Room-Temperature and Transition-Metal-Free Intramolecular α-Arylation of Ketones: A Mild Access to Tetracyclic Indoles and 7-Azaindoles

Article abstract of DOI:10.1021/acs.orglett.8b03831

A novel approach for the synthesis of tetracyclic indoles and 7-azaindoles is reported. The strategy involves four steps, with a fast rt intramolecular α-arylation of ketones as key step. The reaction was inspected synthetically to achieve the synthesis of 11 novel tetracyclic structures with moderate to very good yields (39-85%). Theoretical combined with experimental studies led us to propose a probable polar mechanism (concerted S_NAr).

Full text of DOI:10.1021/acs.orglett.8b03831

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Room-Temperature and Transition-Metal-Free Intramolecular
α‑Arylation of Ketones: A Mild Access to Tetracyclic Indoles and
7
‑Azaindoles
†
,‡
,‡
‡
‡
†
Cher
Silvia M. Barolo, Roberto A. Rossi,* and Maurice Med
†Univ Lyon, Universite
if Adouama, María E. Buden,* Walter D. Guerra, Marcelo Puiatti, Benoît Joseph,
́ ́
‡
,†
́
ebielle*
́
Lyon 1, CNRS, INSA, CPE-Lyon, ICBMS, UMR 5246, 1 rue Victor Grignard, 69622 Villeurbanne Cedex,
France
‡
INFIQC, Facultad de Ciencias Químicas, Universidad Nacional de Cor
doba, X5000HUA Cordoba, Argentina
́ ́
*
S Supporting Information
ABSTRACT: A novel approach for the synthesis of tetracyclic
indoles and 7-azaindoles is reported. The strategy involves four steps,
with a fast rt intramolecular α-arylation of ketones as key step. The
reaction was inspected synthetically to achieve the synthesis of 11
novel tetracyclic structures with moderate to very good yields (39−
8
5%). Theoretical combined with experimental studies led us to
propose a probable polar mechanism (concerted S Ar).
N
ndoles and 7-azaindoles are important heterocycles found in
Thesepreviousreportsencourage ustostudyanovelapproach
to prepared unprecedented 3,4-fused tetracyclic indoles and 7-
azaindoles 4 based on α-arylation of ketones from halo-indole
derivatives (Scheme 1). To the best of our knowledge, there is
only one example reporting the synthesis of such type of
1
I
many natural products and pharmaceutical agents. Among
indole alkaloids, 3,4-fused indoles have been considered
attractive synthetic targets due to their biological activities and
synthetic challenges. Examples include the well-known N-
13
2
skeleton albeit obtained from a Rh-catalyzed reaction. The
methylwelwitindolinone C and its isothiocyanate derivatives,
3
4
9
-deacetylfumigaclavine C, lysergic acid, among others. New
Scheme 1. Synthetic Strategy for 3,4-Fused Tetracyclic
indoles and 7-Azaindoles (4)
synthetic approaches toprepare these compounds and analogues
remain a challenge for organic chemists.
Although various methodologies to prepare 3,4-fused tricyclic
5
indoleshavebeenreported, syntheticapproachestoprepare3,4-
fused tetracyclic indoles are less explored. Currently, some of the
most preferred methods to prepare such skeletons are metal-
catalyzed reactions (mostly Pd). For example, Rawal et al., in
6
their route to the welwitindolinone alkaloids, used Pd-catalyzed
intramolecular enolate arylations. In the same way, other authors
used this methodology to generate a variety of tetracyclic indoles
7
and natural products derivatives in good to excellent yields. In
addition, Garg et al. developed indolyne cyclization (via
8
benzyne) as key step to prepare welwitindolinone alkaloids,
and the Pd-catalyzed intramolecular Heck reaction was used as a
9
key transformation for the synthesis of lysergic acid and
1
0
(
−)-hapalindole U and (+)-ambiguine H.
Inter- and intramolecular α-arylation of ketones involving
11
metal-catalyzed processes has been widely employed. How-
ever, there are still many issues due to the use of hazardous
reagents, additives, and expensive, sensitive reagents, which need
to be overcome. The S 1 reaction has been successfully applied
RN
as a mild alternative for the arylation of α-carbonyl compounds
and is noteworthy in the context of natural products synthesis.
Received: November 30, 2018
12
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
t
synthetic strategy involves, as the first step, the construction of
compounds 3, where 3-acetyl-4-bromoindole (1a) or 3-acetyl-4-
chloro-7-azaindole (1b) derivatives are substituted in the C4
position by an o-aryl halide group via Suzuki−Miyaura reaction
with KO Bu in THF could provide 4a and 4c in 65% and 48%
15,21
yields, respectively (Scheme 2).
To extend the application of the developed methodology, we
evaluated the reactivity of different 3-acetyl-4-arylindoles (3d−
h). Thus, while the precursors substituted with EWG or without
substitution reacted well, giving the tetracyclic indoles with
moderate to very good yields (for 4b, 4d, 4g, and 4h) (Scheme
2), those substituted with EDG did not (4e and 4f). The same
behavior was observed when 3-acetyl-4-aryl-7-azaindole pre-
cursors were employed, giving good yields for EWG and without
substitution (4i,j and 4m,n, 39−84% yields). However, when the
(Scheme 1). Then ketones 3 could undergo an intramolecular α-
arylation to form the 3,4-fused tetracyclic indoles and 7-
azaindoles 4 (Scheme 1).
The precursors 1a and 1b were prepared in two steps from
commercially available 4-bromoindole and 4-chloro-7-azain-
1
4,15
dole.
The following step is Pd-catalyzed cross-coupling
reaction of 1a or 1b, with different 2-halophenyl boronic acids
1
5
2
(
(
2a−i) and 3-acetyl-4-arylindole and 7-azaindole derivatives
photostimulated reaction of 3k (Z = N, R = OMe) was carried
out in NH3(liq) as a solvent, the cyclization product 4k was
15
3a−n) obtained in moderate to excellent yields (29−98%).
Thus, 15 precursors were prepared to evaluate electronic factors
in the cyclization reaction.
22
obtained in 53% yield. It worth noting that under dark
conditions no product 4k was found and the substrate 3k was
recovered completely, ruling out an S Ar mechanism in NH
solvent at this temperature (−33 °C). These results reinforce the
fact that changes in the experimental conditions (temperature,
solvent, and photostimulation) may change the involved
The key step in the sequential synthesis of tetracyclic indoles
and 7-azaindoles involves an intramolecular α-arylation of
indole-derived methyl ketones, 3a−o. The dark reaction of
N
3
1
2
t
indole 3a (Z = W = CH, R = CF , R = H) with KO Bu (5 equiv)
3
23
in DMSO gave the cyclization product 4a in 85% yield (entry
mechanism.
1
6
1
). The yield of 4a did not increase in the presence of
In the intramolecular C−C arylation reaction, a marked
difference is observed depending on the electronic nature of the
substituent in the ring where the leaving group is located. The
reaction of 3 with KO Bu in excess would afford enolate anion 3
(Scheme3). Dependingontheinitiationstep, three pathwaysare
possible (paths A−C). An intermolecular ET (path A) affords
product 4 by S 1 mechanism. The second possibility is an
intramolecular ET (path B) from 3 to the aromatic ring where
the chlorine is found, which gives diradical anion (3 ) . This
intermediate has then two different pathways, path B (radical−
radical coupling) or path B (nucleophilic aromatic substitution
via electron transfer, S (ET)Ar), to finally give product 4. The
third possibility is an addition−elimination mechanism (S Ar,
2+
17
pinacolone enolate ion or Fe salts. Lower conversion and
reducedyieldofcyclizedproduct4a wasfoundwhen thereaction
was performed over ashorter timeor with alower amount of base
t
−
(
entries 2 and 3). The reaction is inhibited in the presence of p-
dinitrobenzene (p-DNB), which is used as a good electron
acceptor in ET reactions (Table 1, entry 4). However, because of
RN
−
•
•−
Table 1. Intramolecular α-Arylation Reactions of 3-Acetyl-4-
a
(
2-chloroaryl)indoles (3a and 3b)
1
t
b
2
entry KO Bu (equiv) additive (equiv) time (min)
yield (%)
18
N
1
2
3
4
5
6
7
8
5
5
2
5
5
5
5
5
40
20
40
20
20
20
120
20
3a, −; 4a, 85
3a, 7; 4a, 78
3a, 36; 4a, 49
3a, 78; 4a, 7
3a, 81; 4a, 4
3b, 56; 4b, 37
3b, 53; 4b, 8
3b, −; 4b, 46
N
path C).
Then the effect of the leaving group for the precursors 3b and
p-DNB (0.4)
TEMPO (0.4)
3
b′ where chlorine and fluorine are the leaving groups,
respectively, was analyzed (Scheme 2). The reaction using
t
KO Bu (5 equiv) in DMSO leads to the formation of the product
4
b in 37% and 56% yield from 3b and 3b′, respectively. It is
hν, 250 W
known that in S Ar mechanisms fluorine is a much better leaving
N
a
18
The reaction was carried out under Ar atmosphere using 3 (1 equiv,
.2 mmol) and KO Bu (5 equiv) in DMSO. Isolated yield.
group than other halogens, which agrees with those results.
However, ET mechanisms could not be ruled out because there
t
b
0
areprecedentswherefluorinatedandchlorinatedanaloguesreact
24
through ET mechanisms with similar conversion. Finally, the
its strong electron-withdrawing character, S Ar displacement of
benzynemechanismisdiscardedsincethesubstrate3m(W=C−
N
1
2
a nitro group is observed with a large variety of nucleo-
Cl, Z = N, R = R = H), which has both ortho positions to the
leaving groupblocked, reactedto givethe cyclization product 4m
(with chlorine atom retention) in 75% yield (Scheme 2).
Since the experimental probes were inconclusive, the
feasibility of the different steps of the proposed mechanism (A,
1
5,18,19
philes.
In addition, it is possible that the enolate might
react with p-DNB by an electron transfer, therefore interrupting
the cyclization process. Moreover, the addition of TEMPO also
causedinhibitionofthe reaction (entry5). However, theabsence
of adduct does not allow us to confirm the presence of radicals as
intermediates.
15
B, and C) was evaluated by computational study (Scheme 3).
For ET mechanisms, we employed the Marcus−Hush theory to
⧧
In comparison, 3-acetyl-4-(2-chlorophenyl)indole (3b, W = Z
CH, R = R = H) was less reactive than 3a, giving only a 37%
calculatetheactivationfreeenergy(ΔG )involvedinanouter-
ET
1
2
15,23
=
sphere ET.
For paths A and B, it was found that the initial
⧧
yield of 4b after 20 min (entry 6, Table 1). If the reaction was
pushed further, similar conversion and lower yield of 4b were
ΔG is endergonic step (48.1 kcal/mol for intermolecular ET
vs 65.4 kcal/mol for intramolecular ET), while for the S Ar
mechanism the ΔG for the coupling is 24.4 kcal/mol. In
addition,computationalcalculationspredictthatifaS Aroccurs,
ET
N
2
0
⧧
obtained (entry 7, Table 1). Moreover, the effect of
photostimulation was evaluated using a fluorescent lamp (250
W), giving full conversion and a slight increase of the yield of 4b
N
this transformation proceeds through a concerted mechanism
and not via a discrete nonaromatic Meisenheimer complex
2
0
t
(
46% yield, entry 8). Interestingly, use of NaO Bu, NaH, or
1
5
−
25
NBu OH in DMSO in the reaction with 3a did not provide 4a,
intermediate 7 . In order to justify the reactivity found only
4
while KHMDS in DMSO only provided 3a in 20% yield. In
addition, the reaction of indole 3a or 7-azaindole derivative 3c
with the potassium enolate, computational calculations were
made by adding discrete molecules of K or Na as counterions.
+
+
B
DOI: 10.1021/acs.orglett.8b03831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Tetracyclic Indoles and 7-Azaindoles (4a−n) through α-Arylation Reaction of 3-Acetyl-4-(2-
chloroaryl)indoles and 3-Acetyl-4-(2-chloroaryl)7-azaindoles (3a−n)
Scheme 3. Different Possible Mechanisms for α-Arylation Reaction of 3a (with MOM Protection)
C
DOI: 10.1021/acs.orglett.8b03831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
For both the K and Na salt, it was found that the C−C coupling
reactions are exergonic at ΔG = −59.0 and −53.0 kcal/mol,
respectively, with activation energies of 24.5 and 27 kcal/mol.
Even though these differences in activation energy are not large,
they agree with the reactivity shown experimentally.
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N
−
path C), where anion 7 represents the structure of the transition
state in the potential energy surface instead of a discrete
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2
(
4
(
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ASSOCIATED CONTENT
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(
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Supporting Information
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76−707.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03831.
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́
(
AUTHOR INFORMATION
■
*
*
*
Soc., Perkin Trans. 1 1997, 2413−2420.
(14) The NH protection with EOM is necessary before cyclization
reaction; indeed, the pKa of ketones and the NH are anticipated to be
close. In the presence of KO Bu, deprotonation will take place at both
sites and can give rise to unwanted side reactions.
Corresponding Authors
E-mail: rossi@fcq.unc.edu.ar.
E-mail: maurice.medebielle@univ-lyon1.fr.
E-mail: eugebuden@yahoo.com.ar.
t
(
15) See the Supporting Information.
ORCID
(16) For a related α-arylation, see: Emery, K.; Tuttle, T.; Murphy, J. A.
Tetrahedron 2016, 72, 7875−7887.
Roberto A. Rossi: 0000-0001-8659-082X
Maurice Med
Notes
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17) Guastavino, J. F.; Rossi, R. A. J. Org. Chem. 2012, 77, 460−472.
́
ebielle: 0000-0002-6032-4790
(18) Terrier, F. Modern Nucleophilic Aromatic Substitution, 1st ed.;
Terrier, F., Ed.; Wiley-VCH: Weinheim, 2013.
t
(
19)p-DNBreactedinthepresenceofKO BuinDMSOafter20minto
The authors declare no competing financial interest.
give the S Ar product.
N
(
20) Probably, the precursor 3b and/or the product 4b, inthe reducing
medium, decompose to other unidentified compounds.
21) As a reviewer suggested, it is known that enolates could form
aggregates in low polar solvents such as THF, and therefore, probably,
the yields of both reactions are lower than in DMSO.
ACKNOWLEDGMENTS
■
(
This work was supported in part by FONCYT, CONICET, and
SeCyT. Additional funding was provided by ECOS-MINCyT
No. A15E02), CNRS-CONICET (No. 248434), MESR (Ph.D.
fellowship to C.A.), CNRS, and Universite Claude Bernard Lyon
. The authors acknowledge anonymous reviewers for their
constructive suggestions.
(
(22) Probably, ET from the excited state of the enolate to the aryl
́
moiety is taking place as an initiation step.
(23)Emery,K. J.;Murphy,J.A.;Tuttle,T. Org. Biomol.Chem. 2017,15,
920−927 and references cited therein .
1
D
DOI: 10.1021/acs.orglett.8b03831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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26) We are not aware of any available electrochemical data of 4-
halogenoindoles and 4-halogeno-7-azaindoles.
(
E
DOI: 10.1021/acs.orglett.8b03831
Org. Lett. XXXX, XXX, XXX−XXX