Platinum-catalyzed domino reaction with benziodoxole reagents for accessing benzene-alkynylated Indoles

Article abstract of DOI:10.1002/anie.201412321

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum-catalyzed cyclization/alkynylation domino process to selectively obtain C5- or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.

Full text of DOI:10.1002/anie.201412321

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201412321
German Edition: DOI: 10.1002/ange.201412321
Heterocycle Synthesis
Platinum-Catalyzed Domino Reaction with Benziodoxole Reagents for
Accessing Benzene-Alkynylated Indoles**
Yifan Li and Jerome Waser*
Abstract: Indoles are omnipresent in natural products, bioac-
tive molecules, and organic materials. Consequently, their
synthesis or functionalization are important fields of research
in organic chemistry. Most works focus on installation or
modification of the pyrrole ring. To access benzene-ring-
functionalized indoles with an unsubstituted pyrrole ring
remains more challenging. Reported herein is a platinum-
catalyzed cyclization/alkynylation domino process to selec-
tively obtain C5- or C6-functionalized indoles starting from
easily available pyrroles. The work combines, for the first time,
a platinum catalyst with ethynylbenziodoxole hypervalent
iodine reagents in a domino process for the synthesis of
polyfunctionalized arene rings and gives access to important
building blocks for the synthesis of bioactive compounds and
organic materials.
F
unctionalized indoles occupy a privileged position in
organic chemistry as they can be found in biomolecules,
drugs, agrochemicals, and materials.[1] To access these impor-
tant building blocks, a first approach consists in the introduc-
tion of functional groups onto simple, commercially available
indoles. To have a more efficient alternative to well-estab-
lished cross-coupling reactions, the transition-metal-catalyzed
À
Figure 1. 5- and 6-Alkynylated indoles: Outside the scope of C H
functionalization.
À
direct functionalization of a C H bond on indoles has been
intensively investigated in the last two decades. Nevertheless,
this approach is mostly limited to the modification of the
more reactive pyrrole ring (innate reactivity, Figure 1a).[2]
The functionalization of the benzene ring has been only rarely
achieved and is limited to C2,C3-disubstituted indoles.[3] One
notable exception is the selective iridium-catalyzed C7-
borylation of indoles reported by Hartwig and co-workers.[4]
We were particularly interested by the introduction of an
alkyne onto the benzyl ring of indoles, as alkynes are key
building blocks in medicinal, synthetic, and materials chemis-
try.[5] Direct alkynylation approaches can be used only to
access 2- and 3-substituted indoles.[6] This is an important
limitation, as either 5- or 6-alkynylated indoles can be found
in bioactive compounds such as the 5-LOX (5-lipoxygenase)
inhibitor 1,[7a] and NMDA (N-methyl-d-aspartate receptor)
antagonist 2 (Figure 1b).[7b] Alkynylated carbazoles are
especially important for organic materials, such as the macro-
cycle 3, an organic sensor for the detection of TNT.[7c] If an
efficient method for the synthesis of benzene-alkynylated
indoles can be developed, more-complex compounds could
À
then be easily obtained by using the well-established C H
functionalization at either the C2- and C3-positions, or
transformations of the triple bond.
À
As C H metalation of the arene ring of indoles is
extremely difficult in the presence of the more reactive C2
À
and C3 C H bonds, we wondered if the desired reactive
intermediate could be generated in situ during a metal-
catalyzed cyclization step (Scheme 1). The use of such domino
or cascade processes is one of the most efficient ways to
increase molecular complexity in organic synthesis,[8] but it
has not yet been applied to the synthesis of benzene
alkynylated indoles. In fact, reported cascade approaches by
the groups of Cacchi and Zhu for the synthesis of alkynylated
indoles have focused on the construction of the pyrrole ring
using palladium catalysis (Scheme 1a).[9] To develop
a domino process to access indoles functionalized on the
benzene ring, another type of cyclization would be needed. In
this respect, we were particularly attracted by the work of the
groups of Alcaide, Hashmi, and Ma, among others, to form
[*] Y. Li, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique FØdØrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
[**] EPFL and F. Hoffmann-La Roche Ltd are acknowledged for financial
support and Alfa Aesar and Johnson Matthey for a gift of PtCl2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412321.
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only one molecule of water is required for aromatization. The
previous catalytic conditions developed in our group for the
domino cyclization/alkynylation of allene ketones[13] were not
suitable for the pyrrole system. After a broad screening of
gold catalysts, the desired product could not be obtained. We
then turned our attention to platinum catalysts
(Table 1).[10c,11a] Preliminary results with PtCl2 were promis-
Table 1: Optimization of the domino cyclization/alkynylation reaction.
Entry Pyr- Catalyst
role
4
Base
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5
5
5
5
5
5
5
5
5
5
5
5
PtCl2
PtCl2/AgOTf 4a Na2CO3 CH3CN
PtCl2/bipy 4a Na2CO3 CH3CN
[Pt(NH3)2Cl2] 4a Na2CO3 CH3CN
4a Na2CO3 CH3CN
13
<5
<5
<5
40
30
21
14
27
<5
<5
<5
91
Scheme 1. Domino processes to access alkynylated indoles.
PtCl2
4a NaHCO3 CH3CN
4a NaHCO3 toluene
4a NaHCO3 THF
4a NaHCO3 MeOH
4b NaHCO3 CH3CN
4c NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN
4a NaHCO3 CH3CN/C6H5Cl
(v/v=1:5)
the benzene ring of heterocycles by the cyclization of
alkynes[10] using well-established p-activation catalysts such
as gold and platinum.[11] In fact, one single example of gold-
catalyzed indole ring formation starting from easily available
pyrrole ethers has been reported.[10b] This precedence pro-
vides a solid basis for the cyclization step of the domino
process, but the envisaged alkynylation appeared highly
challenging, as the generated intermediates are known to
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl4
[Pt(PPh3)4]
6a PtCl2
PtCl2
7
80
À
broadly favor protodemetalation over further C C bond
6a PtBr2
6a PtI2
6a PtBr2
98[b]
<5
45
2
À
formation. The formation of a new C C bond on a Csp center
of an indole arene ring after cyclization has to the best of our
knowledge never been realized.
To solve the challenge associated with the low reactivity of
18
19
6a PtBr2
6a PtBr2
4a NaHCO3 CH3CN/THF
(v/v=1:5)
4a NaHCO3 CH3CN/THF
(v/v=1:10)
96
93
À
gold intermediates in C C bond-forming reactions, our group
has turned to the exceptional reactivity of hypervalent iodine
alkynylation reagents.[6b–d,12] We recently reported the first
successful domino process in the synthesis of 3-alkynylated
furans by the cyclization/alkynylation of allene ketones.[13]
Although this work resulted in the synthesis of regioisomers
[a] Reaction conditions: 5–7 (0.10 mmol), catalyst (10 mol%), 4
(0.20 mmol), base (0.20 mmol), 0.1m, RT, 72 h. Yield is that of the
product isolated after column chromatography. [b] Not reproducible.
bipy=bipyridine, Tf = trifluoromethanesulfonyl, THF=tetrahydrofuran.
À
difficult to access by C H functionalization, it was still limited
to the more reactive heteroarene class of substrates. Herein,
we report that the change to a platinum catalyst in combina-
tion with the ethynylbenziodoxole (EBX) reagent 4a[14] led to
a successful cyclization/alkynylation domino process starting
from pyrrole homopropargylic ethers to give either C5- or C6-
alkynylated indoles in good yields and high regioselectivity
(Scheme 1b). In addition to giving access to important
building blocks and scaffolds, this new transformation also
represents a breakthrough in the field of catalysis and
hypervalent iodine chemistry, as it is the first example of
a platinum-catalyzed process with EBX reagents.
ing, as 13% of the 5-ethynyl indole 8a could be isolated with
sodium carbonate as the base (entry 1). Attempts to modulate
the reactivity of the catalyst by formation of a more electro-
philic platinum salt (entry 2) or using nitrogen-based ligands
(entries 3 and 4) both suppressed the formation of 8a. In
contrast, changing the base to sodium bicarbonate allowed
increasing the yield to 40% (entry 5). Investigation of
solvents showed that CH3CN was best (entries 6–8). Neither
the use of other hypervalent iodine reagents, such as TIPS-
EBX (4b) or alkynyliodonium salt 4c (entries 9,10), nor
platinum(IV) or platinum(0) catalysts (entries 11 and 12) led
to improved results. At this point, we decided to investigate
the influence of the group eliminated in the aromatization
step. Changing the leaving group from hydroxy to methoxy
We started our investigation with the pyrrole derivatives 5
and the hypervalent iodine reagent 4a. The substrate 5 (see
Table 1 for structure) is easily accessible in two steps from
commercially available compounds and the generation of
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led to a major increase in yield to 91% (entry 13). A silyl
ether could also be used,[10b] but led to a lower yield (80%,
entry 14). A bromide counterion led to a slightly higher yield
(entry 15) and iodide completely suppressed the reaction
(entry 16). The results obtained with PtCl2 and PtBr2 were
difficult to reproduce, probably because of the poor solubility
of 4a in CH3CN. Using a cosolvent led to more reproducible
results (entries 17–19), and THF was the best, thus giving the
desired product 8a in 96% yield (entry 18).
a benzyl group were well tolerated (entries 2 and 3), as well as
different substituents on an alkyl chain such as methoxy and
trifluoromethyl (entries 4 and 5). Substitution of the alkyne
was examined next. The desired C5-alkynylated product 8 f
was obtained in 70% yield with a methyl group (entry 6).
With aromatic substituents, formation of the C6-alkynylated
product 10 was observed for the first time. The C5-alkyny-
lated product 8 was still the major product with either
a
phenyl, a tolyl, or a para-bromophenyl substituent
With optimized reaction conditions in hand, we then
examined the scope of the cyclization/ethynylation domino
reaction (Table 2). The indole 8a was obtained in 84% yield
upon isolation from a 0.3 mmol scale reaction (entry 1). Only
C5-ethynylation was observed. Modification of the substitu-
ent on the nitrogen atom was investigated first. A tolyl and
(entries 7–9). The latter case also demonstrated that halogen
substituents were tolerated under the reaction conditions,
thus allowing further functionalization of the products by
classical cross-coupling chemistry. With a naphthyl group,
a 1:1 mixture of regioisomers was obtained (entry 10), and
with a methyl substituent in the propargylic position, the C5-
alkynylated product 8k was obtained in 75% yield (entry 11).
In contrast, when the tertiary ether 6l was used, the C6-
alkynylated product 10e was formed (entry 12). The alkyny-
lated carbazole 8m was obtained in 76% yield (entry 13), and
the domino process could also be applied to the synthesis of
the thiophene-fused heterocycle 8n in 78% yield (entry 14).
Having achieved the synthesis of C5-alkynylated indoles
starting from C2-substituted pyrroles, we then turned to C3-
substituted derivatives to achieve C6 functionalization.
(Table 3). The pyrrole 9a, bearing a terminal alkyne, gave
the C6-alkynylated indole 10a exclusively in 77% yield
(entry 1). Substituted alkynes could also be used to access 6,7-
disubstituted indoles in 47–53% yield (entries 2–4). Starting
from tertiary ethers, 4,6-disubstituted products could be
obtained (entries 5 and 6). In this case, the same products
were obtained as when starting from C2-substituted pyrroles.
We then wondered if more-complex trisubstituted indoles
could be accessed. In fact, the 4,6,7- (10g) and 4,5,6-
substituted (10h) indoles were obtained in 44 and 34%
yield, respectively (entries 7 and 8). Although the yields are
moderate, the synthesis of these polysubstituted compounds
using another method would have been extremely difficult.
Finally, the synthesis of the C6-alkynylated carbazoles 10i,j
was also possible (entries 9 and 10).
Table 2: Scope of 5-alkynylated indoles.
Entry Substrate
Product
Yield [%][a]
1
2
3
4
5
R=Me (6a)
R=tolyl (6b)
R=benzyl (6c)
R=3-methoxy propyl (6d) 8d
R=1,1,1-trifluorobutyl (6e) 8e
8a
8b
8c
84
81
83
80
82
6
7
8
9
10
R=Me (6 f)
R=phenyl (6g)
R=tolyl (6h)
R=p-Br-phenyl (6i)
R=naphthyl (6j)
8 f
70
8g/10c (4:1)
8h/10k (3:1)
8i/10l (2.5:1)
8j/10d (1:1)
70 (56)[b]
69 (52)[b]
62 (44)[b]
31/31
The developed domino process is highly complex. Con-
sequently, any proposal about the reaction mechanism is
highly speculative at this stage of development. Based on the
well-established p-acidity of platinum,[11a] the first step of the
catalytic cycle is most probably activation of the alkyne to
give complex A (Scheme 2). At this point, cyclization could
occur either at the C2- or C3-position of the pyrrole ring to
give intermediates B or D, respectively. Attack on the more
nucleophilic C2 position, thus leading to B is more probable.
From B, two different pathways are possible: a 1,2 shift of the
platinum-bearing vinyl group via the platinum carbene cyclo-
propane intermediate C[11a,15] to give the carbocation D, or
1,2-shift of the alkoxy substituent to give intermediate G.[10]
C5- and C6-metalated intermediates E and H, respectively,
will then be generated from the corresponding compounds D
and G after deprotonation and aromatization by methanol
elimination. The alkynylated products 8 and 10 can be formed
by reaction of 4a with organoplatinum intermediates. At this
point, it is not clear if the alkynylation step proceeds through
an oxidative addition/reductive elimination mechanism on
11
12
75
54
13
14
76
78
[a] Reaction conditions: Substrate 6 (0.30 mmol), PtBr2 (10 mol%), EBX
reagent 4a (0.60 mmol), NaHCO3 (0.60 mmol), THF/CH3CN (3 mL, v/
v=5:1), 72–120 h. Yield is that of the product isolated after column
chromatography. [b] Yield determined by 1H NMR spectroscopy. The
yield of the isolated isomer 8 is given within parenthesis.
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Table 3: Scope of 6-alkynylated indoles.
Entry
Substrate
Product
Yield [%][a]
77
1
2
3
4
R=Me (9b)
R=phenyl (9c)
R=naphthyl (9d)
10b
10c
10d
49
53
47
5
6
R=Me (9e)
R=phenyl (9 f)
10e
10 f
54
65
Scheme 2. Proposed mechanism for the domino cyclization/alkynyla-
tion.
7
8
44
34
The obtained alkynylated indoles are interesting building
blocks, as the unsubstituted pyrrole ring can be easily further
derivatized using established methods, and the terminal
alkyne, obtained after silyl group removal, can serve as
a platform for further functionalization. For example, depro-
tection of the alkyne 8a followed by gold-catalyzed selective
C3 alkynylation with TIPS-EBX (4b)[6b] gave the monopro-
tected diyne 11, which was ready for further selective
derivatization (Scheme 3a). Starting from naphthyl deriva-
tive 10d, deprotection followed by platinum-catalyzed cyclo-
isomerization[18] gave access to the helicene 12 (Scheme 3b).
Helicenes are important molecules in asymmetric catalysis
and material science, but have never been synthesized with
a terminal pyrrole ring to the best of our knowledge.[19]
In conclusion, we have reported a new domino cyclization
strategy for the efficient synthesis of C5- or C6-alkynylated
indoles starting from easily available C2- or C3-substituted
9
10
R=H (9i)
R=OMe (9j)
10i
10j
58
64
[a] Reaction conditions: Substrate 9 (0.30 mmol), PtBr2 (10 mol%), EBX
reagent 4a (0.60 mmol), NaHCO3 (0.60 mmol), THF/CH3CN (3 mL, v/
v=5:1), 72–120 h. Yield is that of the product isolated after column
chromatography.
platinum[16] or by direct nucleophilic attack of the organome-
tallic intermediates onto reagent 4a.
À
If the C3-substituted pyrrole is used as a starting material,
the mechanism is simpler as C2-attack of the indole leads
directly to a six-membered ring and therefore to exclusive
formation of the C6-alkynylated product 10. The observed
regioselectivity for secondary ethers is in accordance with
a shift of the vinyl group. In contrast, shift of the alkoxy group
had been observed in the cyclization step when using gold
catalysts.[10b] This shift may be due to an easier formation of
platinum carbene intermediate C when compared to gold
catalysts.[17] This result further emphasizes an advantage of
the platinum catalyst, as with gold both C2- and C3-
substituted pyrroles would have given C6-alkynylated prod-
ucts. With pyrroles substituted with tertiary ethers, C6-
alkynylated products were observed independent of the
structure of the starting material. In this case, the presence
of the methyl group may further stabilize the transition-state
F and favor the shift of the alkoxy group.
pyrroles. Our strategy is complementary to C H functional-
Scheme 3. Further transformations of the alkynylated indole products.
TBAF=tetra-n-butylammonium fluoride.
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ization, as the benzene positions on indole are difficult to
modify directly because of the higher reactivity of the pyrrole
ring. Key for success was the unprecedented combination of
a platinum catalyst with EBX reagents. The domino process
realized in this work represents a new general strategy for the
synthesis of alkynylated arenes. Further investigations will
focus on the synthesis of other (hetero)arenes and on the
introduction of different functional groups in the final bond-
forming step.[20]
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Keywords: alkynes · cyclization · heterocycles ·
hypervalent compounds · platinum
How to cite: Angew. Chem. Int. Ed. 2015, 54, 5438–5442
Angew. Chem. 2015, 127, 5528–5532
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Received: December 23, 2014
Revised: February 3, 2015
Published online: March 10, 2015
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