A new approach to silicon rhodamines by Suzuki–Miyaura coupling – scope and limitations

Article abstract of DOI:10.3762/bjoc.15.250

Background: Silicon rhodamines are of particular interest because of their advantageous dye properties (fluorescence- and biostability, quantum efficiency, tolerance to photobleaching). Therefore, silicon rhodamines find frequent application in STED (stimulated emission depletion) microscopy, as sensor molecules for, e.g., ions and as fluorophores for the optical imaging of tumors. Different strategies were already employed for their synthesis. Because of just three known literature examples in which Suzuki–Miyaura cross couplings gave access to silicon rhodamines in poor to moderate yields, we wanted to improve these first valuable experimental results. Results: The preparation of the xanthene triflate was enhanced and several boron sources were screened to find the optimal coupling partner. After optimization of the palladium catalyst, different substituted boroxines were assessed to explore the scope of the Pd-catalyzed cross-coupling reaction. Conclusions: A number of silicon rhodamines were synthesized under the optimized conditions in up to 91% yield without the necessity of HPLC purification. Moreover, silicon rhodamines functionalized with free acid moieties are directly accessible in contrast to previously described methods.

Full text of DOI:10.3762/bjoc.15.250

A new approach to silicon rhodamines by Suzuki–Miyaura
coupling – scope and limitations
Thines Kanagasundaram1,2, Antje Timmermann1,2, Carsten S. Kramer*1,§
and Klaus Kopka1,3,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2569–2576.
1Division of Radiopharmaceutical Chemistry, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120
Heidelberg, Germany, 2Institute of Inorganic Chemistry, Im
Neuenheimer Feld 270, 69120 Heidelberg, Germany and 3German
Cancer Consortium (DKTK), Heidelberg, Germany
doi:10.3762/bjoc.15.250
Received: 31 May 2019
Accepted: 02 October 2019
Published: 29 October 2019
Email:
This article is part of the thematic issue "Dyes in modern organic
chemistry".
Carsten S. Kramer* - c.kramer@dkfz-heidelberg.de
* Corresponding author
Guest Editor: H. Ihmels
§ KK and CSK contributed equally to this work and share senior
authorship.
© 2019 Kanagasundaram et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cross coupling; fluorescent dyes; near-infrared (NIR) dyes; silicon
rhodamines; Suzuki–Miyaura coupling
Abstract
Background: Silicon rhodamines are of particular interest because of their advantageous dye properties (fluorescence- and biosta-
bility, quantum efficiency, tolerance to photobleaching). Therefore, silicon rhodamines find frequent application in STED (stimu-
lated emission depletion) microscopy, as sensor molecules for, e.g., ions and as fluorophores for the optical imaging of tumors. Dif-
ferent strategies were already employed for their synthesis. Because of just three known literature examples in which
Suzuki–Miyaura cross couplings gave access to silicon rhodamines in poor to moderate yields, we wanted to improve these first
valuable experimental results.
Results: The preparation of the xanthene triflate was enhanced and several boron sources were screened to find the optimal cou-
pling partner. After optimization of the palladium catalyst, different substituted boroxines were assessed to explore the scope of the
Pd-catalyzed cross-coupling reaction.
Conclusions: A number of silicon rhodamines were synthesized under the optimized conditions in up to 91% yield without the
necessity of HPLC purification. Moreover, silicon rhodamines functionalized with free acid moieties are directly accessible in
contrast to previously described methods.
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Beilstein J. Org. Chem. 2019, 15, 2569–2576.
Introduction
Silicon rhodamines are versatile fluorescent dyes that found ex- biostabilities [23] as well as exhibited high quantum efficien-
tensive use in super-resolution microscopy [1-8] and as probes cies with high tolerance to photobleaching [24]. A silicon
for targeting various biomolecules [9-12] or sensors for metal rhodamine antibody conjugate could also be successfully
ions [13-17], pH [15], voltage [18] or metabolites [19-22]. applied for optical imaging of a xenograft tumor (human malig-
Since our group is interested in synthesizing new tumor tracers nant meningioma) in a mouse model [24]. Again, in direct com-
for intraoperative imaging of cancerous lesions, we were inter- parison with the cyanine dye Cy5.5, the silicon rhodamine
ested in silicon rhodamines due to their fluorescence properties conjugate showed no fading indicating that silicon rhodamine
in the biological window (650 nm to 1350 nm). While clinical- dyes are more suitable for long time observation than cyanine-
ly approved fluorescence dyes like ICG (indocyanine green, based fluorophores [24].
Mw = 775 g/mol) have a high molecular weight and could there-
fore alter pharmacokinetic or -dynamic properties of the tumor Different synthetic approaches were established to form the
tracers, silicon rhodamines are relatively small and already ex- silicon rhodamine framework 1 (Scheme 1). While the group of
amined as fluorophores for the optical imaging of tumors. Wu used a copper(II) bromide-catalyzed solvent-free condensa-
Using silicon rhodamine SiR700 a more enhanced tumor-to- tion of a diarylsilane 2 with various benzaldehydes 3 [25], Sparr
background ratio in optical imaging could be achieved com- and Fischer added the double Grignard reagent 4 to methyl
pared to the cyanine based dyes Cy5.5 and Alexa Fluor® 680 esters 5 [26]. A similar approach was established by Lavis,
[23]. Moreover, silicon rhodamines demonstrated in in vivo herein electrophiles (anhydrides or esters) were added to lithi-
imaging experiments excellent fluorescence properties and um or magnesium organyls 4 [27]. Johnsson and co-workers
Scheme 1: Different synthetic approaches to silicon rhodamine dyes.
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could establish dye formation by addition of aryllithium 7 to the reaction). The reaction of the triflate with cyano-substituted
silicon xanthone 6 [8]. A related strategy, adding lithium com- phenylboroxines 10b and 11b led to silicon rhodamine dyes 14
pound 7 to a preformed tricyclic system 8, was used by Nagano and 15 in poor yields of 23 and 19%, respectively. The reaction
et al. to synthesize the Ge and Sn rhodamine analogues [14].
conditions applied for the cross coupling of the triflate were
similar to those published by Calitree and Detty for the cou-
In a recent publication, Urano et al. synthesized the rhodamines pling of the triflates derived from the O, S, Se, and
13–15 by coupling the triflate of xanthone 12 with boroxines Te-xanthones 16 with various phenylboroxines (bearing nitro,
9b–11b (Scheme 2) [22,28]. Hereby, the boroxines 9b–11b carboxylic acid, methyl and methoxy substituents) [29]. Here
were accessible by thermal dehydration of the corresponding yields of 53–79% were obtained (for O and S analogues;
boronic acids 9a–11a. With this procedure product 13 was ob- 85–99% yields based on recovered starting material (brsm)).
tained in only 6% yield, which is presumably due to a Since the yields reported by Urano for the Si-analogous Suzuki
competing coupling reaction of the boroxine moiety of 9b with reactions were much lower (6–23%) [22], we wanted to exam-
the chlorine atom of 9b or sterical reasons (the chlorine in ine if the aforementioned substrates were outliers and a cross-
2’-position might lead to repulsion during the cross-coupling coupling reaction could be a valuable approach to silicon
Scheme 2: Previous work from Calitree [29] and Urano [22,28] on the Suzuki–Miyaura coupling of triflates, derived from xanthones 12 and 16, with
boroxines.
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Beilstein J. Org. Chem. 2019, 15, 2569–2576.
rhodamines. Thus, we aimed at the optimization of coupling Suzuki–Miyaura cross coupling (Scheme 3, Table 1). Triflate
conditions as well as evaluation of the best boron compounds 21 was obtained without further purification from 12 by addi-
for coupling. Since carboxylic acid-substituted dyes like com- tion of triflic anhydride in dry acetonitrile. Boroxine 18b was
pound 17 (X = Si, R = COOH) can be easily coupled to tumor formed by heating of boronic acid (18a) at 110 °C because it
binding vectors, we wanted to investigate if these dyes are also was shown by Calitree and Detty that free boronic acid leads to
accessible by Suzuki–Miyaura coupling.
the destruction of the triflate, resulting in the corresponding
xanthone [29]. Applying standard conditions on xanthone 12 by
treatment with triflic anhydride in dry acetonitrile and subse-
quent addition of base, catalyst and boroxine 18b yielded the
Results and Discussion
Optimization of reaction conditions
At first we investigated the effects of different catalysts and desired fluorophore 22 in 41% yield together with unreacted
boron compounds on the synthesis of silicon rhodamine 22 via xanthone 12 (Table 1, entry 1). Since the initial triflate forma-
Scheme 3: Optimization of cross-coupling conditions of triflate 21, derived from Si-xanthone 12, with boron species 18b, 19 and 20 (see Table 1).
Table 1: Optimization of cross-coupling conditions of triflate 21, derived from Si-xanthone 12, with boron species 18b, 19 and 20.
Entry
Triflation
Cross coupling
Conditions
Yield (22)
Catalyst
(10 mol %)
Boron
species
(1 equiv)
1
2
1.1 equiv Tf2O, MeCN, rt, 20 min PdCl2(PPh3)2
18b
3 equiv Na2CO3, MeCN, 70 °C, 41%a
overnight
1 equiv Comins’ reagent
(5-Cl-2-pyridyl-NTf2), MeCN, rt,
1 h
–
–
–
–
3
4
5
6
7
8
1.1 equiv Tf2O, DCM, rt, 20 min, PdCl2(PPh3)2
then evaporation
1.1 equiv Tf2O, DCM, rt, 20 min, Pd(PPh3)4
then evaporation
1.1 equiv Tf2O, DCM, rt, 20 min, PdCl2(PPh3)2
then evaporation
1.1 equiv Tf2O, DCM, rt, 20 min, PdCl2(PPh3)2
then evaporation
1.1 equiv Tf2O, DCM, rt, 20 min, PdCl2(PPh3)2
then evaporation
1.1 equiv Tf2O, DCM, rt, 20 min, PdCl2(dppf)
then evaporation
18b
18b
18b
19
3 equiv Na2CO3, MeCN, 70 °C, 49%a,
overnight 80%a,b
3 equiv Na2CO3, MeCN, 70 °C, 39%a,
overnight 82%a,b
3 equiv Cs2CO3, MeCN, 70 °C, n.r.
overnight
3 equiv Na2CO3, MeCN, 70 °C, 48%a
overnight
3 equiv Na2CO3, MeCN, 70 °C, n.r.
overnight
20
18b
3 equiv Na2CO3, MeCN, 70 °C, 67%,
overnight
73%b
aCorrected yield, contamination with [PPh4]+. bBased on recovered starting material (brsm) 12.
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Beilstein J. Org. Chem. 2019, 15, 2569–2576.
tion to 21 was unreliable and often incomplete, leading to lower moderate yields, an inseparable impurity of the cationic fluoro-
yields, Comins reagent was investigated as an alternative trifla- phore was detected. After identifying this impurity as the
tion reagent. Notably, the use of Comins reagent showed no tetraphenylphosphonium cation, we exchanged the triphenyl-
transformation from the yellow xanthone 12 to the deep blue phosphine ligand of the catalyst with dppf (1,1'-bis(diphenyl-
triflate 21 at all (Table 1, entry 2). Exchange of anhydrous phosphino)ferrocene). Remarkably, not only the yield was in-
acetonitrile by anhydrous dichloromethane, which was re- creased with PdCl2(dppf) from 49% to 67%, even the dye 22
moved in vacuo prior to coupling, provided triflate 21 as a blue was obtained with high purity after column chromatography
salt without xanthone residues, hereby the yield could be without the necessity of further HPLC purification (Table 1,
slightly enhanced but still the conditions of the coupling reac- entry 8).
tion led to some back reaction of 21 to 12 (Table 1, entry 3).
While the use of PdCl2(PPh3)2 was successful in the synthesis Exploration of substrate scope
of chalcogenorhodamine dyes [29], the usage of that catalyst Next we explored the substrate scope of the Suzuki–Miyaura
gave just low yields when applied in the synthesis of the silicon coupling by screening commercially available boronic acids
analogues (Scheme 2) [22]. Although Pd(PPh3)4 was not found (Scheme 4, Table 2). Hereby, PdCl2(dppf) was also tested in
to be an effective catalyst for the synthesis of rhodamine and order to suppress the formation of the inseparable phos-
rosamine dyes as well as for their selenium or tellurium analo- phonium cation species. At first, we investigated the use of
gous [29], the usage of that Pd(0) catalyst showed yields 3-boronobenzoic acid (23a) that should lead to a rhodamine
comparable with those obtained with PdCl2(PPh3)2 (Table 1, suitable for coupling to a tumor vector, but boroxine 23b was
entry 4). The exchange of sodium carbonate with cesium converted to 23c with PdCl2(PPh3)2 in poor yields (Scheme 4
carbonate resulted in no reaction at all (Table 1, entry 5). and Table 2, entry 1). However, PdCl2(dppf) performed better
Whereby usage of potassium phenyltrifluoroborate (19) resulted and led to the acid-substituted silicon rhodamine 23c in a mod-
in a yield comparable to boroxine 18b (Table 1, entry 6), usage erate yield of 31% (56% brsm) (Table 2, entry 2). The moder-
of pinacol ester 20 showed no reaction in the cross-coupling ate yield might be explained with the destruction of the triflate
reaction (Table 1, entry 7). Although described optimizations of by the acid moiety of 23c. In order to prevent the destruction of
the reaction conditions could lead to the silicon rhodamine 22 in the initially formed triflate 21, 4-boronobenzaldehyde (24a)
Scheme 4: Coupling reactions of silicon xanthone 12 with different boron species (23b–30b, 31).
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Beilstein J. Org. Chem. 2019, 15, 2569–2576.
new bond formation through reductive elimination should be
less hindered, but remarkably, no reaction was observed either
with the methyl ester 26b or the free acid 27b (Table 2, entries
6 and 7). Next we explored if amino-substituted silicon
rhodamine 28c is accessible via Pd-catalysis. The resulting
rhodamine 28c could be a possible substrate for the conversion
into an azide and follow-up click reactions with alkyne-substi-
tuted tumor vectors. While heating of amine 28a to the corre-
sponding boroxine 28b lead to formation of a brown solid
(presumably due to degradation), the reaction of triflate 21 with
the pinacol ester 31 showed no product formation at all
(Table 2, entries 8 and 9). Since we were able to investigate the
functional group tolerance of the coupling reaction, we shifted
our focus towards heterocyclic boronic acids as substrates.
Since 4’-pyridinyl- [27,30] and 3’-thienyl- [27,31-33] substi-
tuted silicon rhodamines are already known, we investigated the
synthesis of these dyes by Suzuki–Miyaura cross coupling.
Firstly, pyridinylboronic acid 29a was used as a substrate after
heating at 110 °C, but no conversion was observed presumably
due to the formation of an internal salt (protonated pyridine ring
and deprotonated boronic acid) and ensuing difficult formation
of boroxine 29b (Table 2, entry 10). Switching to the neutral
heterocyclic boronic acid 30a, the corresponding thienyl-substi-
tuted silicon rhodamine 30c could be obtained in 37% (56%
brsm) yield with the PdCl2(PPh3)2 catalyst. Remarkably, the
yield could be clearly enhanced by catalysis with PdCl2(dppf)
and the thienyl-substituted fluorophore 30c could subsequently
Table 2: Coupling reactions of silicon xanthone 12 with different boron
species (23b–30b, 31).
Entry
1
Boron source
Catalyst
Yield
23b
PdCl2(PPh3)2
5%a,
46%a,b
(23c)
2
23b
PdCl2(dppf)
31%,
56%b
(23c)
3
4
24b
25b
PdCl2(PPh3)2
PdCl2(PPh3)2
traces
(24c)
43%a,
62%a,b
(25c)
5
25b
PdCl2(dppf)
53%,
66%b
(25c)
6
7
8
9
10
11
26b
27b
28b
31
29b
30b
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
n.r.
n.r.
n.r.
n.r.
n.r.
37%a,
56%a,b
(30c)
12
30b
PdCl2(dppf)
91%
(30c)
aCorrected yield, contamination with [PPh3Ar]+. bBased on recovered
starting material (brsm) 12.
was intended as a coupling substrate but yielded silicon be synthesized in 91% yield.
rhodamine 24c only in traces (Table 2, entry 3). Usage of the
tert-butyl-protected boronobenzoic acid 25a, or its boroxine Table 3 compares the reaction outcome of the silicon rhodamine
counterpart 25b, respectively, gave fluorophore 25c suitable for synthesis via Suzuki coupling with other employed methods:
later coupling reactions in reasonable yields of 43% and 53%, synthesis of the phenyl-substituted silicon rhodamine 22 by
depending on the catalyst used (Table 2, entries 4 and 5). Suzuki cross coupling affords the product in a similar yield
Again, the reaction catalyzed by PdCl2(dppf) resulted in an en- compared to the addition of phenyllithium to xanthone 12 or the
hanced yield compared to catalysis with PdCl2(PPh3)2. Next we attack of the double metallated bis-aniline 4 (R1 = R2 = Me,
aimed at the synthesis of a silicon rhodamine bearing an acid M = Mg) to the benzoic acid methyl ester [26]. However, the
function in 2’-position. With a less bulky methyl ester in the cross coupling of triflate 21 with boroxine 25b led to the ester-
2’-position of the phenylboroxine, the transmetalation and the substituted rhodamine 25c in a reasonable yield of 53% (66%
Table 3: Comparison of common methods for silicon rhodamine synthesis.
Method →
Addition of lithium organyl
Suzuki–Miyaura
cross coupling
Attack of 4 (R1 = R2 = Me,
M = Mg) to 5 (R3 = H)
to 12a
Fluorophore ↓
phenyl-substituted SiR (22)
72%
7%
67%,
73%b
53%,
66%b
72% [26]
tert-butylbenzoic
acid-substituted SiR (25c)
–
thienyl-substituted SiR (30c)
77%
91%
–
aConditions: 7 equiv aryl bromide, 14 equiv t-BuLi, THF, −78 °C, 30 min, then 1 equiv 12 at −78 °C to rt, overnight, then aq HCl, work-up, purification
with DCM/MeOH 99:1 to 9:1. bBased on recovered starting material (brsm) 12.
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Beilstein J. Org. Chem. 2019, 15, 2569–2576.
brsm) while the addition of the lithiated tert-butyl 3-bromoben-
zoate gave the fluorophore 25c in only 7% yield. Finally, the
cross-coupling reaction of 12 and 30b to rhodamine 30c clearly
outperforms the addition of lithiated 2-bromothiophene to
xanthone 12 since 2-bromothiophene might also undergo lithia-
tion in 5-position in competition to the halogen metal exchange
(in general multiple halogenated aryls are problematic nucleo-
philes for these addition reactions).
Supporting Information
Supporting Information File 1
Experimental procedures and NMR spectra of all
synthesized compounds as well as photochromic
characterization data (fluorescence spectra, quantum yield)
of thienyl-substituted silicon rhodamine 30c.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-250-S1.pdf]
Conclusion
Since just three literature examples are known to date in which
Suzuki–Miyaura cross-coupling reactions gave access to silicon
rhodamines in poor to moderate yields (Scheme 2), we wanted
to improve these first valuable experimental results. In general,
the amount of re-isolated starting material 12 could be signifi-
cantly reduced when acetonitrile was exchanged with dichloro-
methane in the triflation reaction to provide triflate 21 neat and
more reliable. Screening of different boron species and cata-
lysts showed that, like in the syntheses of O, S, Se, and
Te-rhodamines, boroxines were a suitable source, but also
potassium trifluoroborates can be taken into consideration for
the reaction design, whereas pinacol esters didn’t show any re-
activity. While PdCl2(PPh3)2 was a sufficient catalyst for the
cross coupling, application of PdCl2(dppf) led to clearly en-
hanced yields: overall the Suzuki–Miyaura cross-coupling reac-
tion gave access to silicon rhodamines with neutral (hetero)aro-
matic xanthene substituents (phenyl: 67%, respectively 73%
brsm; thienyl: 91%) (even though the term ‘dihydrosilaan-
thracene’ is correct to name the Si-anthracene moiety, the term
‘Si-xanthene’ is widely used in the literature (see e.g. [30]); also
the term Si-xanthone (for derivatives of 12) is established
instead of 9-silaanthracen-10(9H)-one). The conditions toler-
ated also the use of the unprotected acid functionality of the
boroxine 23b (23c, 31%, respectively 56% brsm), while appli-
cation of basic boronic acids failed (28, 29), presumably due to
unsuccessful boroxine formation. The main advantage of the
cross coupling is the access to acid-functionalized fluorophores
like 23c that can be immediately coupled to a molecule of
interest (e.g., tumor binding vectors) whereas previously
published methodologies need, e.g., an ester, orthoester or oxa-
zoline protecting group for the acid. But also the tert-butyl
ester-functionalized boroxine 25 is suitable for the cross cou-
pling. With the current catalytic system, coupling of 2-substi-
tuted boroxines (26, 27) remains challenging, but optimizing
the catalytic system with ligands suitable for coupling of multi-
substituted aryls is under current investigation. In conclusion,
several silicon rhodamines could be synthesized under the
optimized conditions, without the necessity of HPLC
purification, in up to 91% yield whereby the free acids are
directly accessible in contrast to the three hitherto described
methods.
Acknowledgements
We are very grateful to the Wilhelm Sander Stiftung for a grant
on bi-modal tumor tracers (2018.024.1). We thank Yvonne
Remde for synthetic support. We are thankful to Jessica
Matthias (group of Stefan Hell, MPI for Medical Research
Heidelberg) for measurement of the UV–vis spectrum of 30c.
ORCID® iDs
Thines Kanagasundaram - https://orcid.org/0000-0001-8265-8591
Antje Timmermann - https://orcid.org/0000-0002-9557-9320
Carsten S. Kramer - https://orcid.org/0000-0001-9932-423X
Klaus Kopka - https://orcid.org/0000-0003-4846-1271
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