Photo Click Reaction of Acylsilanes with Indoles

Article abstract of DOI:10.1002/anie.202101689

Light-mediated coupling of acylsilanes with indoles is reported. This photo click reaction occurs under mild conditions (415 nm) mostly in quantitative yield and provides stable silylated N,O-acetals via light mediated siloxycarbene generation with subsequent indole-N-H insertion. We show that this very efficient and fully atom economic coupling process can be applied to conjugate complex systems, as documented by the clicking of carbohydrates with indole alkaloids. The method is also applicable to the conjugation of polymer chains. The linking acetal moiety can be readily cleaved and it is also shown that wavelength-selective coupling and cleavage with acyl silanes bearing a second photoactive moiety is possible. This is documented by a successful polymerization/depolymerization sequence and by a polymer folding/unfolding process.

Full text of DOI:10.1002/anie.202101689

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Accepted Article
Title: Photo Click Reaction of Acylsilanes with Indoles
Authors: Constantin Stuckhardt, Maren Wissing, and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202101689
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10.1002/anie.202101689
Angewandte Chemie International Edition
RESEARCH ARTICLE
Photo Click Reaction of Acylsilanes with Indoles
Constantin Stuckhardt, Maren Wissing and Armido Studer*
[a]
C. Stuckhardt, M. Wissing and Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of the document.
Abstract: Light-mediated coupling of acylsilanes with indoles is
reported. This photo click reaction occurs under mild conditions
(415 nm) mostly in quantitative yield and provides stable silylated
N,O-acetals via light mediated siloxycarbene generation with
subsequent indole-N−H insertion. We show that this very efficient
and fully atom economic coupling process can be applied to
conjugate complex systems, as documented by the clicking of
carbohydrates with indole alkaloids. The method is also applicable
to the conjugation of polymer chains. The linking acetal moiety can
be readily cleaved and it is also shown that wavelength-selective
coupling and cleavage with acyl silanes bearing a second
photoactive moiety is possible. This is documented by a successful
polymerization/depolymerization sequence and by a polymer
folding/unfolding process.
curing.[21] The ability to generate reactive carbenes which can
undergo fast insertion reactions with high selectivity by visible
light irradiation, along with their ready access render
acylsilanes promising candidates as reactive functionalities in
materials chemistry. Moreover, light-mediated siloxycarbene
generation from an acylsilane is a reversible process.[22] The
reversible nature of the silyl migration provides the reactive
siloxycarbene a formal longer life-time as compared to the life-
time of carbenes generated by other methods. This fact will be
of high importance for X−H insertions in the area of materials
science, where diffusion of the reaction partners may become
the limiting factor. Herein we report our first results on the
photo click reaction of acylsilanes with indoles.
Photochemistry has recently gained great attention in
synthetic chemistry and also in materials science, since light is
cheap, allows for spatiotemporal control and can be tuned in
terms of its wavelength and intensity, without producing any
waste.[1] These features render photochemistry highly valuable
in synthesis and light-mediated processes have also found
applications in biological chemistry.[2] Considering materials
science, systems bearing photoswitches[3] and photocleavable
functional groups[4] have been designed. Moreover, light-
mediated cycloaddition reactions[5] or photopolymerizations[6]
have been applied to the construction of novel materials. As
the irradiation wavelength can be easily varied, great efforts
have been devoted to the development of wavelength-
orthogonal processes,[7] for example in the polymer field,[8] in
surface science,[9] in supramolecular chemistry,[10] and even in
the context of photoredox catalysis.[11]
Encouraged by our recent studies on the use of acylsilanes
for light-mediated metal nanoparticle generation,[12] we
decided to apply such silanes as photolinkers for the mild
conjugation (click reaction[13]) of complex systems. Acylsilanes
feature an elongated bond between the carbonyl group and the
silyl moiety which is cleaved upon visible light irradiation (for
acylsilanes with a π-system in conjugation to the carbonyl
group).[14] Thereby, a siloxycarbene is generated, a reactive
intermediate whose utility in organic synthesis has been
studied. Synthetic applications of acylsilanes include additions
to carbon-carbon[15] or carbon-oxygen[16] multiple bonds as well
as to alkyl boronates,[17] among others.[18] Insertion of in situ
generated siloxycarbenes into hydrogen-heteroatom (H−X)
bonds have also been reported.[19] These H−X insertions
usually occur with high efficiency. Regarding materials science,
acylsilanes have only found limited applications, as light-
responsive polymerisation initiators[20] and for visible light
Scheme 1. A) Insertion of siloxycarbenes generated from acylsilanes into
H−X bonds of alcohols and thiols provides unstable protected X,O-acetals.
B) Indole-derived silylated N,O-acetals show higher stability, reminiscent of
the stability of aminals 6.
We first investigated the insertion of the carbene 2
generated from benzoylsilane 1a upon 415 nm irradiation into
H−X bonds of alcohols and thiols and found, in agreement with
the literature[19], efficient formation of the corresponding O-silyl-
protected X,O-acetals 3 (Scheme 1 A). However, the insertion
products 3 were susceptible towards hydrolysis to give
1
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benzaldehyde (4, see SI). Upon storage (neat) and also in
solution in various solvents tested, decomposition of 3 was
observed and therefore these acetal functionalities are not
suitable as linking moieties in materials science. Motivated by
the mostly quantitative X−H insertion reaction of 2 we were
looking for reaction partners that lead to stable X,O-acetals and
identified the indole moiety as an ideal functionality. Hence,
blue light irradiation of a solution of an equimolar amount of
acylsilane 1a and indole in acetonitrile, THF or
dichloromethane afforded quantitatively the insertion
product 5a (Scheme 1 B). In contrast to the X,O-acetals 3,
TMS-protected hemiaminal 5a was bench stable for at least
several weeks and stable in solution in various solvents (in
benzene, in THF/D2O at 60 °C, in wet acetonitrile at 80 °C).
Slow decomposition was observed in acid-containing
chloroform and in wet DMSO at 100 °C. The improved stability
of 5a can be explained by the lower leaving group ability of the
indolide anion (pKa = 21 in DMSO[23]) as compared to the
alcoholates and thiolates in its congeners 3. Moreover, the
indole N-atom in 5a shows a low basicity leading to an
increased acetal stability towards acid hydrolysis. Our findings
are in line with the unusual high stability of pyrrolyl and indolyl
carbinols 6a and 6b (Scheme 1 C).[24] Besides the indole
functionality, a few other RX−H coupling partners can be used
although only the stability of amide-derived X,O-acetals can
compete with that of acetal 5a (see SI for detailed stability
studies). Of note, attempted insertion of 2 into the N−H bond of
aliphatic and aromatic amines failed, probably due to a
competing dark reaction.[25]
Scheme 2. Variation of the acylsilane. Reaction conditions: acylsilane
(0.1 mmol, 1.0 equiv), indole (0.1 mmol, 1.0 equiv.), CH3CN (2 mL), three 3
W 415 nm LED’s, room temperature. [a] Irradiation for 7.5 h in MeCN
(0.5 mL). [b] Irradiation for 60 min until full consumption of 1h.
If required, the N,O-acetal of type 5 can be readily
converted under mild conditions to the corresponding aldehyde
and indole. For example, treatment of 5a with CsF in
acetonitrile provided quantitatively benzaldehyde and indole.
Thus, the indole moiety can be protected and deprotected
under mild conditions in excellent yields in both directions. To
document the potential of this novel conjugation method, the
indole N−H insertion was applied to more complex systems.
The indole core is ubiquitous in organic chemistry and is found
in various alkaloids and also in drugs, making such compounds
viable targets for our method. Along these lines, we decided to
apply the N−H insertion to the conjugation of indole alkaloids
with the β-D-glucose derivative 8 (for the synthesis of 8, see
SI) and chose gramine (7), which is a simple natural product
occurring in maple and barley,[26] as a first substrate.
Pleasingly, 415 nm light irradiation of a solution of equimolar
amounts of 8 and gramine (7) gave the TMS-protected
We then investigated the scope with respect to the
acylsilane reagent in the reaction with indole (Scheme 2).
Pleasingly, the photochemical insertion proceeded well when
aroylsilanes bearing electron rich (1b), electron deficient (1c)
or sterically demanding (1d) aryl moieties were employed and
acetals 5b-5d were obtained in quantitative yields. With the
aliphatic acylsilane 1e, the insertion product 5e was formed in
64% yield, which was increased to 76% for insertion product 5f
hemiaminal
9
in >95% yield as
a
1:1 mixture of
diastereoisomers (Scheme 3). Reaction of 8 with the more
complex alkaloid pergolide (10), a well-known dopamine
agonist which is dispensed to patients with Parkinson’s
disease[27], under similar conditions worked equally well and
the targeted conjugate 11 was formed in excellent yield.
Deconjugation was documented on 9 by treatment with CsF in
acetonitrile to give the glucose derivative 8’ in 96% yield along
with gramine (7, 86%). The slightly reduced yield of recovered
7 was due to product loss during isolation.
bearing
a
triethylsilyl group. When employing the
corresponding acylsilane with a bulky diphenyl(tert-butyl)silyl
group, the corresponding insertion product could not be
separated from side products although crude NMR and high
resolution mass spectrometry confirmed the formation of the
acetal. Interestingly, the X−H insertion product is formed in
quantitative yield when phenol is used as coupling partner for
aliphatic acylsilanes (see SI). Benzoylsilanes 1g and 1h
bearing larger silyl substituents also engage in the reaction
with indole. For the triethylsilyl derivative, N−H-insertion
proceeded quantitatively (5g, 99%), whereas
a slightly
reduced yield was noted for the triisopropyl congener (5h,
90%).
2
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Scheme 3. Light-induced coupling of glucose derivative 8 with indole
alkaloids.
Having established that the light-mediated coupling works
efficiently on low molecular weight compounds, we further
applied the conjugation method to polymers. To this end,
various polymeric acylsilanes were prepared by living radical
polymerization (RAFT, see SI). Irradiation of the high
molecular weight homopolymer 12 (Mn ≈ 23.5 kg mol-1) in dry
CH2Cl2 in the presence of indole provided the poly-acetal 13
(Mn ≈ 24.7 kg mol-1, Scheme 4 A). Based on NMR analysis, a
quantitative transformation of the acylsilane moieties into the
corresponding acetal functionalities was achieved.[28]
Moreover, the method could be applied to the functionalization
of statistical copolymers. The methyl acrylate containing
copolymer 14a (Mn ≈ 7.3 kg mol-1) and the copolymer 14b (Mn
≈ 4.8 kg mol-1) bearing basic tertiary amino groups in their side
chains were both capped with indole quantitatively (15a, 15b,
Scheme 4 B). We also found quantitative coupling with an
amide functionality by capping the benzyl acrylate containing
copolymer 14c (Mn ≈ 20.1 kg mol-1) with N-methylbenzamide
to give polymer 15c. Moreover, the method was also applied
to chemically modify the copolymer 16 (Mn ≈ 11.8 kg mol-1)
containing additionally orthogonally addressable C≡C triple
bonds. Thus, 415 nm irradiation of 16 in the presence of indole
led to chemoselective functionalization of the acylsilyl side
chains (17, Scheme 4 C). Alternatively, the alkyne side chains
could be functionalized selectively via cycloaddition with
benzyl azide using CuBr/pentamethyldiethylenetriamine
(PMDETA) as catalyst system to give the polymeric triazole 18.
Importantly, the acylsilane moiety remained unreacted and
based on proton NMR analysis, both orthogonal
transformations occurred in quantitative yields. Moreover,
iterative double functionalization of copolymer 16 was
achieved by applying both click reactions subsequently. This
was documented by performing the cycloaddition reaction on
polymer 17 to give 19, again in quantitative yield based on
proton NMR analysis. Due to poor solubility of functionalized
copolymer 18, applying our photo-click reaction to form doubly
functionalized polymer 19 via the alternative route was not
implemented.
Scheme 4. Indole/acylsilane conjugation in polymeric systems.
Next, we applied the click reaction to light-induced polymer
network formation. A concentrated solution of polymeric
acylsilane 12 (Mn ≈ 23.5 kg mol-1) and poly 5-vinylindole 20 (Mn
≈ 1.7 kg mol-1) in acetonitrile was charged onto a rheometer
and irradiated with a blue LED (Scheme 5). The reaction
progress was monitored by measuring the changes in viscosity
η during continuous shearing of the sample (Figure 1). As
expected, a strong increase in the viscosity was observed,
after irradiation for 120 seconds. After 10 min, the sample
solidified.
3
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Figure 1. Polymer network formation monitored via changes in viscosity of
the reaction solution.
In addition to side chain functionalization, the method can
also be applied to block copolymer synthesis by reacting
polymers containing single indole or acylsilyl moieties at the
terminus. Poly(methyl methacrylate) 21 (Mn ≈ 1.5 kg mol-1)
bearing an acyl silane entity at the terminus was successfully
conjugated with the bis-indolyl-polyethylene glycol (PEG) 22
(Mn ≈ 1.4 kg mol-1) to provide the ABA triblock copolymer 23
(Scheme 6 A). The successful conjugation of the two short
polymers was confirmed by NMR spectroscopy (see SI) and
GPC analysis (Figure 2). Furthermore, we demonstrated
cleavage of the triblock copolymer 23 by treatment with CsF in
THF/water to reform 22 along with the poly(methyl
methacrylate) 21’. The ligation method is also applicable to link
high molecular weight polymers. Hence, acylsilyl-terminated
poly(methyl methacrylate) 24 (Mn ≈ 58.2 kg mol-1) and indole-
terminated polystyrene 25 (Mn ≈ 54.2 kg mol-1) were efficiently
coupled to give the diblock copolymer 26 (Scheme 6 B). In
addition, we demonstrated quantitative coupling of two narrow
dispersity polymethylacrylates terminated with an indole (27,
Mn = 52.7 kg mol-1) and with an acylsilyl group (28, Mn = 52.0
kg mol-1) to give polymer 29 (Mn = 103 kg mol-1, Scheme 6C).
Scheme 5. Polymer network formation via light-mediated crosslinking of
polymeric acylsilane 12 and polyindole 20.
4
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10.1002/anie.202101689
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RESEARCH ARTICLE
Scheme 6. Block copolymer synthesis.
B)
A)
C)
Figure 2. GPC traces of A) polymer 21 (black), triblock copolymer 23 (red) and cleaved polymer 21’ (blue), B) poly(methyl methacrylate) 24 (red), polystyrene 25
(black) and block copolymer 26 (blue), C) polymer 27 (black), 28 (red), 29 (blue).
Next, we aimed for the application of the method to λ-orthogonal
systems which can engage in wavelength-controlled processes.
Acylsilane 30 (see SI) bearing an additional orthogonally UV-
photoadressable α-alkoxy ketone moiety and the indole
functionality was designed. This monomer should allow for a
wavelength-controlled polymerization and depolymerization
sequence using light as the only “reagent”, as sketched at the top
of Scheme 7. Polymerization was conducted upon 415 nm
irradiation of 30 via multiple siloxycarbene/N-H insertions to give
polyaminal 31, as analyzed using GPC and NMR methods. The
polymers obtained were terminated by an aldehyde moiety which
was formed by reaction of the siloxycarbene intermediate with
trace amounts of water. Integration of the aldehyde proton against
the benzylic CH2 protons showed a ratio of 1:44, which allows to
5
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10.1002/anie.202101689
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RESEARCH ARTICLE
estimate an average chain length of 22 monomers for 31 (Mn ≈
14.6 kg mol-1). Surprisingly, this is in good agreement with the
polymer’s GPC data revealing a Mn of around 13.8 kg mol-1 using
poly(methyl methacrylate) as the standard. The polymer was also
investigated by differential scanning calorimetry (DSC) which
allowed to determine its glass transition as Tg = 55 °C.
Depolymerization could be achieved by UV-light irradiation (254
nm) of 31 to provide carboxylic acid 32. The UV-induced cleavage
of such an -alkoxy ketone moiety to give a benzofuran and a
carboxylic acid functionality is an established photoreaction.[29]
However, the N,O-acetal moiety of compound 32 that also
contains an acid functionality was found to be instable under the
reaction conditions and acid-induced acetal cleavage eventually
provided the fragments 33 and 34 as the final products, as
confirmed by NMR analysis (see SI).
nanoparticles 36 were formed, showing globular shape as
compared to the linear precursor polymer 14c. The altered shape
of the nanoparticles led to longer retention times in GPC analysis
(Figure 3), which is characteristic for folded polymers with
increased compactness. Notably, this effect outcompetes the
significant gain in the polymer’s actual molecular weight due to
incorporation of the crosslinkers. The nanoparticle can be
retransformed into linear polymer chains by UV-light mediated
cleavage of the α-alkoxy ketone crosslinkers. Hence, 254 nm
irradiation of a solution of cross-linked polymer 36 in THF gave
the polymer 37 bearing N,O-acetal functionalities at their side
chains. As expected, this unfolding process to yield linear polymer
chains caused a decrease in retention time of the GPC trace
(Figure 3, blue line).[31] Since the observed changes in retention
time were minimal, as it is always the case when single chain
collapse is monitored, we mimicked and reproduced this process
by using resorcinol as a commercial crosslinker (see SI). Again,
light-mediated single chain collapse led to smaller apparent
molecular weights, as determined by GPC. Cleavage of the
crosslinkers was achieved by acidic hydrolysis, again causing a
shift of the GPC traces towards higher molecular weights.
Scheme 7. Wavelength-controlled crosslinking and crosslinker cleavage in
single polymer chains.
Finally, we could show that such λ-orthogonal photochemistry can
be used to control intramolecular crosslinking and crosslinker
cleavage in polymer chains, as depicted in Scheme 8. To this end,
linear copolymer 14c was prepared by living radical
polymerization of benzyl acrylate and acylsilane monomers.
Irradiation of a dilute solution of polymer 14c in the presence of
photocleavable crosslinker 35 (c (35) ≈ 1.8 ∙ 10-4 M) with blue light
led to folding of single polymer strands by multiple intramolecular
crosslinking events (see 36).[30] Thereby, single chain polymer
6
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Figure 3. Single chain crosslinking and crosslinker cleavage monitored by GPC.
In summary, we have introduced the visible light-mediated
coupling between acylsilanes and indole derivatives as a valuable
photoclick reaction for conjugation of small molecules and
macromolecules. The mild photoreaction is highly efficient, fast
and selective, giving rise to robust and thermally stable N,O-
acetal connections which do not hydrolyse in neutral media in
various solvents. The method’s applicability to a variety of
systems has been documented by quantitative coupling of a sugar
derivative to two indole alkaloids and by the conjugation,
crosslinking and folding of polymers. Importantly, the silyloxy
acetal moiety can be readily cleaved under mild conditions,
rendering acylsilanes promising novel indole N-protecting groups.
Notably, photochemical X−H insertion leading to stable products
also works on amides and phenols as the coupling partners of the
acyl silanes. Moreover, we have shown that a combination of
acylsilane and an additional UV-cleavable moiety can be used for
wavelength-selective polymerization/depolymerization with light
as the only “reagent”. We are confident that the herein introduced
acylsilane/indole photo click reaction will find many applications
in organic synthesis and also in the field of materials science.
Acknowledgements
We thank the Verband der Chemischen Industrie (fellowship to C.
S.) and the Deutsche Forschungsgemeinschaft DFG (SFB858)
for their support. We thank Benedikt Nowak and Bart Jan Ravoo
for help and access to the rheometer. We thank Elke Hagemeier
for measuring DSC.
Conflict of Interest
There is no conflict of interest.
Keywords: Acylsilanes • Indoles • Click-Chemistry • Polymers •
Photochemistry
Scheme 8. Wavelength-controlled folding and unfolding of a linear polymer.
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10.1002/anie.202101689
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
C. Stuckhardt, M. Wissing, A. Studer
Page No. – Page No.
Photo Click Reaction of Acylsilanes
with Indoles
Photo Click. Visible light-mediated coupling of acylsilanes with indoles is reported.
This photoreaction occurs under mild conditions mostly in quantitative yield and
provides stable silylated N,O-acetals. The potential of the method is documented by
the successful coupling of carbohydrates with indole alkaloids and by the conjugation
of polymers.
9
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