Merger of Visible-Light Photoredox Catalysis and C-H Activation for the Room-Temperature C-2 Acylation of Indoles in Batch and Flow

Article abstract of DOI:10.1021/acscatal.7b00840

A mild and versatile protocol for the C-H acylation of indoles via dual photoredox/transition-metal catalysis was established in batch and flow. The C-H bond functionalization occurred selectively at the C-2 position of N-pyrimidylindoles. This room-temperature protocol tolerated a wide range of functional groups and allowed for the synthesis of a diverse set of acylated indoles. Various aromatic as well as aliphatic aldehydes (both primary and secondary) reacted successfully. Interestingly, significant acceleration (20 to 2 h) and higher yields were obtained under micro flow conditions.

Full text of DOI:10.1021/acscatal.7b00840

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Letter
Merger of Visible Light Photoredox Catalysis and C–H Activa-tion for
the Room Temperature C-2 Acylation of Indoles in Batch and Flow
Upendra K. Sharma, Hannes P.L. Gemoets, Felix Schröder, Timothy Noël, and Erik V. Van der Eycken
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017
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ACS Catalysis
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Merger of Visible Light Photoredox Catalysis and C–H Activa-
tion for the Room Temperature C-2 Acylation of Indoles in
Batch and Flow
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Upendra K. Sharma‡,a, Hannes P. L. Gemoets‡,c, Felix Schrödera, Timothy Noël*,c and Erik V. Van der
Eycken*,a,b
aLaboratory for Organic & MicrowaveꢀAssisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU
Leuven), Celestijnenlaan 200F, Bꢀ3001, Leuven, Belgium. erik.vandereycken@chem.kuleuven.be
bPeoples Friendship University of Russia (RUDN University) 6 MiklukhoꢀMaklaya street, Moscow, 117198, Russia.
cDepartment of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University
of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands. t.noel@tue.nl
ABSTRACT: A mild and versatile protocol for the C−H acylation of indoles via dual photoredox/transitionꢀmetal catalysis was
established in batch and flow. The C−H bond functionalization occurred selectively at the Cꢀ2 position of Nꢀpyrimidylindoles. This
room temperature protocol tolerated a wide range of functional groups and allowed for the synthesis of a diverse set of acylated
indoles. Various aromatic as well as aliphatic aldehydes (both primary and secondary) reacted successfully. Interestingly, signifiꢀ
cant acceleration (20 h to 2 h) and higher yields were obtained under micro flow conditions.
KEYWORDS: C−H acylation, Photocatalysis, dual catalysis, Palladium catalysis, indoles, flow chemistry.
With the genesis of transition metalꢀcatalyzed C–H activation
strategies,1,2 direct Csp2–H bond acylation has witnessed a
substantial growth over the past decade.3,4 Despite extensive
progress in the field, the low reactivity and limited selectivity
continue to be the two main bottlenecks in this field. Thereꢀ
fore, the development of mild and widely applicable C–H acꢀ
ylation methodologies are of relevant importance.3c
Figure 1: Natural products containing 2ꢀacylindole framework.
Recently, visible light photoredox catalysis has played a treꢀ
mendous role for the translation of single electron transfer
processes into mild catalytic cycles. Its popularity stems from
the access to unique synthetic pathways which have previously
been elusive.5 More specifically, the power of singleꢀelectron
transfer processes enabled by photoredox catalysis has providꢀ
ed new opportunities for transition metal catalyzed crossꢀ
coupling reactions.6,7 In addition, these dual catalytic strategies
allow to carry out the reaction at room temperature.
However, to the best of our knowledge, aldehydes, while beꢀ
ing the most abundant acyl surrogates, have never been invesꢀ
tigated for the C–H acylation of (hetero)arenes via dual photoꢀ
redox/palladium catalysis at room temperature. This prompted
us to develop a novel methodology with aldehydes as acyl
surrogates for the direct Cꢀ2 acylation of indoles at ambient
temperature by merging visible light photoredox catalysis and
C–H activation.
(Hetero)arylketones are important structural components preꢀ
sent in various natural products, pharmaceuticals and organic
materials (Figure 1).8 Palladiumꢀcatalyzed, ligandꢀdirected C–
H acylations of (hetero)arenes with aldehydes, alcohols or
toluene as acyl surrogates have been described over the past
decade as a powerful and versatile tool in organic chemistry.9
In these examples, the PdII and PdIV catalytic cycle appears to
be the major pathway and utilizes stoichiometric amounts of
oxidants in combination with elevated reaction temperatures to
enable the desired transformation.
More recently, single electron transfer pathways have been
investigated to generate acyl radicals under mild reaction conꢀ
ditions.10 Hereto, αꢀketoacids have been explored as acyl radiꢀ
cal precursors to enable the room temperature acylation of aryl
rings via a dual photoredox/palladium catalytic strategy.11
We commenced our investigations with the C–H acylation of
Nꢀpyrimidylindole (1a) using 4ꢀmethylbenzaldehyde (2b) as a
coupling partner under standard batch conditions (See Supꢀ
porting Information, Table S1). In the presence of Pd(OAc)2
(10 mol%), Ru(bpy)2Cl2 (2 mol%), PivOH (50 mol%) and
TBHP (4 equiv.) in acetonitrile (ACN, 0.1 M) under argon,
and exposed to a 24W CFL light source, we were pleased to
1
find selectively the Cꢀ2 acylated product 3b with a 75% Hꢀ
NMR yield after 20 h. Prolonged reaction times resulted in a
further increase in yield up to 84% after 36 h. Further optimiꢀ
zation was carried out employing 4ꢀfluorobenzaldehyde (2i) in
combination with a more efficient 3.12W blue LED (λmax
=
465 nm) light source (Table 1). When screening different phoꢀ
tocatalysts, facꢀ[Ir(ppy)3] was found to be superior
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Table 1: Optimization of reaction conditions in batch for the
Cꢀ2 acylation of indoles.a
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8
F
Pd(OAc)2 (10 mol%)
fac-[Ir(ppy)3] (2 mol%)
Boc-Val-OH (20 mol%)
TBHP (4.0 equiv)
N
CHO
N
+
O
N
N
ACN (0.1M)
Blue LED, Ar atm
room temp, 20h
N
F
N
1a
2i
3i
(2.0 equiv.)
19FꢀNMR
Entry
Changes to standard conditions
9
Yield (%)
73 (72)
70 (66)
26
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1
2
none
Ru(bpy)3Cl2, 36 h
facꢀ[Ir(dFꢀppy)3]
facꢀ[Ir(ppy)2(dtbpy)]PF6
[Ir(dFꢀCF3ꢀ ppy)2(dtbpy)]PF6
[MesꢀAcr]ClO4
no ligand
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Figure 2: Yield vs time plot for the direct Cꢀ2 acylation of Nꢀ
pyrimidylindole (1a) with 4ꢀfluorobenzaldehyde (2i).
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(72% vs 89%) can be attributed to the homogeneous irradiaꢀ
tion of the reaction mixture.
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PivOH
73
9
AcꢀIleꢀOH
71
With optimized reaction conditions in hand, we evaluated the
scope of the reaction (Table 2). The acylation reaction toleratꢀ
ed a wide variety of substituents on the benzaldehyde coupling
partner. Indole acylation with benzaldehyde (3a) and aldeꢀ
hydes bearing alkyl/aryl substituents (3b, 3c, 3d), were well
tolerated and high yielding (70ꢀ88% yield). When using the
sterically demanding mesitaldehyde (3e), a moderate yield of
44% was obtained. Bearing an electron donating substituent
(4ꢀOMe), substrate 3f afforded excellent isolated yields of
73% and 79% in batch and flow respectively. Moreover, it was
demonstrated that benzaldehydes bearing a free hydroxyl
group (3g, 3h) showed some reactivity (22ꢀ44%). Aldehydes
containing electron withdrawing groups such as 4ꢀF (3i), 4ꢀ
CF3 (3j), 4ꢀBr (3k), 3ꢀNO2 (3o) and 4ꢀCN (3p) all gave the
desired product in good yield (54ꢀ89%). However, 3ꢀ
bromobenzaldehyde (3l) gave a lower yield (28%), while 4ꢀ
nitrobenzaldehyde (3n) did not yield any product. Furtherꢀ
more, 3ꢀiodobenzaldehyde (3m) gave a moderate yield (53ꢀ
56%).
The latter example together with 3g and 3h (free hydroxyl
functionality) showcase the mild character of our room temꢀ
perature protocol, since such functional group tolerability is
unprecedented for the high temperature C–H acylation protoꢀ
cols of (hetero)arenes. Moreover, functional handles such as
iodine provide opportunities for further decoration of the molꢀ
ecule (e.g., via crossꢀcoupling).
Subsequently, relevant heterocyclic aldehydes were explored
as potential acyl source. Reactions with furfural (3q) and theꢀ
naldehyde (3s) were both high yielding in batch as well as in
flow (68ꢀ85%). Interestingly, 5ꢀhydroxymethylfurfural (3r), a
versatile platform chemical,17 showed some reactivity albeit
with a lower isolated yield (34%).
10
11
AcꢀValꢀOH
68
BocꢀIleꢀOH
70
aReaction conditions: 0.5 mmol of Nꢀpyrimidylindole, 10 mol%
Pd(OAc)2, 2 mol% facꢀ[Ir(ppy)3], 20 mol% BocꢀValꢀOH, 2.0
equiv. of 4ꢀfluorobenzaldehyde and 4.0 equiv. TBHP in ACN
(0.1 M) for 20 h, blue LED light, isolated yield in parentheses.
(Table 1, Entries 1ꢀ5). The use of an organic dye, such as 9ꢀ
mesitylꢀ10ꢀmethylacridinium perchlorate ([MesꢀAcr]ClO4),
resulted in a modest yield of 38% (Table 1, Entry 6). Furtherꢀ
more, replacing PivOH with monoꢀprotected amino acids
(MPAA) as ligands12 resulted in an improved reactivity and
avoided the observed induction period (Table 1, Entries 8ꢀ11
and Figure 2). Optimal reactivity was observed using Bocꢀ
protected Lꢀvaline: a yield of 73% was obtained within 20 h
under blue light irradiation (Figure 2).
One of the major limitations of photochemical transformations
in batch is the soꢀcalled light attenuation effect through abꢀ
sorbing media as dictated by the BouguerꢀLambertꢀBeer law.
This becomes especially apparent when the reaction is scaled
by increasing the reactor dimensions. However, such limitaꢀ
tions can easily be overcome by using continuousꢀflow capilꢀ
laries.13 These reactors allow for homogeneous irradiation of
the reaction mixture and thus leads to a reduction in reaction
time, a lower catalyst loading and an optimal scalability.14,15
Bearing this in mind, we developed a photomicroreactor asꢀ
sembly consisting of a 3D printed holder containing a 3 mL
perfluoroalkoxy alkane capillary reactor (PFA, I.D. 750 µm,
see ESI Picture S1) in order to investigate our Cꢀ2 acylation
protocol in micro flow.16 Translating the optimal batch reacꢀ
tion conditions to flow yielded 34% of the desired product 3i
within 2 h residence time (see ESI, Table S2, entry 5). Addiꢀ
tional flow optimization showed that the iridium loading could
be decreased four times (0.5 mol%) while the concentration
could be doubled (0.2 M) without any loss of reactivity. Furꢀ
thermore, with 4 equiv. of 2i and 6 equiv. of TBHP, an imꢀ
proved isolated yield of 89% was obtained for 3i (see Table 2).
This dramatic improvement in the reaction rate (20 h vs 2 h)
and yield
Next, we explored the potential of aliphatic aldehydes to enꢀ
gage in the direct Cꢀ2 acylation protocol. Primary aliphatic
aldehydes such as (ꢀ)ꢀcitronellal (3t) and 7ꢀhydroxycitronellal
(3u) gave high to excellent yields (up to 95%). Notably, when
using cyclohexanecarboxaldehyde (2v) as a branched aldeꢀ
hyde, no decarbonylation was observed, despite the fact this
side reaction was described in the literature.18
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Table 2: Batcha and Flowb scope.
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aReaction conditions batch: 1.0 mmol of Nꢀpyrimidylindole, 10 mol % Pd(OAc)2, 2 mol % facꢀ[Ir(ppy)3], 20 mol % BocꢀValꢀOH, 2.0
equiv. of aldehyde and 4.0 equiv. TBHP in ACN (0.1 M), blue LED light, 20h reaction time; Reaction conditions flow: 1.0 mmol of Nꢀ
b
pyrimidylindole, 10 mol % Pd(OAc)2, 0.5 mol % facꢀ[Ir(ppy)3], 20 mol % BocꢀValꢀOH, 4.0 equiv. of aldehyde and 6.0 equiv. TBHP in
c
d
ACN (0.2 M), blue LED light, 2h residence time; reported yields are isolated yields; 3h residence time, 8.0 equiv. TBHP; 4.36 mmol
scale. e<2.5 equiv. of aldehyde (due to limited solubility), 29% starting material recovered.
Instead, the acyl radical could be successfully trapped, renderꢀ
ing the desired product 3v in a high yield (81%). NꢀBocꢀ
piperidineꢀ4ꢀcarboxaldehyde (3w) gave a moderate yield of
54% in flow conditions. The lower yield was mainly due to the
limited solubility of the aldehyde in the reaction mixture.
However, the use of Bocꢀprolinal as a coupling partner did not
yield any product (3x).
In general, it was observed that, in addition to the reduced
reaction time and lower catalyst loadings, the obtained isolated
yields were higher under micro flow conditions when comꢀ
pared to the batch counterparts. Moreover, in order to demonꢀ
strate the practical utility of the developed protocol, a continuꢀ
ousꢀflow gramꢀscale experiment with Nꢀpyrimidylindole (1a)
and (ꢀ)ꢀcitronellal (2t) was carried out. With a simple numꢀ
beredꢀup scaleꢀup procedure19 (2 x 3mL photomicroreactors),
1.41g (93%) of isolated product 3t could be obtained in less
than 9 hours of operation time (2h residence time). Finally, the
scope of various indole derivatives was evaluated with substitꢀ
uents on the 3, 5, 6 and 7 position (4aꢀ4e). Moderate to good
yields (55ꢀ75%) were obtained for the latter substrates. Moreꢀ
over, among different Nꢀsubstitution or directing groups evalꢀ
uated, the Nꢀpyrimidyl group proved to be superior (4fꢀ4h).
Encouraged by the obtained results, we further investigated
the possibility of using benzyl alcohols as acylation reagents.
Benzyl alcohols can be readily oxidized into the corresponding
benzaldehydes in the presence of the oxidant TBHP.20 As
shown in Scheme 1a, benzyl alcohol with 4ꢀOMe (5a) or 4ꢀF
(5b) as substituent, could be successfully used as acyl surroꢀ
gates, rendering 3f and 3i in 57% and 66% respectively. To
further enhance the synthetic utility of this process, facile reꢀ
moval of the Nꢀpyrimidyl group was carried out in a traceless
fashion using sodium methoxide in DMSO for 24 h at 100 oC,
with an overall yield of 73% 3ff (Scheme 1b).
In order to gain more insight into the reaction mechanism,
some control experiments were carried out (Scheme 2). When
the reaction was carried out with 1a and 2i in absence of phoꢀ
tocatalyst, TBHP or light, only traces of acylated product were
observed (Scheme 2a). Moreover, upon the addition of radical
scavengers, such as 2,2,6,6ꢀtetramethylpiperidylꢀ1ꢀoxyl
(TEMPO) or butylated hydroxytoluene (BHT) to the reaction
mixture, suppression of the reaction is taking place, suggesting
that a SETꢀtype mechanism is at hand. Moreover, the mass of
the trapped acyl radical with TEMPO (Scheme 3, 2i'') was
detected via GCꢀMS analysis.
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Scheme 1: a) evaluation of benzyl alcohols as acyl surroꢀ
gates; b) traceless deprotection.
Finally, kinetic isotope experiments (KIE) of 1a and its deuꢀ
terated analogue 1aꢀD1 were performed under optimized conꢀ
ditions revealing a noticeable KIE effect (kH/kD = 3.4, Scheme
2b). This indicates that the C–H bond cleavage might be the
rate limiting step.21 Based on our observations and analogous
literature precedents,7,9,11 a plausible reaction mechanism was
proposed (Scheme 3). The reaction starts with the formation of
a five membered palladacycle A. Meanwhile, an acyl radical is
generated via the photocatalytic process. Herein, the photoexꢀ
citation of the photocatalyst produces the excited state (Ir3+*),
which is oxidatively quenched by t-BuOOH to generate the
key radical intermediate tꢀBuO·. Next a hydrogen abstraction
occurs between the tꢀBuO· radical and 4ꢀfluorobenzaldehyde
(2i) to afford the acyl radical 2i’. The acyl radical 2i′ is then
trapped by the palladacycle A which results in the formation
of intermediate B. Intermediate B can undergo a single elecꢀ
tron oxidation to PdIV, which closes the photocatalytic cycle
via a back electron donation. Finally, a reductive elimination
takes place, releasing the desired product 3i and regenerating
the PdII catalyst. Further efforts towards a detailed mechanistic
understanding of this transformation is currently pursued in
our labs.
Scheme 3: Proposed Pd(II)/Pd(IV) cycle for the Cꢀ2 acylaꢀ
tion of indoles.
ꢀtended from aromatic to both primary and secondary aliphatic
aldehydes with good to excellent yields. Moreover, continuꢀ
ousꢀflow chemistry proved its effectiveness by decreasing the
reaction time up to 10 times (2h vs 20h), the catalyst loading 4
times (0.5 mol % vs 2 mol %), increasing the yields and scalꢀ
ing the reaction conditions. In addition, the scope could be
further extended to benzyl alcohols as abundant acyl surroꢀ
gates. Finally, KIE experiments suggest the C−H activation to
be the rate limiting step.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
Complete experimental details and characterization data for the
synthesized compound (PDF).
AUTHOR INFORMATION
Corresponding Author
*erik.vandereycken@chem.kuleuven.be
*t.noel@tue.nl.
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
UKS is thankful to University of Leuven for a postdoctoral felꢀ
lowship and University of Eindhoven for allowing a visiting postꢀ
doc tenure. FS is grateful to Flanders Innovation & Entrepreneurꢀ
ship (VLAIO) for providing a PhD scholarship. We acknowledge
the support by COST (European Cooperation in Science and
Technology) Action (CA15106) CHꢀActivation in Organic Synꢀ
thesis. The publication was financially support by The Ministry of
Education and Science of the Russian Federation (the Agreement
number 02.a03.0008). Financial support is also provided by the
Scheme 2: a) Control experiments; b) KIE experiments.
In summary, a room temperature Cꢀ2 acylation protocol for
indoles was developed via a productive merger of visible light
photoredox catalysis and C–H functionalization. The reaction
was conducted both in batch and flow and is compatible with a
wide variety of functional groups. The protocol could be exꢀ
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54, 1625ꢀ; g) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science
Dutch Science Foundation (NWO) via an ECHO grant (Grant No.
2014, 345, 433ꢀ436; h) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc.
2012, 134, 9034ꢀ9037; i) Kalyani, D.; McMurtrey, K. B.; Neufeldt, S.
R.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 18566ꢀ18569.
8. a) Shiri, M. Chem. Rev. 2012, 112, 3508–3549; b) Kochanꢀ
owskaꢀKaramyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489–
4497; c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103; d)
Sundberg, R. J. Indoles, Academic, New York, 1996.
9. For selected examples on the Cꢀ2 acylation of (hetero)arenes, see
a) Kumar, G.; Sekar, G. RSC Adv. 2015, 5, 28292ꢀ28298; b) Wang,
W.; Liu, J.; Gui, Q.; Tan, Z. Synlett 2015, 26, 771ꢀ778. c) Li, C.; Zhu,
W.; Shu, S.; Wu, X.; Liu, H. Eur. J. Org. Chem. 2015, 3743–3750; d)
Yan, X. ꢀB.; Shen, Y. ꢀW.; Chen, D. ꢀQ.; Gao, P.; Li, Y. ꢀX.; Song, X.
ꢀR.; Liu, X. ꢀY.; Liang, Y. ꢀM. Tetrahedron 2014, 70, 7490ꢀ7495. e)
Pan, C.; Jin, H.; Liu, X.; Cheng, Y.; Zhu, C. Chem. Com-
713.013.001) and a VIDI grant for T.N. (Grant No. 14150).
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ABBREVIATIONS
nd = not detected; TBHP = tertꢀbutyl hydroperoxide; PFA = perꢀ
fluoroalkoxy alkane; ACN = acetonitrile.
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