Pd-Catalyzed α-Arylation of Sulfones in a Three-Component Synthesis of 3-[2-(Phenyl/methylsulfonyl)ethyl]indoles

Article abstract of DOI:10.1021/acscatal.6b00027

A novel four-step domino process for the synthesis of 3-[2-(aryl/alkylsulfonyl)ethyl]indoles starting from readily available 2-iodoanilines is reported. The domino reaction is based on the intramolecular palladium-catalyzed α-arylation of sulfones, which was combined with both intermolecular aza-Michael and Michael addition reactions using vinyl sulfones as the electrophile. The domino process produced good yields and tolerated the presence of substituents with different electronic properties on the aniline ring. In addition, density functional theory (DFT) calculations were carried out to gain more insight into the formation of the observed indole derivatives.

Full text of DOI:10.1021/acscatal.6b00027

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Article
Pd-Catalyzed #-Arylation of Sulfones in a Three-Component
Synthesis of 3-[2-(phenyl/methylsulfonyl)ethyl]indoles
Daniel Sole, Ferran Pérez-Janer, Ester Zulaica, Javier F. Guastavino, and Israel Fernandez
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00027 • Publication Date (Web): 01 Feb 2016
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PdꢀCatalyzed αꢀArylation of Sulfones in a Threeꢀ
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Component Synthesis of 3ꢀ[2ꢀ
(phenyl/methylsulfonyl)ethyl]indoles
,†
†
†
†,§
,‡
Daniel Solé,* Ferran Pérez-Janer, Ester Zulaica, Javier F. Guastavino, Israel Fernández*
†
Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan
XXIII s/n, 08028 Barcelona, Spain
‡
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Centro de Innovación en
Química Avanzada (ORFEOꢀCINQA), Universidad Complutense de Madrid, Ciudad
Universitaria, 28040 Madrid, Spain
ABSTRACT.
A
novel fourꢀstep domino process for the synthesis of 3ꢀ[2ꢀ
(aryl/alkylsulfonyl)ethyl]indoles starting from readily available 2ꢀiodoanilines is reported. The
domino reaction is based on the intramolecular palladiumꢀcatalyzed αꢀarylation of sulfones,
which was combined with both intermolecular azaꢀMichael and Michael addition reactions using
vinyl sulfones as the electrophile. The domino process produced good yields and tolerated the
presence of substituents with different electronic properties on the aniline ring. In addition,
Density Functional Theory (DFT) calculations were carried out to gain more insight into the
formation of the observed indole derivatives.
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KEYWORDS: Palladiumꢀcatalyzed, Arylation, Domino reactions, Indoles, Density functional
calculations.
1. INTRODUCTION
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Indole is a commonly found heterocycle in biologically active natural products and unnatural
1
pharmaceuticals. For this reason, it is not surprising that since Fischer’s pioneering indole
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synthesis in 1883, numerous methodologies have been reported for the construction and
3
functionalization of the indole skeleton. Besides the vast array of more traditional reactions,
recent advances in the area of transition metalꢀcatalyzed transformations have led to the
development of several new reliable methods for the synthesis of indoles from simple starting
4
materials. Among the variety of crossꢀcoupling reactions, the palladiumꢀcatalyzed arylation of
5
acidic C─H bonds is of particular interest for the synthesis of this heteroaromatic compound
6
,7
from nonꢀaromatic precursors.
In the context of our research on palladiumꢀbased methodologies for the synthesis of nitrogen
8
heterocycles, we have reported the palladiumꢀcatalyzed intramolecular αꢀarylation of βꢀ(2ꢀ
9
10
iodoanilino) esters and amides to give indoleꢀ3ꢀcarboxylic acid derivatives. In parallel with
these studies, and in order to create more complex and diverse scaffolds from readily accessible
starting materials, we have also explored the integration of the palladiumꢀcatalyzed αꢀarylation
1
1
reaction into oneꢀpot sequences. This research allowed us to recently achieve an efficient
synthesis of highly functionalized tetrahydroisoquinolines by a domino azaꢀMichael/αꢀ
arylation/Michael addition process based on the use of sulfones either as electrophiles or
1
2
nucleophiles. Continuing these studies, we decided to explore the synthesis of indole
derivatives by means of a multistep sequence involving the use of sulfones (Scheme 1). When
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starting from 2ꢀhaloaniline A, the aforementioned threeꢀstep domino process could be expected
to generate a 3ꢀ(sulfonyl)indoline intermediate (i. e. D), a type of compound known to undergo
1
3,14
βꢀelimination of sulfinic acid to afford indoles.
We postulated that this additional step would
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allow us to prepare 3ꢀ[2ꢀ(aryl/alkylsulfonyl)ethyl]indoles in a new fourꢀstep domino process
from readily available 2ꢀhaloanilines.
Scheme 1. Generic plan for the domino azaꢀMichael/αꢀarylation/Michael addition/βꢀelimination
process leading to 3ꢀ[2ꢀ(aryl/alkylsulfonyl)ethyl]indoles
Among the various substitution patterns of the indole nucleus, compounds bearing the (3ꢀ
indolyl)ethyl moiety are particularly challenging synthetic targets due to the diversity of
15,16
biologically active tryptamine analogues.
Thus, a general approach to this type of compound
using the proposed domino azaꢀMichael/αꢀarylation/Michael addition/βꢀelimination strategy
would complement existing methodologies and in some instances provide a more attractive
17
option.
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A successful domino process should occur under conditions that allow the desired sequence of
events to take precedence over any undesired competitive reactions. Thus, in our strategy, the
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starting iodoaniline A would have to be consumed rapidly by the azaꢀMichael addition to avoid
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an intramolecular Heck process proceeding as the first step. Similarly, the competitive Heck
reaction should not interfere with the palladiumꢀcatalyzed αꢀarylation reaction of intermediate B.
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Finally, the 3ꢀ(sulfonyl)indoline intermediate C should be immediately trapped to prevent a
premature βꢀelimination leading to the nonꢀsubstituted indole.
The work described herein explores the viability of the proposed palladiumꢀcatalyzed αꢀarylation
of sulfones in a fourꢀstep domino process to obtain 3ꢀ[2ꢀ(phenyl/methylsulfonyl)ethyl]indoles
from readily available starting materials. To this end, a detailed joint experimental and
computational study was carried out to provide insight into the formation of the target indole
through this multicomponent domino reaction.
2. RESULTS AND DISCUSSION
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During the optimization of the domino process leading to tetrahydroisoquinolines, we realized
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that the most challenging step of the sequence was the sulfone αꢀarylation reaction. So, before
embarking on the development of a domino process to access 3ꢀsubstituted indoles, we first
examined the palladiumꢀcatalyzed αꢀarylation of βꢀ(2ꢀiodoanilino) sulfones. Sulfones 1a-c were
chosen for this purpose (Table 1).
Treatment of 1a with the Pd (dba) /xantphos couple as the precatalyst and K PO as the base in
2
3
3
4
DMF, an effective combination for the domino sequence starting from closely related 2ꢀ
1
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iodobenzylamines, resulted in the decomposition of the starting material (entry 1, Table 1).
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When using the same combination of palladium source and ligand, with Cs CO as the base in
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THF, the starting aryl iodide 1a was recovered unchanged (entry 2, Table 1). Substituting the
ligand for BINAP resulted, once again, in the formation of a complex reaction mixture (entry 3,
Table 1).
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a
Table 1. Optimization of the αꢀarylation conditions
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b
entry sulfone catalyst (equiv.) base (equiv.) solvent time
H NMR ratio yield (%)
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Pd (dba) (0.075) K PO (3)
xantphos (0.15)
DMF
THF
THF
72 h
72 h
72 h
70 h
ꢀꢀꢀ
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d
Pd (dba) (0.075) Cs CO (3)
1a
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xantphos (0.15)
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Pd (dba) (0.05) Cs CO (3)
ꢀꢀꢀ
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BINAP (0.1)
e
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1b
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Pd(PPh ) (0.1)
K PO (2.5) DMF
3a (44%)
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Pd(PPh ) (0.1)
K PO (2.5) THF
72 h 2a:3a (1:2)
3a (73%)
3a (68%)
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Pd(PPh ) (0.05) Cs CO (2.5) THF
72 h 2a:3a (2:1)
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Pd(PPh ) (0.1)
K PO (3)
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DMF
THF
72 h
3b (65%)
3b (64%)
3b (52%)
3b (42%)
2c (40%)
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Pd(PPh ) (0.1)
K PO (3)
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72 h
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Pd(PPh ) (0.05) Cs CO (2.5) THF
72 h
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e
0
Pd(PPh ) (0.1)
K PO (3)
3
DMF
THF
120 h
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e
e
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Pd(PPh ) (0.1)
K PO (3)
3
115 h 2c:3b (5:1)
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b (41%)
2c (7%)
b (76%)
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1c
Pd(PPh ) (0.1)
Cs CO (2.5) THF
120 h 2c:3b (5:1)
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3
a
b
The reactions were carried out in a sealed tube at 120 ºC. Yields refer to pure products
c
d
e
isolated by flash chromatography. Complex mixture. Yield not quantified. Small amounts of
the hydrodehalogenation compound (≤10%) were also observed in the crude reaction mixture.
Pd (dba) : Tris(dibenzylideneacetone)dipalladium(0). Xantphos: 4,5ꢀBis(diphenylphosphino)ꢀ
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3
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,9ꢀdimethylxanthene. BINAP: 2,2’ꢀBis(diphenylphosphino)ꢀ1,1’ꢀbinaphthalene.
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In contrast, the reaction of 1a with Pd(PPh ) and K PO in DMF afforded the product 3a
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resulting from the elimination of phenylsulfinic acid from the initially formed αꢀarylation
compound 2a (entry 4, Table 1). The use of THF as the solvent, maintaining the same
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combination of reagents and catalyst, led to the formation of a 1:2 mixture of indoline 2a and
indole 3a (entry 5, Table 1), whereas a ratio of 2:1 was observed when the base was changed
from K PO to Cs CO (entry 6, Table 1). However, after column chromatography of these
3
4
2
3
reaction mixtures, only indole 3a was isolated, as a result of the SiO ꢀpromoted elimination of
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phenylsulfinic acid from 2a.
Phenyl sulfone 1b, which bears a methyl group at the aniline nitrogen atom, exclusively afforded
indole 3b when submitted to the reaction conditions optimized for the αꢀarylation of 1a (entries
7ꢀ9, Table 1). It should be noted that the corresponding indoline intermediate C was not
observed in any of the crude reaction mixtures of these runs.
Methyl sulfone 1c was also efficient in the αꢀarylation reaction, with a similar behavior to
phenyl sulfone 1a, although the process was slower. While indole 3b was directly obtained when
using DMF as the solvent (entry 10, Table 1), the annulation reaction in THF afforded mixtures
of indoline 2c and the indole 3b (entries 11 and 12, Table 1). Interestingly, although 2c partially
evolved to indole 3b during the chromatographic purification, in this case the indoline was stable
enough to be isolated and characterized.
At this point, the best conditions for the αꢀarylation of βꢀ(2ꢀiodoanilino) sulfones involved the
use of Pd(PPh ) as the catalyst and either K PO or Cs CO as the base in THF. On the other
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2
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hand, the results in Table 1 show that both phenyl and methyl sulfones could a priori be useful to
develop the proposed reaction cascade, since the corresponding 3ꢀsulfonyl indolines partially
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survived under the αꢀarylation conditions. However, in the phenylsulfonyl series, changing the
substituent at the nitrogen atom from benzyl to methyl resulted in a fast elimination of
phenylsulfinic acid, which could hamper the use of Nꢀmethyl derivatives in the domino process.
With this information in hand, without any further optimization, we then focused on combining
the αꢀarylation reaction with the next steps of the domino process, namely the Michael addition
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of the 3ꢀsulfonyl indoline intermediate C and the subsequent βꢀelimination from the resulting
alkylated indoline D (Scheme 1 and Table 2).
a
Table 2. αꢀArylation/Michael addition/βꢀelimination domino process
b
entry sulfone Michael acceptor base (equiv.) solvent yield (%)
c
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1a
1a
1a
1a
1b
1b
1c
1c
K PO (3)
THF
THF
DMF
DMF
THF
THF
THF
THF
THF
ꢀꢀꢀ
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4
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Cs CO (3)
4a (48%)
4a (19%)
4a (27%)
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c
K PO (3)
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c,e
Cs CO (3)
2
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f
Cs CO (3)
4d (43%)
4b (73%)
2
3
g
Cs CO (3)
2
3
g
Cs CO (3)
4c (45%)
4c (44%)
4b (40%)
2
3
h
Cs CO (3)
2
3
i
Cs CO (3)
2
3
a
Reaction conditions: 1 (0.2 mmol), Pd(PPh ) (10 mol%), Michael acceptor (2 equiv.), and
3
4
b
base (3 equiv.) in the indicated solvent in a sealed tube at 120 ºC for 72 h. Yields refer to pure
products isolated by flash chromatography. Complex mixture. NꢀBenzylꢀ4ꢀmethylꢀNꢀ[2ꢀ
phenylsulfonyl)ethyl]aniline (5a) was also isolated (17%). Significant amounts of Nꢀbenzylꢀpꢀ
c
d
e
(
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toluidine were observed in the reaction mixture. 5a (20%) was also isolated. Small amounts of
the corresponding hydrodehalogenation product (< 10%) were also observed in the crude
h
reaction mixture.
N,4ꢀDimethylꢀNꢀ[2ꢀ(methylsulfonyl)ethyl]aniline (5c) was also isolated
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(20%). 5c (26%) was also isolated.
Treatment of 1a with Pd(PPh ) and K PO in the presence of phenyl vinyl sulfone in THF
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4
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4
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afforded a complex mixture in which only trace amounts of the desired indole 4a were observed,
together with the reduction compound 5a and some products arising from the Heck reaction of
the starting aryl iodide (entry 1, Table 2). However, to our delight, changing the base to Cs CO3
2
resulted in a clean reaction mixture, from which indole 4a (48%) and the reduction compound 5a
(
17%) were isolated (entry 2, Table 2). When the reactions were performed in DMF using either
K PO or Cs CO as the base, indole 4a was also obtained, although in significantly lower yields
3
4
2
3
(entries 3 and 4, Table 2).
The threeꢀstep domino process of 1a with methyl vinyl sulfone afforded indole 4d in 43% yield
entry 5, Table 2). Phenyl sulfone 1b, which bears a methyl group at the nitrogen atom, gave
(
indoles 4b (73%) and 4c (45%) when submitted to the domino reaction with phenyl vinyl sulfone
(entry 6, Table 2) and methyl vinyl sulfone (entry 7, Table 2), respectively. This indicates that
the Michael addition of the 3ꢀsulfonyl indoline intermediate to the vinyl sulfone is faster than the
βꢀelimination of sulfinic acid, even for those substrates having a methyl substituent at the
nitrogen atom (vide supra).
Finally, methyl sulfone 1c also underwent the domino reaction, either with methyl vinyl sulfone
(entry 8, Table 2) or phenyl vinyl sulfone (entry 9, Table 2), to afford, respectively, indoles 4c
(44%) and 4b (40%).
The promising results obtained in these threeꢀstep domino reactions constituted a good starting
point to develop the initially proposed fourꢀstep domino process, which would simplify the
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preparation of 3ꢀ[2ꢀ(sulfonyl)ethyl]indoles starting from the readily available Nꢀalkylꢀ2ꢀ
iodoanilines. NꢀBenzylꢀ2ꢀiodoaniline was chosen to test our proposal (Table 3).
Table 3. Optimization of the azaꢀMichael/αꢀarylation/Michael addition/βꢀelimination domino
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a
process
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entry catalyst (equiv.) Michael acceptor solvent yield (%)
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THF
DMF
THF
6a (33%)
6a (28%)
SM
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Pd(PPh ) (0.1)
3
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Pd (dba) (0.075)
2
3
(
oꢀtolyl) P (0.15)
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xantphos (0.15)
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THF
THF
THF
THF
THF
THF
THF
THF
THF
SM
2
3
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Pd (dba) (0.075)
6a (54%)
6a (69%)
6a (80%)
6a (65%)
6a (65%)
2
3
BINAP (0.15)
Pd (dba) (0.075)
2
3
dppf (0.15)
Pd (dba) (0.075)
e
2
3
dppf (0.15)
g
Pd (dba) (0.075)
e,f
e
2
3
dppf (0.15)
Pd (dba) (0.075)
2
3
dppp (0.15)
h
0
Pd (dba) (0.075)
7
2
3
dtpf (0.15)
i
11
12
Pd (dba) (0.075)
e
6a/7 (1:1)
2
3
dppe (0.15)
j
Pd (dba) (0.075)
6b (33%)
6b (58%)
2
3
dppf (0.15)
k
13
Pd (dba) (0.075)
2
3
BINAP (0.15)
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6
a
Reaction conditions: NꢀBenzylꢀ2ꢀiodoaniline (0.2 mmol), [Pd] and ligand (see table), Michael
acceptor (2.1 equiv.), and Cs CO (3 equiv.) in the indicated solvent in a sealed tube at 120 ºC
for 72 h. Yields refer to pure products isolated by flash chromatography. NꢀBenzylaniline (7)
was also isolated (10%). 7 was also isolated (17%). Michael acceptor (2.4 equiv.). The
reaction was run at 80 ºC. NꢀBenzylꢀ2ꢀiodoaniline (8%) was recovered. Yield not quantified,
2
3
b
c
d
e
f
g
h
i 1
minor amounts of 6a (≤10%) were also observed in the reaction mixture. H NMR ratio, yieldsk
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
j
not quantified. EꢀNꢀBenzylꢀ2ꢀ[2ꢀ(methylsulfonyl)ethenyl]aniline (8) was also isolated (14%).
8
(13%) was also isolated. dppf: 1,1’ꢀBis(diphenylphosphino)ferrocene. dtpf: 1,1’ꢀBis(diꢀtertꢀ
butylphosphino)ferrocene.
Bis(diphenylphosphino)ethane.
dppp:
1,3ꢀBis(diphenylphosphino)propane.
dppe:
1,2ꢀ
When Nꢀbenzylꢀ2ꢀiodoaniline was treated with phenyl vinyl sulfone in the presence of Pd(PPh3)4
and Cs CO in THF, an effective combination to promote the threeꢀstep domino process from 1a,
2
3
indole 6a was obtained in a modest 33% yield, together with Nꢀbenzylaniline (7), which resulted
from the reduction of the starting 2ꢀiodoaniline (entry 1, Table 3). Although the use of a more
18
polar solvent should facilitate the initial azaꢀMichael addition, the yield of indole 6a was in fact
slightly lower when the reaction was performed in DMF (entry 2, Table 3). In view of these poor
results, we decided to optimize the fourꢀstep domino reaction by using different commercially
available phosphines as the ligand. The use of either (oꢀtolyl) P or xantphos resulted in the
3
recovery of the starting material (entries 3 and 4, Table 3). Surprisingly, although BINAP had
failed to promote the αꢀarylation from phenyl sulfone 1a (see Table 1), its use in the present
domino process resulted in the formation of 6a in an acceptable 54% yield (entry 5, Table 3).
Using dppf allowed us to obtain indole 6a in 69% yield (entry 6, Table 3), while in the presence
of the ligand dppp, 6a was isolated in 65% yield (entry 9, Table 3). We were also able to increase
the yield of 6a up to 80% by using dppf and a slightly higher quantity of the Michael acceptor
(
entry 7, Table 3). Lower reaction temperatures resulted in the recovery of small amounts of the
starting material (entry 8, Table 3). Other bidentate ligands were less amenable to promoting the
fourꢀstep domino process. For instance, the most hindered dtpf mainly resulted in the formation
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of the hydrodehalogenation product 7 (entry 10, Table 3), whereas a 1:1 mixture of 6a and 7 was
obtained when using dppe (entry 11, Table 3).
The fourꢀstep domino process of Nꢀbenzylꢀ2ꢀiodoaniline with methyl vinyl sulfone using dppf as
the ligand afforded a complex mixture from which indole 6b was isolated in 33% (entry 12,
Table 3). Interestingly, the replacement of the ligand by BINAP allowed us to obtain 6b in an
acceptable 58% yield (entry 13, Table 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
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42
43
44
45
46
47
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50
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53
54
55
56
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58
59
60
a
Table 4. Synthesis of 3ꢀ[2ꢀ(phenyl/methylsulfonyl)ethyl]indoles
Michael
acceptor
yield
(%)
entry
ligand
product
b
1
2
3
4
5
6
7
8
9
BINAP
dppp
9a, R = Me, R’’ = Ph
(71%)
(50%)
(45%)
(69%)
(67%)
(45%)
(89%)
(83%)
(56%)
(45%)
(79%)
(57%)
(45%)
(85%)
(70%)
9a, R = Me, R’’ = Ph
BINAP
dppf
9b, R = Me, R’’ = Me
10a, R = Pr, R’’ = Ph
dppf
10b, R = Pr, R’’ = Me
BINAP
dppf
10b, R = Pr, R’’ = Me
11a, R = Et, R’’ = Ph
dppf
4a, R = Bn, R’ = Me, R’’= Ph
4d, R = Bn, R’ = Me, R’’ = Me
4d, R = Bn, R’ = Me, R’’ = Me
12a, R = Bn, R’ = MeO, R’’ = Ph
12b, R = Bn, R’ = MeO, R’’ = Me
13a, R = Pr, R’ = MeO, R’’ = Ph
14a, R = Bn, R’ = Cl, R’’ = Ph
14b, R = Bn, R’ = Cl, R’’ = Me
dppf
10
11
12
13
14
15
BINAP
dppf
dppf
dppf
dppf
BINAP
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1
6
dppf
15a, R = Bn, R’ = Cl, R’’ = Ph
(65%)
(40%)
(75%)
17
BINAP
dppf
15b, R = Bn, R’ = Cl, R’’ = Me
16a, R = Bn, R’ = F, R’’ = Ph
18
19
dppf
16b, R = Bn, R’ = F, R’’ = Me
(73%)
(72%)
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2
0
1
dppf
17a, R = Bn, R’ = CO Me, R’’ = Ph
2
2
BINAP
dppf
17b, R = Bn, R’ = CO Me, R’’ = Me (56%)
2
22
17b, R = Bn, R’ = CO Me, R’’ = Me (62%)
2
23
dppf
18a, R = Pr, R’ = CO Me, R’’ = Ph
(81%)
(60%)
2
24
dppf
18b, R = Pr, R’ = CO Me, R’’ = Me
2
a
Reaction conditions: NꢀAkylꢀ2ꢀiodoaniline (0.2 mmol), Pd (dba) (7.5 mol%), ligand (see
2
3
table, 15 mol%), Michael acceptor (2.1ꢀ2.4 equiv.), and Cs CO (3 equiv.) in THF in a sealed
tube at 120 ºC for 72 h. Yields refer to pure products isolated by flash chromatography.
2
3
b
As shown in Table 4, a variety of diversely substituted 3ꢀ(sulfonylethyl)indoles were prepared
through the fourꢀstep domino process when using either phenyl vinyl sulfone or methyl vinyl
sulfone as the Michael acceptor. The generality and functional group tolerance of the reaction is
well illustrated by the fact that both electronꢀdonating and electronꢀwithdrawing groups were
perfectly accommodated on the aromatic ring. Overall, the phenyl sulfone afforded better results
than the methyl sulfone due to its higher electrophilicity as well as the higher acidity of its αꢀCꢀ
H bonds, which favors both the αꢀarylation and the Michael addition. In this context, it should be
noted that the initial azaꢀMichael addition took place without any appreciable interference from
the competitive Heck reaction. The same behavior was also observed in our previously
1
2
developed threeꢀstep domino process leading to tetrahydroisoquinolines. This absence of
competition contrasts with what occurred in a related oneꢀpot azaꢀMichael addition/αꢀarylation
2
3
process using acrylates as the Michael acceptor. In this case, it was impossible to develop a real
2
4
domino reaction because, in the presence of the Pd catalyst, the Heck coupling with the
1
9
acrylate took place before the azaꢀMichael addition.
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Some additional comments on the fourꢀstep domino reactions described above (Tables 3 and 4)
are warranted. In these reactions, the expected reduction products of the initially formed
intermediates B (Scheme 1) were never observed, yet they were a common sideꢀproduct (i. e. 5a-
c) in the threeꢀstep domino processes starting from sulfones 1a-c (see Table 2). This fact,
together with the isolation of significant amounts of Nꢀbenzylaniline (7), as well as the
apparently contradictory results obtained with BINAP, suggested that a sequence of events
different from those depicted in Scheme 1 could be operating in the fourꢀstep domino reaction.
Indeed, all these results could be easily accommodated by an alternative sequence of reactions
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49
50
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52
53
54
55
56
57
58
59
60
(Scheme 2) in which the formation of indoline C begins with the oxidative addition of the
iodoaniline to Pd(0). The resulting Pd(II) intermediate E would then undergo deprotonation and
azaꢀMichael addition to the vinyl sulfone to give intermediate F. The latter would evolve to
indoline C by means of coordination of the sulfone anion and subsequent reductive elimination.
Scheme 2. Alternative sequence of events for the domino process
In search of evidence for the proposed azaꢀMichael/αꢀarylation/Michael addition/βꢀelimination
sequence, further experiments were performed. Treatment of indole 3b with phenyl vinyl sulfone
in the presence of Pd(PPh ) and Cs CO in THF at 120 ºC resulted in the recovery of the starting
3
4
2
3
material. On the other hand, the treatment of a 8.3:1 mixture of indoline 2c and indole 3b with
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5
5
6
methyl vinyl sulfone and Cs CO in THF at 120 ºC, both with and without Pd(PPh ) , resulted in
2
3
3 4
the formation of a 6.4ꢀ6.9:1 mixture of indoles 4c and 3b (Scheme 3). These results therefore
confirm that indole 4c was generated by the Michael addition of indoline 2c to methyl vinyl
sulfone followed by βꢀelimination of sulfinic acid, rather than by the metalꢀpromoted
0
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0
1
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3
4
5
6
7
8
9
0
2
5
nucleophilic addition of indole 3b to the vinyl sulfone.
Scheme 3. Reaction of indoline 2c with methyl vinyl sulfone
More illustratively, the reactions of Nꢀbenzylꢀ2ꢀiodoaniline with the dideuterated phenyl vinyl
sulfone 19-D under optimized conditions (see for instance Table 3, entry 7) afforded indole 6a-
2
D , bearing deuterium labels at Cꢀ2 of the indole nucleus as well as at the β position of the 3ꢀ
3
(phenylsulfonyl)ethyl chain (Scheme 4). This result provides further experimental evidence for
the proposed azaꢀMichael/αꢀarylation/Michael addition/βꢀelimination sequence of events.
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Scheme 4. Reaction of Nꢀbenzylꢀ2ꢀiodoaniline with sulfone 19-D2
2
6
Density functional theory (DFT) calculations were carried out to gain more insight into the
mechanism of the sulfone αꢀarylation as well as the other key steps of the domino sequence
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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51
52
53
54
55
56
57
58
59
60
described above. First, we focused on the αꢀarylation process involving an analogous compound
of 1c (Table 1), where the methyl group in the aromatic ring was replaced by a hydrogen atom.
Our calculations started from species INT0, the intermediate formed upon the initial oxidative
addition of the 2ꢀiodoaniline derivative to the model Pd(PMe ) catalyst (Figure 1). In the
3 2
–
2
presence of CO3 as the base, deprotonation of the slightly acidic hydrogen atom attached to a
carbon atom linked to the sulfone group may occur, therefore leading to INT1 species in a
slightly exergonic process (∆G = –4.0 kcal/mol). This intermediate would then evolve to
R
complex INT2 by exergonic coordination of the carbanion to the transition metal (∆G = –14.9
R
kcal/mol) and release of a phosphine ligand. From this species, the αꢀarylation would take place
directly via TS1, a transition state associated with the formation of the new C–C bond. This
exergonic step (∆G = –14.2 kcal/mol) occurs with an activation barrier of 28.6 kcal/mol, which
R
is fully compatible with a process occurring at 120 ºC. Therefore, this reaction mechanism
resembles the one we previously proposed for the αꢀarylation reaction involving related ketone
8
l
and ester derivatives.
Nevertheless, an alternative reaction pathway involving a key C–H activation step can be also
envisaged. Thus, the initial intermediate INT0 may be readily transformed into complex INT3
through a highly exergonic (∆G = –26.6 kcal/mol) iodide and phosphine ligand replacement
R
–2
promoted by bidentate CO . This complex would be then converted into complex INT4 via
3
TS2 with an activation barrier of 26.1 kcal/mol in a slightly endergonic transformation (∆G =
R
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4
4
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5
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5
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5
5
5
6
+
2.7 kcal/mol). As depicted in Figure 1, this saddle point is associated with the concerted
hydrogen migration from the sulfone to the carbonate ligand and Pd–C bond formation. In this
sense, this transformation is analogous to related concerted metallationꢀdeprotonation (CMD) C–
0
1
2
3
4
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0
27
28
H activations which are assisted by acetate or carbonate. From INT4, the final indoline 2M
can be directly produced through TS3 in a reductive elimination process associated with the
formation of the new C–C bond. Although this reaction is exergonic (∆G = –9.2 kcal/mol), it
R
proceeds with a relatively high activation barrier of 37.4 kcal/mol. Therefore, INT4 may release
–
the HCO ligand first and be transformed into INT5, where the reductive elimination reaction
3
≠
via TS4 is computed to be kinetically far more favorable (∆G = 13.9 kcal/mol, from INT5).
–
2
Additionally, due to the excess of CO3 in the process, INT2 may alternatively be converted
into INT6 through a carbonate/iodide ligand exchange. This transformation seems feasible in
view of the high exergonicity (∆G = –18.5 kcal/mol) computed for this ligand exchange.
R
However, the corresponding reductive elimination via TS5 would proceed with a much higher
≠
activation barrier (∆G = 42.9 kcal/mol) than the process involving TS4, which renders this
alternative pathway very unlikely. Therefore, based on the computed data, it can be concluded
that the INT3 →INT4 →INT5 →2M pathway, which involves an initial CMD reaction
followed by a reductive elimination step, seems to be the most plausible reaction mechanism for
the palladiumꢀcatalyzed formation of indolines from βꢀ(2ꢀiodoanilino) sulfones.
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44
45
46
47
48
49
Figure 1. Computed reaction profiles for the palladium catalyzed αꢀarylation reaction of INT0. Relative free energies (ꢁG , at 298
K) and bond distances are given in kcal/mol and angstroms, respectively. All data were computed at the PCM(tetrahydrofuran)ꢀ
B3LYPꢀD3/def2ꢀTZVP//PCM(tetrahydrofuran)ꢀB3LYPꢀD3/def2ꢀSVP level.
2
98
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5
6
As indicated in the reaction profile depicted in Figure 1, the preferred pathway involves the
formation of the coordinatively unsaturated palladium(II) complex INT5. We hypothesize that
the involvement of the bidentate phosphine ligands used in the experiments must occur from this
intermediate. To find computational evidence for this hypothesis, we explored the feasibility of
the final reductive elimination reaction from INT5’, the analogous species to INT5 bearing an
additional phosphine ligand (i.e. a model bidentate ligand of the dppp ligand, with phenyl groups
replaced by methyl groups). As expected, our calculations (Figure 2) indicate that the
coordination of the free phosphine leading to the coordinatively saturated complex INT7 is
0
1
2
3
4
5
6
7
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9
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1
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7
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9
0
1
2
3
4
5
6
7
8
9
0
highly exergonic (∆G = –18.5 kcal/mol). From this species, the reductive elimination reaction
R
occurs via TS6, the corresponding saddle point associated with the formation of the new C–C
bond and release of the Pd(dppp) catalyst. From the data in Figure 2, it becomes clear that the
≠
process involving the bidentate ligand proceeds with a much higher activation barrier (∆G =
29.5 kcal/mol) and a lower exergonicity (∆G = –9.7 kcal/mol) than the analogous process
R
≠
involving the monodentate ligand (∆G = 13.9 kcal/mol and ∆G = –19.5 kcal/mol, see Figure
R
1), which nicely agrees with the experimental findings obtained during the optimization of the αꢀ
arylation reaction (see Table 1).
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56
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60
Figure 2. Computed reductive elimination reaction involving INT5’. Relative free energies
(ꢁG , at 298 K) and bond distances are given in kcal/mol and angstroms, respectively. All data
2
98
were computed at the PCM(tetrahydrofuran)ꢀB3LYPꢀD3/def2ꢀTZVP//PCM(tetrahydrofuran)ꢀ
B3LYPꢀD3/def2ꢀSVP level.
We then focused on understanding the negligible interference from the competitive Heck
coupling reaction in the fourꢀstep domino process from Nꢀalkylꢀ2ꢀiodoanilines (see above,
Tables 3 and 4). To this end, we computed the two possible reaction pathways, namely azaꢀ
Michael reaction vs Heck reaction, starting from INT8, the intermediate formed upon the initial
oxidative addition of the 2ꢀiodoꢀNꢀmethylaniline to the model Pd(PMe ) catalyst (Figure 3).
3
2
–
2
This species, in the presence of CO3 as the base, may deprotonate, leading to the anionic
complex INT9 in an exergonic process (∆G = –9.9 kcal/mol). Then, INT9 would react with the
R
corresponding vinyl sulfone to produce INT10 through TS7, a saddle point associated with the
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≠
formation of the N–C bond (∆G = 8.2 kcal/mol) in an azaꢀMichael type process. Final
protonation of INT10 leads to the formation of INT0, the common intermediate in the processes
involving both 2ꢀiodoanilines (Tables 3 and 4) and compounds 1 (Table 1 and 2). As clearly seen
in Figure 3, the alternative Heck coupling reaction is not competitive in this transformation. This
0
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is mainly due to the high endergonicity (∆G = 20.2 kcal/mol) associated with the initial
R
dissociation of a phosphine ligand, which is required to create a vacant coordination to allocate
the incoming vinyl sulfone ligand. In addition, the electronꢀwithdrawing effect of the SO Me
2
group reduces the coordination ability of the attached double bond, which also renders the
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coordination of the vinyl sulfone to INT11 endergonic (∆G = 4.8 kcal/mol). Although the
R
≠
subsequent insertion step via TS8 proceeds with a relatively low activation barrier (∆G = 11.5
kcal/mol), this highly unfavorable phosphine/vinyl sulfone ligand interchange makes the
alternative Heck reaction very unlikely, which is fully compatible with the experimental
observations.
The beneficial effect of bidentate phosphine ligands observed during the optimization of the
fourꢀstep domino process (see for instance, Table 3) is also in nice agreement with the expected
even higher endergonicity associated with the generation of the coordinatively unsaturated
species (i.e. INT 11), which is required for the Heck coupling when using a chelating phosphine.
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Figure 3. Computed reaction profiles for competitive azaꢀMichael and Heck coupling reactions
from INT8. Relative free energies (ꢁG , at 298 K) and bond distances are given in kcal/mol
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and angstroms, respectively. All data were computed at the PCM(tetrahydrofuran)ꢀB3LYPꢀ
D3/def2ꢀTZVP//PCM(tetrahydrofuran)ꢀB3LYPꢀD3/def2ꢀSVP level.
Finally, we addressed the last steps of the domino process which involve the transformation of
intermediate C (Scheme 1) into the observed 3ꢀ[2ꢀ(phenyl/methylsulfonyl)ethyl]indoles. Our
DFTꢀcalculations began from intermediate 2M, the indoline formed during the palladiumꢀ
catalyzed αꢀarylation (or CMDꢀreductive elimination) process described above (see Figure 1).
Deprotonation of the highly acidic benzylic hydrogen atom by the base would lead to the
≠
formation of carbanion 2M-an, from which a rapid (∆G = 6.4 kcal/mol) and exergonic (∆G = –
R
3.7 kcal/mol) Michael addition would take place via TS9. Protonation of intermediate 3M-an
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would then produce the 3ꢀ(sulfonyl)indoline intermediate 3M, which would be transformed into
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0
the final indole 4M through TS10. As depicted in Figure 4, this final fiveꢀmembered ring
transition state is associated with a concerted βꢀelimination reaction of sulfinic acid. Despite the
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concomitant rupture of both the S–C and C–H bonds, the process was computed to be highly
≠
exergonic (∆G = –16.5 kcal/mol) and to proceed with a feasible activation barrier (∆G = 18.1
R
kcal/mol). This can be ascribed to the gain in aromaticity in the final indole derivative which
therefore constitutes the thermodynamic driving force of the entire transformation.
Figure 4. Final transformation of indoline 2M into indole 4M. Relative free energies (ꢁG , at
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298 K) and bond distances are given in kcal/mol and angstroms, respectively. All data were
computed at the PCM(tetrahydrofuran)ꢀB3LYPꢀD3/def2ꢀTZVP//PCM(tetrahydrofuran)ꢀB3LYPꢀ
D3/def2ꢀSVP level.
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In summary, we have developed a set of reaction conditions for a new fourꢀstep domino process
toward 3ꢀ[2ꢀ(aryl/alkylsulfonyl)ethyl]indoles from readily available 2ꢀiodoanilines. In this threeꢀ
component domino process, the crucial intramolecular palladiumꢀcatalyzed αꢀarylation of
sulfones is combined with intermolecular azaꢀMichael and Michael additions to vinyl sulfones,
as well as a highly selective βꢀelimination of sulfinic acid, avoiding any undesired competitive
reactions. A series of diversely substituted 3ꢀ[2ꢀsulfonylethyl]indoles were easily synthesized in
moderateꢀtoꢀhigh yields. According to DFT calculations, after the initial oxidative addition to the
palladium catalyst, an azaꢀMichael reaction occurs without any significant interference from the
alternative Heck coupling reaction. The αꢀarylation process would then occur through a
CMD/reductive elimination process thus leading to indoline derivatives. The latter species are
finally converted into the observed 3ꢀ[2ꢀ(aryl/alkylsulfonyl)ethyl]indoles through two
consecutive reaction steps involving an initial rapid Michael addition followed by an exergonic
and concerted βꢀelimination reaction of sulfinic acid.
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3. EXPERIMENTAL SECTION
Representative procedure for the domino reactions (Table 3, Entry 7). A mixture of Nꢀ
benzylꢀ2ꢀiodobenzylamine (80 mg, 0.26 mmol), Pd (dba) (18 mg, 0.019 mmol), dppf (21 mg,
2
3
0.039 mmol), phenyl vinyl sulfone (104 mg, 0.62 mmol), and Cs CO (253 mg, 0.78 mmol) in
2
3
THF (8 mL) was stirred at 120 ºC in a sealed tube for 72 h. The reaction mixture was poured into
water and extracted with Et O. The organic extracts were washed with brine, dried, and
2
concentrated. The residue was purified by flash chromatography (SiO , from hexanes to hexanesꢀ
2
EtOAc 1:4) to give sulfone 6a (78 mg, 80%) as an amorphous brown solid.
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. COMPUTATIONAL DETAILS
All the calculations reported in this paper were obtained with the GAUSSIAN 09 suite of
3
1
programs. Electron correlation was partially taken into account using the hybrid functional
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usually denoted as B3LYP in conjunction with the D3 dispersion correction suggested by
3
3
34
Grimme and coꢀworkers using the doubleꢀζ quality plus polarization def2ꢀSVP basis set for
35
all atoms. Reactants and products were characterized by frequency calculations, and have
positive definite Hessian matrices. Transition structures (TS’s) 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
3
6
the Intrinsic Reaction Coordinate (IRC) method. Solvents effects were taken into account using
3
7
the Polarizable Continuum Model (PCM). Single point calculations on the PCM(THF)ꢀ
B3LYPꢀD3/def2ꢀSVP geometries were performed to estimate the change in the Gibbs energies at
3
4
the B3LYPꢀD3 level using the tripleꢀζ quality plus polarization def2ꢀTZVP basis set for all
atoms. This level is denoted PCM(THF)ꢀB3LYPꢀD3/def2ꢀTZVP//PCM(THF)ꢀB3LYPꢀD3/def2ꢀ
SVP.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures, characterization data and copies of
NMR spectra for all new compounds, as well as Cartesian coordinates of all species described in
the text. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for D.S.: dsole@ub.edu
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*
Eꢀmail for I.F.: israel@quim.ucm.es
Present Addresses
§
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
Nacional de Córdoba, Córdoba, Argentina X5000HUA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support for this work from the Spanish Ministerio
de Economía y Competitividad, Fondos Europeos para el Desarrollo Regional (MINECOꢀ
FEDER) (grant numbers CTQ2012ꢀ31391, CTQ2013ꢀ44303ꢀP, and Red de Excelencia
Consolider CTQ2014ꢀ51912ꢀREDC).
REFERENCES
(1) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996; p 1ꢀ169. (b) Joule, J. A. In
Science of Synthesis; George Thieme Verlag: Stuttgart, 2000; Vol. 10; p 526ꢀ585. (c) Bonner, S.
M.; Im, G.ꢀY. J.; Garg, N. K. In Heterocycles in Natural Product Synthesis; Majundar, K. C.,
Chattopadhyay, S. K., Eds.; WileyꢀVCH: Weinheim, 2011; p 211ꢀ225. (d) Ishikura, M.; Abe, T.;
Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694ꢀ752, and previous reviews in these series.
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2
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
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5
5
5
5
5
5
5
5
5
6
(
2) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241ꢀ2245.
(3) For recent reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875ꢀ
2
911. (b) Vicente, R. Org. Biomol. Chem., 2011, 9, 6469ꢀ6480. (c) Taber, D. F.; Tirunahari, P.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
K. Tetrahedron 2011, 67, 7195ꢀ7210.
(4) For recent reviews, see: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285ꢀ2309. (b)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873ꢀ2920. (c) Zeni, G.; Larock, R. C. Chem. Rev.
2
006, 106, 4644ꢀ4680. (d) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269ꢀ10310. (e) Platon,
M.; Amardeil, R.; Djakovitch, L.; Hierso, J.ꢀC. Chem. Soc. Rev., 2012, 41, 3929ꢀ3968. (f) Guo,
T.; Huang, F.; Yu, L.; Yu, Z. Tetrahedron Lett. 2015, 56, 296ꢀ302.
(5) For reviews, see: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234ꢀ245. (b)
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082ꢀ1146. (c) Johansson, C. C. C.; Colacot, T. J.
Angew. Chem. Int. Ed. 2010, 49, 676ꢀ707. (d) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.;
JohanssonꢀSeechurn, C. C. C.; Colacot, T. J. Eur. J. Org. Chem. 2015, 38ꢀ49.
(
6) Potukuchi, H.K.; Spork, A. P.; Donohoe, T. J. Org. Biomol. Chem., 2015, 13, 4367ꢀ4373.
7) For recent examples, see: (a) Kale, A. P.; Kumar, G. S.; Mangadan, A. R. K.; Kapur, M. Org.
(
Lett. 2015, 17, 1324ꢀ1327. (b) RottaꢀLoria, N. L.; Borzenko, A.; Alsabeh, P. G.; Lavery, C. B.;
Stradiotto, M. Adv. Synth. Catal. 2015, 357, 100ꢀ106. (c) Zoller, J.; Fabry, D. C.; Ronge, M. A.;
Rueping, M. Angew. Chem. Int. Ed. 2014, 53, 13264ꢀ13268.
(8) (a) Solé, D.; Peidró, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225ꢀ2228. (b) Solé, D.; Vallverdú,
L.; Bonjoch, J. Adv. Synth. Catal. 2001, 343, 439ꢀ442. (c) Solé, D.; Diaba, F.; Bonjoch, J. J. Org.
Chem. 2003, 68, 5746ꢀ5749. (d) Solé, D.; Vallverdú, L.; Solans, X.; FontꢀBardia, M.; Bonjoch, J.
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4
5
6
7
8
9
J. Am. Chem. Soc. 2003, 125, 1587ꢀ1594. (e) Solé, D.; Urbaneja, X.; Bonjoch, Adv. Synth. Catal.
2004, 346, 1646ꢀ1650. (f) Solé, D.; Urbaneja, X.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 3131ꢀ
3135. (g) Solé, D.; Serrano, O. J. Org. Chem. 2010, 75, 6267ꢀ6270. (h) Solé, D.; Bennasar, M.ꢀ
10
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12
13
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44
45
46
47
48
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53
54
55
56
57
58
59
60
L.; Jiménez, I. Synlett 2010, 944ꢀ946. (i) Solé, D.; Bennasar, M.ꢀL.; Jiménez, I. Org. Biomol.
Chem., 2011, 9, 4535ꢀ4544. (j) Solé, D.; Fernández, I.; Sierra, M. A. Chem. Eur. J. 2012, 18,
6
950ꢀ6958. (k) Solé, D.; Mariani, F.; Fernández, I.; Sierra, M. A. J. Org. Chem. 2012, 77,
0272ꢀ10284. (l) Solé, D.; Fernández, I. Acc. Chem. Res. 2014, 47, 168ꢀ179.
1
(9) Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 2476ꢀ2479.
(
(
(
(
10) Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372ꢀ9378.
11) Solé, D.; Serrano, O. Org. Biomol. Chem. 2009, 7, 3382ꢀ3384.
12) Solé, D.; PérezꢀJaner, F.; Mancuso, R. Chem. Eur. J. 2015, 21, 4580ꢀ4584.
13) Fort the βꢀelimination of sulfinic acid from 3ꢀ(arylsulfonyl)indolines, see: Babu, G.; Orita,
A.; Otera, J. Org. Lett. 2005, 7, 4641ꢀ4643.
(14) Gray, V. J.; Wilden, J. D. Tetrahedron Lett. 2012, 53, 41ꢀ44.
(15) For recent examples of pharmacologically interesting 3ꢀ(2ꢀsubstitutedꢀethyl)indole
compounds, see: (a) Jiaranaikulwanitch, J.; Govitrapong, P.; Fokin, V. V.; Vajragupta, O.
Molecules 2012, 17, 8312ꢀ8333. (b) Palangsuntikul, R.; Berner, H.; Berger, M. L.; Wolschann,
P. Molecules 2013, 18, 8799ꢀ8811. (c) Vo, V. A.; Lee, J.ꢀW.; Park, J.ꢀH.; Kwon, J.ꢀH.; Lee, H.
J.; Kim, S.ꢀS.; Kwon, Y.ꢀS.; Chun, W. Biomol Ther 2014, 22, 200ꢀ206. (d) Samuel, T.;
Yehualaeshet, T.; Serbessa, T.; Fadlalla, K. U. S. Pat. Appli. Publ. (2015), US 20150164860 A1
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0150618. (e) Xie, F.; Kniess, T.; Neuber, C.; DeutherꢀConrad, W.; Mamat, C.; Lieberman, B.
P.; Liu, B.; Mach, R. H.; Brust, P.; Steinbach, J.; Pietzch, J.; Jia, H. Med. Chem. Commun., 2015,
, 1093ꢀ1103. (f) de la Fuente Revenga, M.; FernándezꢀSáez, N.; HerreraꢀArozamena, C.;
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0
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MoralesꢀGarcía, J. A.; AlonsoꢀGil, S.; PérezꢀCastillo, A.; Caignard, D.ꢀH.; Rivara, S.;
RodríguezꢀFranco, M. I. J. Med. Chem. 2015, 58, 4998ꢀ5014. (g) Itadani, S.; Yashiro, K.;
Aratani, Y.; Sekiguchi, T.; Kinoshita, A.; Moriguchi, H.; Ohta, N.; Takahashi, S.; Ishida, A.;
Tajima, Y.; Hisaichi, K.; Ima, M.; Ueda, J.; Egashira, H.; Sekioka, Y.; Kadode, M.; Yonetomi,
Y.; Nakao, T.; Inoue, A.; Nomura, H.; Kitamine, T.; Fujita, M.; Nabe, T.; Yamaura, Y.;
Matsumura, N.; Imagawa, A.; Nakayama, Y.; Takeuchi, J.; Ohmoto, K. J. Med. Chem. 2015, 58,
6
093ꢀ6113.
(16) The 3ꢀ[2ꢀ(sulfonyl)ethyl]indoles have shown interesting antiinflammatory activity. See for
example: McKew, J. C.; Foley, M. A.; Thakker, P.; Behnke, M. L.; Lovering, F. E.; Sum, F.ꢀW.;
Tam, S.; Wu, K.; Shen, M. W. H.; Zhang, W.; Gonzalez, M.; Liu, S.; Mahadevan, A.; Sard, H.;
Khor S. P.; Clark, J. D. J. Med. Chem. 2006, 49, 135ꢀ158.
(
17) For the synthesis of 3ꢀ[2ꢀ(phenylsulfonyl)ethyl]indoles, see: (a) Slätt, J.; Romero, I.;
Bergman, J Synthesis 2004, 2760ꢀ2765. (b) Ma, S.; Yu, S.; Peng, Z.; Guo, H. J. Org. Chem.
006, 71, 9865ꢀ9868. (c) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Scapolla, C.;
2
Tavani, C. Tetrahedron Lett. 2012, 53, 752ꢀ757. (d) Nörder, A.; Warren, S. A.; Herdtweck, E.;
Huber, S. M.; Bach, T. J. Am. Chem. Soc. 2012, 134, 13524ꢀ13531. (e) Matsuzaki, K.;
Furukawa, T.; Tokunaga, E.; Matsumoto, T.; Shiro, M.; Shibata, N. Org. Lett. 2013, 15, 3282ꢀ
3285.
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18) De Castries, A.; Escande, A.; Fensterbank, H.; Magnier, E.; Marrot, J.; Larpent, C.
Tetrahedron 2007, 63, 10330ꢀ10336, and references therein.
(19) For tandem Heck/azaꢀMichael addition processes with acrylic acid derivatives, see: (a)
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Priebbenow, D. L.; Stewart, S. G.; Pfeffer, F. M. Org. Biomol. Chem., 2011, 9, 1508ꢀ1515. (b)
Priebbenow, D. L.; Pfeffer, F. M.; Stewart, S. G. Eur. J. Org. Chem. 2011, 1632ꢀ1635. (c) Chen,
K.; Pullarkat, S. A. Org. Biomol. Chem., 2012, 10, 6600ꢀ6606. (d) Zang, Q.; Javed, S.; Porubsky,
P.; Ullah, F.; Neuenswander, B.; Lushington, G. H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R.
ACS Combi. Sci. 2012, 14, 211ꢀ217.
(20) For the conjugate addition of carbon nucleophiles to vinyl sulfones, see: Xie, Y.ꢀX.; Song,
R.ꢀJ.; Liu, Y.; Wang, Z.ꢀQ.; Xiang, J.ꢀN.; Li, J.ꢀH. Synthesis, 2014, 46, 203ꢀ211, and references
therein.
(21) For the intermolecular αꢀarylation of sulfones, see: (a) Kashin, A. N.; Mitin, A. V.;
Beletskaya, I. P.; Wife, R. Tetrahedron Lett. 2002, 43, 2539ꢀ2542. (b) Niwa, T.; Yorimitsu, H.;
Oshima, K. Tetrahedron 2009, 65, 1971ꢀ1976. (c) Zhou, G.; Ting, P. C.; Aslanian, R. G.
Tetrahedron Lett. 2010, 51, 939ꢀ941. (d) Zheng, B.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 15,
1690ꢀ1693. (e) Nambo, M.; Crudden, C. M. Angew. Chem. Int. Ed. 2014, 53, 742ꢀ746.
(22) Significant signals of indoline 2a from a crude reaction mixture containing 2a and 3a (2:1):
1
H NMR (CDCl , 300 MHz) δ 2.29 (s, 3H), 3.50 (dd, J = 11.7 and 9.6 Hz, 1H), 3.78ꢀ3.85 (m,
3
1H), 3.81 (d, J = 15.0 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 4.70 (dd, J = 9.6 and 2.1 Hz, 1H), 6.18
(d, J = 8.4 Hz, 1H).
(23) Reddy, A. G. K.; Satyanarayana, G. Tetrahedron, 2012, 68, 8003ꢀ8010.
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