalysed reactions of N-phenylsulfonylindole
18. Performing the a-arylation of 18 using BINAP as the
ligand afforded the desired pyrrolo[3,4-b]indole 32 in 58% yield
(Table 2, entry 6).35 PPh3 and dppe were less effective for the
present a-arylation–dehydrogenation reaction (Table 2, entries 7
and 8).
Scheme 8 a-Arylation reaction of ester 12.
Scheme 9 a-Arylation reaction of ester 5.
The Pd-catalysed cyclization was extended to a-aminoesters 7
and 14, and carboxamide 22 (Table 3). Knowing the efficiency of
Pd(PPh3)4 for the synthesis of both isoindoles and isoindolines
starting from a-(2-iodobenzylamino) esters,12h we decided to
initially centre our studies on the ligand PPh3. As shown in Table 3,
the a-arylation process starting from a-amino esters allowed either
the pyrrolo[3,4-b]indoles or the corresponding dihydro derivatives
to be selectively obtained by changing the reaction conditions.
Thus, while treatment of 7 with Pd(PPh3)4 and K3PO4 together
with a catalytic amount of phenol in DMF afforded the product
resulting from the a-arylation–dehydrogenation process 33 (Table
3, entry 1), the use of Pd(PPh3)4 in combination with Cs2CO3 as
the base in THF gave the dihydro derivative 34 (Table 3, entry
2). The use of BINAP instead of PPh3 under the latter reaction
conditions afforded a complex mixture in which 34 was again the
main product (not in the table).
Similar results were obtained in the Pd-catalysed cyclization of
3-iodoindole 14, which afforded the pyrrolo[3,4-b]indole 35 when
using the K3PO4/phenol couple in DMF (Table 3, entry 3) and
the dihydro derivative 36 when the reaction was performed in the
presence of Cs2CO3 in THF (Table 3, entry 4). Whereas BINAP
was equally effective as PPh3 for the preparation of 36 (Table 3,
entry 5), the other ligands gave very low yields (not in the table).
The instability and high tendency to undergo aerial oxidation of
pyrrolo[3,4-b]indole derivatives, which hampers their isolation,35
could account for the moderate-to-low yields obtained in the a-
arylation of a-amino carbonyl substrates.
make these intermediates unreactive under the reaction conditions
and would result in the removal of the Pd catalyst from the catalytic
cycle.
On the other hand, it should be noted that the moderate
efficiency of the a-arylation reactions of the b-amino ketone
and b-amino ester substrates is partially a consequence of their
marked tendency to undergo retro-aza-Michael fragmentation,
which result in the formation of diverse degradation compounds
(see for example Table 1, entry 13).
At this point we turned our attention to the a-arylation
reactions of a-amino carbonyl derivatives to provide pyrrolo[3,4-
b]indoles (Table 2).32 We have previously described how isoin-
doles can be directly obtained by sequential palladium-catalysed
arylation–dehydrogenation of a-(2-iodobenzylamino) ketones.12c
We have also reported that isoindoles and isoindolines can be
selectively synthesized by means of palladium-catalysed arylation
of a-amino esters.12h
The use of Pd(PPh3)4 as the catalyst and Cs2CO3 as the base
in THF, a combination that is effective for the preparation of
isoindoles from a-amino ketones,12c was found to be less efficient
for the present a-arylation–dehydrogenation process. For example,
treatment of 6 under these reaction conditions resulted in the
recovery of significant amounts of the starting material together
with minor amounts of 29 (not in the table). A similar result
was obtained when dppe was used as the ligand instead of PPh3
(not in the table). Complete conversion of the starting material
was observed when using BINAP as the ligand, and pyrrolo[3,4-
b]indole 29 was obtained in 35% yield (Table 2, entry 1). The use
of Pd(PPh3)4 in the presence of K3PO4 together with a catalytic
amount of phenol in DMF also resulted in the total consumption
of the starting material, but the isolated yield of 29 was reduced
to 25% (Table 2, entry 2).
Finally, the a-arylation of carboxamide 22 was explored.
In contrast to the reactions of a-aminoesters, treatment of
22 with Pd(PPh3)4 in the presence of K3PO4 and phenol in
DMF afforded the dihydro derivative 37 in 58% yield, with the
product arising from the subsequent aromatization reaction being
undetected (Table 3, entry 7). The same result was obtained,
although in inferior yields, when the reaction was conducted
using K3PO4 as the base in THF in the presence of the ligands
PPh3, BINAP or the monophosphine L2 (Table 3, entries 6, 8
and 9).
Interestingly, the use of both catalysts Pd-BINAP (Table 2,
entry 3) and Pd(PPh3)4 (Table 2, entry 4) for the reaction of
3-iodoindole 13 resulted in the formation of nearly equimolar
mixtures of the pyrrolo[3,4-b]indole 30 and alcohol 31, the latter
resulting from the addition of the arylpalladium intermediate to
the ketone carbonyl. While we were unable to increase the ratio
of the arylation product, we observed that when using dppe as
the ligand the nucleophilic addition to the carbonyl group was
Conclusions
The present paper reports our studies on the implementation of
the palladium-catalysed intramolecular arylation of enolate-type
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Table 2 a-Arylation of a-aminoketones: synthesis of pyrrolo[3,4-b]indoles
Base (equiv.);
Catalyst (equiv.) additive (equiv.)
Entry a-Aminoketone
Solvent
T/time
Products (yield)a
1
2
6
6
Pd2(dba)3 (0.05); Cs2CO3 (3)
BINAP (0.1)
Tolueneb 110 ◦C/72 h 29 (35%)
90 ◦C/23 h
Pd(PPh3)4 (0.1)
K3PO4 (3); phenol DMF
(0.3)
29 (25%)
3
4
5
13
13
13
Pd2(dba)3 (0.05); Cs2CO3 (3)
BINAP (0.1)
Tolueneb 110 ◦C/72 h 30 (31%)
31 (35%)
31 (30%)
31 (48%)
Pd(PPh3)4 (0.1)
K3PO4 (3); phenol DMF
(0.3)
90 ◦C/24 h
30 (24%)
Pd(OAc)2 (0.2);
dppe (0.25)
Cs2CO3 (3)
Tolueneb 110 ◦C/72 h
6
7
8
18
18
18
Pd2(dba)3 (0.05); Cs2CO3 (3)
BINAP (0.1)
Tolueneb 110 ◦C/72 h 32 (58%)
90 ◦C/24 h
Tolueneb 110 ◦C/72 h 32 (15%)
Pd(PPh3)4 (0.1)
K3PO4 (3); phenol DMF
(0.3)
32 (30%)
Pd(OAc)2 (0.2);
dppe (0.25)
Cs2CO3 (3)
a Yield refers to pure isolated products. b Reactions were run in a sealed tube.
nucleophiles in the synthesis of indolo-b-fused nitrogen heterocy-
cles. The use of enolates derived from ketones, esters, and amides
has been explored for the preparation of annelated 5- and 6-
membered azaheterocycles. By means of this methodology, di-
versely substituted pyrido[3,4-b]indoles (b-carbolines), pyrido[4,3-
b]indoles (g-carbolines), and pyrrolo[3,4-b]indoles were prepared.
The results obtained in the annulation reactions show that the
phosphine of choice for these processes is highly substrate-
dependent. A lack of bite-angle effects, probably due to the
coordination ability of the tether amino group, was also revealed.
On the whole, BINAP proved to be the most versatile ligand,
although it did not always give the highest yield. Thus, the use
of BINAP produced acceptable results (40–58% yield) in the a-
arylation reactions of all substrates except 2-iodoindole 5, which
was recovered unchanged, and 2-iodoindoles 7 and 21, which in the
presence of this ligand performed the annulation in very low yields.
It should be noted that the obligatory use of weak bases (Cs2CO3
and K3PO4) in the above a-arylation reactions, which results in a
low concentration of the enolate in the reaction mixture, could
be another important factor in understanding the low efficiency
of some of the reactions. In this context, among the carbonyl
moieties, annulation reactions of b-amino ester substrates proved
especially troublesome probably due to their higher pKa values.
The reactions of a-amino carbonyl compounds gave different
results depending on the nature of the carbonyl group. Thus, start-
ing from a-amino ketones, pyrrolo[3,4-b]indoles were obtained
by means of an a-arylation–dehydrogenation process, while the
a-arylation of amide 22 exclusively afforded the corresponding
dihydro derivative. In contrast, the annulation processes of a-
amino esters allowed either the fully aromatic compounds or their
dihydro derivatives to be selectively obtained depending on the
reaction conditions. Further experimentation will be performed
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Table 3 a-Arylation of a-aminoesters 7 and 14, and amide 22: synthesis of pyrrolo[3,4-b]indoles
Base (equiv.)
Entry Starting material
Catalyst (equiv.) additive (equiv.) Solvent Temp./time Products (yield)a
1
2
7
7
Pd(PPh3)4 (0.1) K3PO4 (3);
phenol (0.3)
Pd(PPh3)4 (0.1) Cs2CO3 (3)
DMF
THFb
90 ◦C/24 h 33 (50%)
110 ◦C/72 h
34 (31%)c
3
14
Pd(PPh3)4 (0.1) K3PO4 (3);
phenol (0.3)
Pd(PPh3)4 (0.1) Cs2CO3 (3)
Pd2(dba)3 (0.1); Cs2CO3 (3)
BINAP (0.2)
DMF
90 ◦C/24 h 35 (60%)
4
5
14
14
THFb
THFb
110 ◦C/72 h
110 ◦C/48 h
36 (56%)
36 (50%)
6
7
22
22
Pd(PPh3)4 (0.1) K3PO4 (3)
Pd(PPh3)4 (0.1) K3PO4 (3);
phenol (0.3)
Pd2(dba)3 (0.1); K3PO4 (3)
BINAP (0.2)
Pd2(dba)3 (0.1); K3PO4 (3)
L2 (0.2)
THFb
DMF
110 ◦C/48 h
90 ◦C/24 h
37 (54%)
37 (58%)
8
9
22
22
THFb
THFb
110 ◦C/42 h
110 ◦C/48 h
37 (50%)
37 (40%)
a Yield refers to pure isolated products. b Reactions were run in a sealed tube. c 1H NMR analysis of the crude reaction mixture gave 34 as the main product
together with trace amounts of 33. However, after column chromatography 33 was isolated in 15% yield.
in order to expand the present methodology to the synthesis of
other indolo-fused nitrogen heterocycles.
400 instrument. Chemical shifts are reported in ppm downfield
(d) from Me4Si. IR spectra were recorded on a Nicolet Avatar-
320 Fourier transform IR spectrometer and data are reported in
reciprocal centimetres (cm-1).
Experimental
General
General methods for the Pd-catalysed reactions
All commercially available reagents were used without further
purification. Solvents were dried prior to use according to
standard methods. Drying of organic extracts during workup of
reactions was performed over anhydrous MgSO4. Evaporation of
solvents was accomplished with a rotatory evaporator. Thin-layer
chromatography was carried out using commercial aluminium-
backed silica gel plates and the spots were located with UV light
(254 nm), iodoplatinate reagent or 1% aqueous KMnO4. Flash
chromatography was carried out on SiO2 (silica gel 60, 230–
Representative procedure for the Pd-catalysed reactions in a
sealed tube (Table 1, entry 6). A mixture of ketone 4 (75 mg, 0.20
mmol), Cs2CO3 (195 mg, 0.60 mmol), Pd2(dba)3 (9 mg, 0.01 mmol),
and L2 (8 mg, 0.02 mmol) in toluene (8 mL) was stirred at 110 ◦C in
a sealed tube for 72 h. The reaction mixture was poured into water
and extracted with Et2O. The organic extracts were washed with
brine, dried, and concentrated. The residue was purified by flash
chromatography (from CH2Cl2 to CH2Cl2–MeOH 1%) to give 23
as a yellow oil (25 mg, 51%).
1
400 mesh ASTM). Unless otherwise noted, H- and 13C NMR
spectra were recorded in CDCl3 solution, using Me4Si as the
internal standard, with a Varian Gemini 300 or a Varian Mercury
Representative procedure for the Pd-catalysed reactions in DMF
(Table 3, entry 3). A mixture of ester 14 (75 mg, 0.17 mmol),
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K3PO4 (108 mg, 0.51 mmol), phenol (5 mg, 0.051 mmol), and
Pd(PPh3)4 (20 mg, 0.017 mmol) in DMF (3 mL) was stirred at
90 C for 24 h. The reaction mixture was poured into water and
138.6 (C), 204.2 (C). IR (NaCl) n 2937, 2798, 1720, 1642, 1450,
1365, 1232, 1170, 1148, 1088, 752 cm-1. ESI-HRMS [M+H]+ calcd
for C20H21N2O3S 369.1267, found 369.1270.
◦
extracted with Et2O. The organic extracts were washed with 1 N
NaOH solution and brine, dried, and concentrated. The residue
was purified by chromatography (from hexanes to 9 : 1 hexanes-
EtOAc) to give 35 as an orange oil (32 mg, 60%).
Methyl 2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-
4-carboxylate (27). Purification by flash chromatography (from
CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
(CDCl3, 300 MHz) d 2.57 (s, 3H), 2.82 (dd, J = 11.7 and 4.8
Hz, 1H), 3.24 (dd, J = 11.7 and 5.1 Hz, 1H), 3.48 (d, J = 14.7
Hz, 1H), 3.61 (s, 3H), 3.73 (s, 3H), 3.83 (d, J = 14.7 Hz, 1H), 3.96
(dd, J = 5.1 and 4.8 Hz, 1H), 7.09 (ddd, J = 8.1, 7.2, and 1.2 Hz,
1H), 7.18 (ddd, J = 8.1, 7.2, and 1.2 Hz, 1H), 7.27 (d, J = 8.1 Hz,
1H), 7.52 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 125.5 MHz) d
29.2 (CH3), 39.4 (CH), 45.7 (CH3), 51.4 (CH2), 52.0 (CH3), 55.1
(CH2), 104.3 (C), 108.8 (CH), 118.8 (CH), 119.3 (CH), 121.0 (CH),
126.4 (C), 134.5 (C), 137.2 (C), 173.9 (C). IR (NaCl) n 2949, 2788,
1732, 1652, 1613, 1470, 1437, 1380, 1325, 1248, 1194, 1059, 749
cm-1. ESI-HRMS [M+H]+ calcd for C15H19N2O2 259.1441, found
259.1443.
4-Acetyl-2,5-dimethyl-2,3,4,5-tetrahydro-1H -pyrido[4,3-b]-
indole (23). 1H NMR (CDCl3, 400 MHz) d 2.17 (s, 3H), 2.51 (s,
3H), 2.82 (dd, J = 11.6 and 4.8 Hz, 1H), 3.14 (dd, J = 11.6 and 2.8
Hz, 1H), 3.40 (d, J = 13.6 Hz, 1H), 3.57 (s, 3H), 3.70 (broad s, 1H),
4.02 (d, J = 13.6 Hz, 1H), 7.11 (dd, J = 8 and 7.2 Hz, 1H), 7.22
(dd, J = 8 and 7.2 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.47 (d, J = 8
Hz, 1H). 13C NMR (CDCl3, 100.5 MHz) d 28.8 (CH3), 29.5 (CH3),
45.7 (CH3), 48.8 (CH), 51.6 (CH2), 56.1 (CH2), 109.1 (CH), 109.8
(C), 118.1 (CH), 119.2 (CH), 121.6 (CH), 125.1 (C), 131.2 (C),
137.4 (C), 209.9 (C). IR (NaCl) n 2938, 2788, 1708, 1666, 1612,
1469, 1361, 1319, 1247, 1133, 742 cm-1. Anal. Calcd for C15H18N2O
(242.32).1/2H2O: C, 71.69; H, 7.62; N, 11.15. Found: C, 71.58; H,
7.56; N, 10.85.
Methyl 2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-
4-carboxylate (28). Purification by flash chromatography (from
CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
(CDCl3, 300 MHz) d 2.54 (s, 3H), 2.79 (dd, J = 11.7 and 4.2
Hz, 1H), 3.41 (dd, J = 11.7 and 3.9 Hz, 1H), 3.41 (d, J = 13.8 Hz,
1H), 3.63 (s, 3H), 3.74 (s, 3H), 3.82 (broad s, 1H), 3.98 (d, J = 13.8
Hz, 1H), 7.08 (ddd, J = 8.1, 7.2, and 1.2 Hz, 1H), 7.20 (ddd, J =
8.1, 7.2, and 1.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1
Hz, 1H). 13C NMR (CDCl3, 75.5 MHz) d 29.7 (CH3), 40.3 (CH),
45.7 (CH3), 51.8 (CH2), 52.5 (CH3), 55.9 (CH2), 108.9 (CH), 109.6
(C), 118.1 (CH), 118.9 (CH), 121.4 (CH), 124.8 (C), 130.0 (C),
137.4 (C), 172.3 (C). IR (NaCl) n 2944, 2789, 1732, 1616, 1471,
1388, 1318, 1250, 1136, 1052, 993, 741 cm-1. ESI-HRMS [M+H]+
calcd for C15H19N2O2 259.1441, found 259.1442.
4-Acetyl-2,9-dimethyl-2,3,4,9-tetrahydro-1H -pyrido[3,4-b]-
indole (24). Purification by flash chromatography (from CH2Cl2
1
to 1% CH2Cl2–MeOH) gave a yellow oil. H NMR (CDCl3, 400
MHz) d 2.15 (s, 3H), 2.54 (s, 3H), 2.75 (dd, J = 11.6 and 4.8 Hz,
1H), 3.13 (dd, J = 11.6 and 4.4 Hz, 1H), 3.45 (dd, J = 14.4 and
1.2 Hz, 1H), 3.64 (s, 3H), 3.78 (dd, J = 4.8 and 4.4 Hz, 1H), 3.89
(d, J = 14.4 Hz, 1H), 7.11 (ddd, J = 8, 7.2, and 0.8 Hz, 1H), 7.21
(ddd, J = 8, 7.2, and 1.2 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.41 (d,
J = 8 Hz, 1H). 13C NMR (CDCl3, 100.5 MHz) d 28.5 (CH3), 29.3
(CH3), 45.7 (CH3), 47.7 (CH), 51.4 (CH2), 55.3 (CH2), 105.3 (C),
108.9 (CH), 118.2 (CH), 119.5 (CH), 121.2 (CH), 126.3 (C), 134.8
(C), 137.2 (C), 211.4 (C). IR (NaCl) n 2940, 2786, 1702, 1651,
1612, 1470, 1355, 1324, 1242, 1188, 1138, 747 cm-1. ESI-HRMS
[M+H]+ calcd for C15H19N2O 243.1492, found 243.1499.
3-Acetyl-2,4-dimethyl-2,4-dihydropyrrolo[3,4-b]indole
(29).
Purification by flash chromatography (from CH2Cl2 to 1%
CH2Cl2–MeOH) gave an orange oil. 1H NMR (CDCl3, 400 MHz)
d 2.65 (s, 3H), 4.01 (s, 3H), 4.07 (s, 3H), 7.08 (s, 1H), 7.12 (ddd, J
= 8.5, 7.5, and 1 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.32 (td, J = 7.5
and 1 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H). 13C NMR (CDCl3, 125.5
MHz) d 30.5 (CH3), 34.1 (CH3), 39.8 (CH3), 109.4 (CH), 114.9
(C), 119.4 (CH), 119.6 (C), 119.8 (CH), 120.1 (CH), 123.9 (CH),
128.4 (C), 128.9 (C), 146.4 (C), 184.7 (C). ESI-HRMS [M+H]+
calcd for C14H15N2O 227.1179, found 227.1179.
4-Acetyl-2-methyl-9-phenylsulfonyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole (25). Purification by flash chromatography
(from CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
(CDCl3, 300 MHz) d 2.05 (s, 3H), 2.52 (s, 3H), 2.72 (dd, J = 11.7
and 4.8 Hz, 1H), 3.08 (dd, J = 11.7 and 3.9 Hz, 1H), 3.66 (dd, J =
4.8 and 3.9 Hz, 1H), 3.67 (d, J = 16.5 Hz, 1H), 4.26 (d, J = 16.5 Hz,
1H), 7.21–7.35 (m, 3H), 7.43 (m, 2H), 7.54 (m, 1H), 7.79 (m, 2H),
8.13 (d, J = 8 Hz, 1H). 13C NMR (CDCl3, 75.5 MHz) d 28.4 (CH3),
45.4 (CH3), 47.5 (CH), 53.2 (CH2), 54.5 (CH2), 114.4 (CH), 115.2
(C), 118.6 (CH), 123.9 (CH), 124.6 (CH), 126.3 (2 CH), 129.0 (C),
129.3 (2 CH), 133.9 (CH), 134.5 (C), 136.3 (C), 138.4 (C), 209.3
(C). IR (NaCl) n 2944, 2796, 1707, 1606, 1451, 1380, 1226, 1174,
1119, 1089, 752 cm-1. ESI-HRMS [M+H]+ calcd for C20H21N2O3S
369.1267, found 369.1265.
1-Acetyl-2,4-dimethyl-2,4-dihydropyrrolo[3,4-b]indole
(30).
Purification by flash chromatography (Et2O and 1% Et2O-
1
diethylamine) gave an orange oil (first product on elution). H
NMR (CDCl3, 300 MHz) d 2.87 (s, 3H), 3.69 (s, 3H), 4.16 (3H),
6.71 (s, 1H), 7.15 (ddd, J = 8.1, 7.2, and 1.2 Hz, 1H), 7.27 (d, J =
7.2 Hz, 1H), 7.40 (td, J = 7.2 and 1.2 Hz, 1H), 8.11 (d, J = 8.1
Hz, 1H). 13C NMR spectrum could not be obtained because 30
decomposed during the experiment.
1-Acetyl-2-methyl-9-phenylsulfonyl-2,3,4,9-tetrahydro-1H-py-
rido[3,4-b]indole (26). Purification by flash chromatography
(from CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
(CDCl3, 300 MHz) d 2.45 (s, 3H), 2.50 (m, 1H), 2.57 (s, 3H), 2.80–
3.12 (m, 3H), 4.86 (s, 1H), 7.19–7.25 (m, 3H), 7.38–7.44 (m, 3H),
7.51 (m, 1H), 7.77–8.83 (m, 2H). 13C NMR (CDCl3, 75.5 MHz) d
16.6 (CH2), 28.0 (CH3), 42.4 (CH3), 44.9 (CH2), 67.9 (CH), 113.9
(CH), 118.2 (C), 118.7 (CH), 123.3 (CH), 124.6 (CH), 126.9 (2
CH), 129.1 (2 CH), 129.5 (C), 130.6 (C), 133.6 (CH), 135.8 (C),
2,4,9-Trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-4-ol
(31). Purification by flash chromatography (Et2O and 1% Et2O-
1
diethylamine) gave a yellow oil (second product on elution). H
NMR (CDCl3, 300 MHz) d 1.73 (s, 3H), 2.47 (d, J = 11.4 Hz, 1H),
2.54 (s, 3H), 2.85 (d, J = 11.4 Hz, 1H), 3.20 (d, J = 14.4 Hz, 1H),
3.48 (s, 3H), 3.69 (d, J = 14.4 Hz, 1H), 7.11 (ddd, J = 7.8, 6.9, and
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1.2 Hz, 1H), 7.19 (ddd, J = 8.1, 6.9, and 1.2 Hz, 1H), 7.27 (d, J = 8.1
Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H). 13C NMR (CDCl3, 75.5 MHz) d
25.2 (CH3), 29.1 (CH3), 45.9 (CH3), 51.8 (CH2), 68.2 (CH2), 77.2
(C), 108.8 (CH), 113.3 (C), 119.4 (CH), 119.8 (CH), 121.0 (CH),
124.8 (C), 134.6 (C), 137.2 (C). IR (NaCl) n 3342, 2939, 2793,
1470, 1377, 1323, 1101, 742 cm-1. ESI-HRMS [M+H]+ calcd for
C14H19N2O 231.1492, found 231.1492.
(CDCl3, 400 MHz) d 3.62 (s, 3H), 3.76 (3H), 3.89 (dd, J = 12.8
and 3.2 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 4.28 (d, J = 13.6 Hz,
1H), 4.29 (dd, J = 12.8 and 4 Hz, 1H), 4.92 (dd, J = 4 and 3.2
Hz, 1H), 7.10 (m, 1H), 7.17 (m, 1H), 7.24–7.38 (m, 4H), 7.46 (m,
2H), 7.52 (d, J = 8 Hz, 1H). 13C NMR (CDCl3, 125.5 MHz) d 31.2
(CH3), 51.2 (CH2), 51.9 (CH3), 58.7 (CH2), 66.3 (CH), 109.6 (CH),
112.3 (C), 118.7 (CH), 119.8 (CH), 120.8 (CH), 122.8 (C), 127.3
(CH), 128.4 (2 CH), 128.9 (2 CH), 138.8 (C), 141.0 (C), 142.9 (C),
172.9 (C). IR (NaCl) n 2946, 2800, 1748, 1694, 1593, 1494, 1457,
1370, 1320, 1265, 1197, 1169, 1131, 1073, 741 cm-1. ESI-HRMS
[M+H]+ calcd for C20H21N2O2 321.1598, found 321.1594.
1-Acetyl-2-methyl-4-phenylsulfonyl-2,4-dihydropyrrolo[3,4-b]
indole (32). Purification by flash chromatography (CH2Cl2) gave
1
an orange oil. H NMR (CDCl3, 400 MHz) d 2.73 (s, 3H), 4.11
(3H), 7.23 (s, 1H), 7.26–7.42 (m, 4H), 7.47 (m, 1H), 7.78 (m, 2H),
7.95 (d, J = 8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3,
125.5 MHz) d 31.0 (CH3), 39.5 (CH3), 113.4 (CH), 115.0 (CH),
120.9 (C), 121.5 (C), 122.6 (CH), 123.7 (C), 124.0 (CH), 126.3
(CH), 126.6 (2 CH), 129.0 (2 CH), 129.8 (C), 133.8 (CH), 136.9
(C), 142.4 (C), 187.6 (C). IR (NaCl) n 2956, 1648, 1494, 1466,
1369, 1294, 1219, 1176, 1150, 1090, 954, 756 cm-1. ESI-HRMS
[M+H]+ calcd for C19H17N2O3S 353.0954, found 353.0955.
2 - Benzyl - N,N,4 - trimethyl - 1,2,3,4 - tetrahydropyrrolo[3,4 - b]-
indole-1-carboxamide (37). Purification by flash chromatography
(from CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
(CDCl3, 400 MHz) d 2.93 (s, 3H), 2.99 (s, 3H), 3.64 (s, 3H), 3.94
(dd, J = 12.4 and 2.4 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 4.24 (d,
J = 13.2 Hz, 1H), 4.32 (dd, J = 12.4 and 4 Hz, 1H), 5.12 (dd, J =
4 and 2.4 Hz, 1H), 7.07 (m, 1H), 7.15 (m, 1H), 7.24–7.43 (m, 7H).
13C NMR (CDCl3, 125.5 MHz) d 31.2 (CH3), 36.5 (CH3), 36.8
(CH3), 51.4 (CH2), 58.2 (CH2), 66.8 (CH), 109.7 (CH), 113.9 (C),
118.2 (CH), 119.6 (CH), 120.6 (CH), 122.4 (C), 127.2 (CH), 128.4
(2 CH), 128.8 (2 CH), 139.1 (C), 140.9 (C), 143.2 (C), 171.8 (C).
IR (NaCl) n 2930, 1692, 1637, 1494, 1459, 1381, 1263, 1141, 746
cm-1. ESI-HRMS [M+H]+ calcd for C21H24N3O 334.1914, found
334.1927.
Methyl
2-benzyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indole-3-
carboxylate (33). Purification by flash chromatography (from
hexanes to 5% hexanes-EtOAc) gave an orange oil. 1H NMR
(CDCl3, 400 MHz) d 3.81 (s, 3H), 3.99 (s, 3H), 5.69 (s, 2H),
7.07–7.14 (m, 3H), 7.20–7.35 (m, 6H), 7.70 (d, J = 8 Hz, 1H). 13
C
NMR (CDCl3, 125.5 MHz) d 32.1 (CH3), 50.5 (CH3), 54.0 (CH2),
100.9 (C), 109.0 (CH), 115.3 (C), 118.6 (CH), 119.0 (CH), 119.4
(C), 119.9 (CH), 124.0 (CH), 126.5 (2 CH), 127.3 (CH), 128.6 (2
CH), 138.7 (C), 141.6 (C), 146.3 (C), 161.1 (C). IR (NaCl) n 2946,
1684, 1588, 1448, 1315, 1229, 1198, 1093, 741 cm-1. ESI-HRMS
[M+H]+ calcd for C20H19N2O2 319.1441, found 319.1430.
Acknowledgements
We thank the “Ministerio de Educacio´n y Ciencia”, Spain, for
financial support (project CTQ2009-07175).
Methyl 2-benzyl-4-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]in-
dole3-carboxylate (34). Purification by flash chromatography
(CH2Cl2) gave a yellow oil. H NMR (CDCl3, 300 MHz) d 3.68
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(s, 3H), 3.71 (3H), 3.97 (dd, J = 11.4 and 2.4 Hz, 1H), 4.11 (d, J
= 13.2 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H), 4.35 (dd, J = 11.4 and
3.9 Hz, 1H), 4.85 (dd, J = 3.9 and 2.4 Hz, 1H), 7.08 (m, 1H), 7.19
(m, 1H), 7.25–7.45 (m, 7H). 13C NMR (CDCl3, 75.5 MHz) d 30.9
(CH3), 52.2 (CH3), 52.9 (CH2), 58.4 (CH2), 65.1 (CH), 109.7 (CH),
116.4 (C), 119.1 (CH), 119.6 (CH), 121.2 (CH), 122.5 (C), 127.2
(CH), 128.4 (2 CH), 128.8 (2 CH), 138.7 (C), 139.0 (C), 141.4 (C),
171.9 (C). IR (NaCl) n 2948, 2805, 1736, 1685, 1588, 1466, 1315,
1259, 1197, 1130, 1094, 740 cm-1. ESI-HRMS [M+H]+ calcd for
C20H21N2O2 321.1598, found 321.1599.
Methyl 2-benzyl-4-methyl-2,4-dihydropyrrolo[3,4-b]indole-1-
carboxylate (35). 1H NMR (CDCl3, 400 MHz) d 3.66 (s, 3H),
4.01 (s, 3H), 5.82 (s, 2H), 6.75 (s, 1H), 7.12–7.17 (m, 3H), 7.20–
7.33 (m, 4H), 7.39 (m, 1H), 8.22 (d, J = 8 Hz, 1H). 13C NMR
(CDCl3, 125.5 MHz) d 31.0 (CH3), 51.0 (CH3), 52.8 (CH2), 105.0
(CH), 108.2 (CH), 109.6 (C), 118.2 (CH), 119.8 (C), 120.9 (C),
123.1 (CH), 125.2 (CH), 126.7 (2 CH), 127.4 (CH), 128.6 (2 CH),
135.8 (C), 138.7 (C), 146.4 (C), 161.7 (C). IR (NaCl) n 2946,
1693, 1625, 1594, 1516, 1495, 1474, 1449, 1380, 1337, 1297, 1194,
1146, 1096, 745 cm-1. ESI-HRMS [M+H]+ calcd for C20H19N2O2
319.1441, found 319.1436.
9 (a) R. J. Sundberg, Indoles, Academic Press: London, 1996; (b) J. A.
Joule, in Science of Synthesis, George Thieme Verlag: Stuttgart, 2000,
vol. 10; (c) H. Kazuhiro and T. Kawassaki, Nat. Prod. Rep., 2007, 24,
843, and previous reviews in this series.
Methyl 2 - benzyl - 4 - methyl - 1,2,3,4 - tetrahydropyrrolo[3,4 - b]-
indole-1-carboxylate (36). Purification by flash chromatography
(from CH2Cl2 to 1% CH2Cl2–MeOH) gave a yellow oil. 1H NMR
10 (a) For general reviews on the palladium-catalysed formation of
heterocyclic compounds, see: J. J. Li and G. W. Gribble, Palladium in
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Amsterdam, 2000; (b) Handbook of Organopalladium Chemistry for
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4544 | Org. Biomol. Chem., 2011, 9, 4535–4544
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