Bromo- or Methoxy-Group-Promoted Umpolung Electron Transfer Enabled, Visible-Light-Mediated Synthesis of 2-Substituted Indole-3-glyoxylates

Article abstract of DOI:10.1021/acs.orglett.8b02725

A visible-light-mediated radical tandem cyclization of ortho-isocyano-α-bromo cinnamates to 2-substituted indole-3-glyoxylates is achieved by formation of both C-C/C-S and C-O bonds. The reaction proceeds through a hitherto unprecedented bromine- or metho

Full text of DOI:10.1021/acs.orglett.8b02725

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bromo- or Methoxy-Group-Promoted Umpolung Electron Transfer
Enabled, Visible-Light-Mediated Synthesis of 2‑Substituted Indole-
3-glyoxylates
Adiyala Vidyasagar, Jinwei Shi, Peter Kreitmeier, and Oliver Reiser*
̈
University of Regensburg, Institute of Organic Chemistry, Universitatsstr. 31, 93053, Regensburg, Germany
S
* Supporting Information
ABSTRACT: A visible-light-mediated radical tandem cyclization of ortho-isocyano-α-bromo cinnamates to 2-substituted
indole-3-glyoxylates is achieved by formation of both C−C/C−S and C−O bonds. The reaction proceeds through a hitherto
unprecedented bromine- or methoxy-group-promoted umpolung back electron transfer from an α-carbonyl radical to the
photocatalyst. This method allows preparation of diverse 2-arylated or 2-thioarylated indole-3-glyoxylates. The glyoxylate group
installed in the products can be utilized for several biologically relevant manipulations.
itrogen-containing heterocyclic compounds, and in
quenching cycle of a ruthenium-based photocatalyst.11 In
Nparticular indoles, are prevalent structures in many contrast, the radical intermediate A is difficult to oxidize
(Figure 1c, Path A, E° = +1.85 V vs SCE)12 due to the
generation of a positive charge adjacent to the carbonyl group.
The latter, however, is necessary when radicals are generated
by the commonly encountered oxidative quenching cycle of a
photocatalyst to keep the catalytic photoredox system alive.
A suitable modification of the cinnamyl ester group could
allow such an umpolung in a photoredox process. Thus,
moving to the readily available α-bromo cinnamates 2a, we
questioned if the extra bromo group introduced might allow
oxidation (umpolung electron transfer) of radical A by altering
its redox potential and/or stabilizing the carbocation formed
next to the carbonyl center to complete the photoredox cycle.
Thus, we envisioned that the synthesis of indol-3-glyoxylates
should become directly possible, generating a moiety which
has been proven to be versatile for the generation of a great
variety of functional groups13 (diols, amino alcohols, amino
acids; Figure S4, Supporting Information (SI)) that would be
useful for the synthesis of various indole-based bioactive
compounds. Especially maleimide derivatives are readily
accessible from indol-3-glyoxylates, which have several bio-
logical activities viz. cyclin D1/CDK4,14 Angiogenisis,15
Protein Kinase C,16 and Mdm2 inhibition properties.17
natural alkaloids and biologically important pharmacophores.1
Among them, 2-(2-phenyl-1H-indol-3-yl)acetic acids represent
a prominent subclass, which exhibit a wide range of biological
activities.2 The importance of these molecules is reflected in
the number of synthetic methods developed over the past
years,3 and especially o-alkenylarylisonitriles have been popular
precursors for construction of the indol-3-acetic acid frame-
work.4 Related to our work described here, Fukuyama et al.
disclosed a Bu3SnH-mediated radical reaction of o-alkenylar-
ylisonitriles to synthesize 2-stannylated indole derivatives
(Figure 1a).5 This method has gained much attention, being
manifested in several indole-based natural product syntheses.6
Later, Chatani et al. developed a tin-free, copper-catalyzed
method to synthesize 2-borylated derivatives (Figure 1a).7
Both methods subsequently allow a palladium-mediated
coupling to attain 2-substituted indoles. Very recently, Jamison
and co-workers developed a copper-catalyzed method to
cyclize 1 with arylboronic acids to obtain the corresponding
2-arylated indole derivatives.8
Visible-light photocatalysis9 has emerged as a powerful tool
for the generation of radicals and thus might provide an
alternative to achieve the title reaction in a step economic way
without the need to use stoichiometric amounts of boron or tin
reagents. Radical addition onto 1 followed by 5-exo-trig
cyclization provides an α-carbonyl radical intermediate A
(Figure 1b, c), which can be easily reduced to its enolate10
(Figure 1c, path B). Very recently, this pathway has been
demonstrated with the cyclization of 1 induced by visible-light-
mediated generation of P-radicals utilizing a reductive
Given that α-bromo cinnamates are capable substrates
themselves in accepting electrons in a visible-light-mediated
photoredox process (e.g., Ered (2a) = −1.33 V vs SCE),18 the
redox potentials of an external radical generated by an SET
Received: August 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02725
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
yield (%)
b
1
Eosin Y
[Ir{(dtbbpy)(ppy)2}]PF6
[Ru(bpy)3Cl2]
[Cu(dap)2]Cl
Ir(ppy)3
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
No catalyst
37
41
38
21
42
69 (66 )
ND
25
2
3
4
b
5
6
c
d
7
e
8
f
9
28
36
29
g
10
11
a
Reaction conditions: 2a (0.25 mmol), photocatalyst (1 mol %),
aryldiazonium salt (2 equiv), H2O (2 equiv), irradiation at 455 nm for
12 h; NMR yields with diphenylmethane as an internal standard.
b
c
d
e
Irradiation at 530 nm. Isolated yield. No light. 1 equiv of
f
g
aryldiazonium salt. No water added. 1 equiv of H2O. ND: not
detected.
produce diverse arylated indole derivatives 3a−t (Scheme 1),
which were confirmed by NMR and MS data and further by
the X-ray structure of 3b.
a
Scheme 1. Arylation Substrate Scope
Figure 1. Previous known methods for indole synthesis from o-
alkenylaryl isonitriles and present method.
must be carefully matched. Thus, we have initially chosen aryl
diazonium salts as aryl radical precursors with a relatively low
reduction potential (Ered = −0.03 to −0.5 V vs SCE),19 which
can be reduced by many common photocatalysts.
Indeed, treating 2a with 4-fluorophenyl diazonium tetra-
fluoroborate20 in the presence of various common photoredox
catalysts (1 mol %, Table 1, entries 1−6) and H2O as a
terminal nucleophile resulted in the complete consumption of
the starting material after 12 h, and 2-(4-fluorophenyl)-indole-
3-glyoxylate (3a) was obtained. [Ir{dF(CF3)ppy}2(dtbbpy)]-
PF6 (EIr(IV)/Ir(III)* = −0.89 V vs SCE; EIr(III)/Ir(IV) = +1.69 V vs
SCE; dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethyl-
pyridine, dtb-bpy = 4,4′-di-tert-butyl-2,2′-dipyridyl; Table 1,
entry 6) performed best, giving rise to 3a in 66% isolated yield,
which is attributed to its high oxidation potential necessary to
achieve the oxidation of an α-carbonyl radical intermediate of
type A (Figure 1b,c). It is noteworthy that the reaction also
proceeds without a photocatalyst, albeit with significantly
reduced yield, suggesting that the reaction can also be carried
on via a radical chain process (Table 1, entry 11). Attempts to
increase the reaction yield by varying the amount of diazonium
salt, water or replacing the latter by alcohols to avoid
hydrolysis of the isontrile that was observed as a competing
process were not successful (Table S2, Supporting Informa-
tion).
a
Reaction conditions: see Table 1, isolated yields.
With the optimized reaction conditions in hand, we explored
the substrate scope: a variety of substituted isonitriles (2a−f)
could be transformed into the corresponding indole deriva-
tives. Both electron-withdrawing and -donating groups
containing aryl diazonium salts reacted smoothly with 2 to
To extend the scope of this reaction, thiyl radicals, generated
from the corresponding disulfides,21 underwent the analogous
reaction with 2a−f to provide 2-aryllthio-indole-3-glyoxylates
4a−h (Scheme 2). This transformation is oxygen sensitive.
Proper degassing is required to avoid the formation of 3-
B
DOI: 10.1021/acs.orglett.8b02725
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Letter
bromo-2-quinolones as a side product (Scheme S3, Supporting
Information).
Scheme 3. Functionalization of Indole 3-Glyoxylate
Derivatives and Application in Synthesis Benzodiazepine
Receptor Ligand
a
Scheme 2. Aryl Thiiyl Substrate Scope
a
Reaction conditions: 2a−f (0.25 mmol), diaryl disulfide (2 equiv),
H2O (2 equiv), and irradiation at 455 nm for 48 h, isolated yields.
Besides many transformations known for the functionaliza-
tion of indole-3-glyoxylates13−17 (Figure S4, Supporting
Information), the selective reduction of this moiety is possible
as demonstrated for derivatives 3a and 3h, thus bridging
glyoxylates 3 to the likewise medicinally important 2-(2-
phenyl-1H-indol-3-yl)acetic acids of type 5 (Scheme 3a). The
exhaustive reduction of 3h with LiAlH4 provided alcohol 6 in
69% yield (Scheme 3a), which can be converted into
differently functionalized furoindolines 7.22
Scheme 4. Plausible Reaction Mechanism
Indole-3-glyoxylamide derivatives are well-known ligands for
peripheral benzodiazepine receptor (translocator protein) at
nanomolar/subnanomolar concentrations and stimulators for
steroid biosynthesis in rat C glioma cells.23 Aiming for the
synthesis of a representative member of this compound class,
we converted the carboxylic ester in 8 to an amide 11 via the
carboxylic acid 9, which unexpectedly was accompanied by an
exchange of Br for OMe (Scheme 3b). Alternatively, 9 was
synthesized in three steps from ortho-nitrotoluene on a 10 g
scale, avoiding the use of ethyl bromoacetate, which is a potent
lacrymator (see SI). Gratifyingly, the methoxy group can take
the role of bromo, and thus, the photocyclization of 11 with 4-
fluorobenzenediazonium tetrafluoroborate under optimized
conditions previously established furnished 12 in 50% yield
on a 2.5 mmol scale (Scheme 3b). Likewise, the photoreaction
of 11 with PhSSPh to 13a proceeded smoothly, but in this case
13b was identified as a byproduct, which arises by H atom
transfer from the radical intermediate II (Scheme 4).
exo-trig cyclization to produce intermediate II, i.e., an α-
carbonyl radical.25 In general, radicals next to a carbonyl center
(E° = +1.85 V vs SCE)12 resist oxidation; however, the
tactically introduced bromo or methoxy group can now reverse
the electron flow (umpolung), thereby closing the photoredox
cycle.
A plausible mechanism for the reaction can be proposed
(Scheme 4) in agreement with control experiments that were
carried out. Upon excitation of the iridium photocatalyst by
visible light, an electron transfer to the radical precursor (aryl
diazonium salt or diaryl disulfide) occurs to generate a radical
R1·, which adds onto the isonitrile (2a or 10) to produce
imidoyl radical I.24 The imidoyl radical then undergoes a 5-
When the reaction was performed between compound 1,26
having no bromine group in the cinnamate moiety, and p-tolyl
disulfide, only the formation of 14a and 14b occurred in minor
amounts (Scheme 5a and Figure S3, Supporting Information),
C
DOI: 10.1021/acs.orglett.8b02725
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Scheme 5. Mechanistic and Control Experiments
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Oliver.Reiser@chemie.uni-regensburg.de.
ORCID
Oliver Reiser: 0000-0003-1430-573X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (GRK 1626 Photocatalysis), the Alexander von
Humboldt Foundation (fellowship for A.V.), and the China
Scholarship councel (CSC, fellowship for J.S.). We are also
thankful to the following colleagues (all University of
Regensburg): Dr. Santosh Pagire and Mr. Asik Hossain for
fruitful discussions, Ms. B. Hischa for carrying out the X-ray
crystal structure analyses of 3b and 4g, and Mrs. R. Hoheisel
for cyclic voltammetry measurements.
again proving that the role of the bromo group in the back
electron transfer process to the catalyst or to substrate serving
as the radical precursor is crucial. HRMS of the product 3h
formed with 18O enriched water (Scheme 5b and Figure S2,
Supporting Information) showed a high level (>50%) of
incorporation of 18O in to the product, confirming that the
resulting radical II is oxidized to carbocation III and
subsequently trapped with H2O. Successive elimination of
H+ and HBr followed by tautomerization via intermediate IV
results in formation of the product. We assume that the
oxidation of II to III is more facile for the bromo containing
starting materials 2 compared to methoxy compound 11 since
a reduced product such as 13b formed by H-abstraction
(PhSH as H-donor via PhSSPh → PhS· + PhS− → PhSH) is
not observed in the sequence of 2 to 4 (Scheme 2).
In conclusion, we have developed a photoredox-mediated
radical process to synthesize 2-aryl or 2-phenylthio-indole-
ethyl-3-glyoxylates. We propose that a bromine-/methoxy-
group-promoted umpolung electron transfer from an α-
carbonyl radical (oxidation) to the photocatalyst or to the
radical precursor is the driving force for the reaction to occur.
The present method shows a uniquely different method for the
utilization of vinyl bromides in photoredox catalysis beyond
the generation of vinyl radicals. The synthesized derivatives are
important building blocks for many natural products and
pharmaceutically important compounds. The glyoxylate func-
tional group can be utilized for further manipulations to install
different groups onto the indole core.
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