Synthesis of Double-Bond-Substituted Hemithioindigo Photoswitches

Article abstract of DOI:10.1021/acs.orglett.7b03574

A very short, high yielding, and convergent synthesis with broad substrate scope, enabling access to a very diverse range of hemithioindigos with 4-fold substituted double-bonds, is presented. With this method, carbon as well as nitrogen, oxygen, or sulfur based substituents can easily be introduced, delivering a wide array of novel structural motifs. Irradiation studies with visible light demonstrate proficient photoswitching properties of these chromophores at wavelengths up to 625 nm.

Full text of DOI:10.1021/acs.orglett.7b03574

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Double-Bond-Substituted Hemithioindigo
Photoswitches
Aaron Gerwien, Till Reinhardt, Peter Mayer, and Henry Dube*
Ludwig-Maximilians-Universitat Munchen, Department fur Chemie and Munich Center for Integrated Protein Science CIPSM,
̈
̈
̈
81377 Munich, Germany
S
* Supporting Information
ABSTRACT: A very short, high yielding, and convergent synthesis with broad
substrate scope, enabling access to a very diverse range of hemithioindigos with
4-fold substituted double-bonds, is presented. With this method, carbon as well
as nitrogen, oxygen, or sulfur based substituents can easily be introduced,
delivering a wide array of novel structural motifs. Irradiation studies with visible
light demonstrate proficient photoswitching properties of these chromophores
at wavelengths up to 625 nm.
emithioindigo (HTI) is a chromophore1 of very high
current interest because of its efficient photoswitching
For the introduction of two carbon-based substituents R1 and
H
R2 at the stilbene fragment, most published synthetic schemes
rely on condensation reactions between benzothiophenone and
either ketones and analogues,9 electron-poor double-bonds
bearing a leaving group,10 or reverse condensations between
oxidized benzothiophenones and enolates or enols.11 Addition-
ally, very limited and few examples are described employing
Friedel−Crafts acylations,12 ring contraction reactions,13 rear-
rangement reactions of N-tosylsulfilimines14 or thiochromanone
sulfoxides,15 addition of diazomethane,16 or Grignard addition to
ketone-substituted hydroxyl-benzothiophenone.17 However, in
all hitherto described cases many synthetic steps are usually
required, yields are low, and the scope as well as the functional
group tolerance is very limited. The situation is similarly
restricted for the introduction of one carbon-based substituent
in combination with a heteroatom-substituent, e.g., amine18 or
thioether18e,19 groups.
properties2 in the visible part of the electromagnetic spectrum.
For this reason, HTI has attracted increasing attention for
applications in biological,3 supramolecular,4 or medicinal
chemistry5 as well as in the realms of molecular machines6 or
molecular computing.7 HTIs consist of a central double-bond,
which bears a thioindigo moiety at one end and a so-called
stilbene fragment at the other end (Figure 1). The central
Figure 1. Hemithioindigo chromophore and derivatives with 4-fold
substituted double-bond.
In the present work, we describe a short, modular, and high
yielding synthesis for 4-fold double-bond substituted HTIs,
which provides a vast range of highly interesting substitution
patterns. The convergent nature of this synthesis allows facile
generation of a multitude of new HTI chromophores and
photoswitches with group variation at both molecular fragments.
This protocol also allows the easy generation of precursor HTI
structures ready for further late-stage functionalization via, e.g.,
cross-coupling chemistry or peptide conjugation. Apart from
carbon-based substituents, introduction of heteroatoms such as
oxygen, sulfur, or nitrogen at the central double-bond is also
possible in a very convenient and straightforward way (Scheme
1).
double-bond undergoes photoisomerization after irradiation
with a suitable wavelength, usually from the thermodynamically
stable Z to the metastable E configuration. The complementary E
to Z photoisomerization takes place after irradiation with longer
wavelengths (positive photochromism).
A number of different synthetic schemes are available to obtain
HTI chromophores.8 However, the overwhelmingly prevalent
structural motive contains a stilbene fragment with only one, and
typically aromatic, substituent. HTIs bearing instead two
substituents at that side of the double-bond (i.e., an overall 4-
fold substituted double-bond) are known in the literature, but
only limited and (in most cases) cumbersome syntheses are
available for this scarcely explored class of potential photo-
switches. We have used HTIs with 4-fold-substituted double-
bonds in the context of light driven molecular motors6a and also
recently presented a new synthesis to access sterically more
hindered derivatives, which showcases the importance of this
substitution pattern for advanced functions.6b
Our synthesis commences with inexpensive commercially
available starting materials, i.e., different thiosalicylic acids (for
introduction of different thioindigo fragments) and α-
bromoketones (Scheme 2). A nucleophilic substitution reaction
Received: November 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03574
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Organic Letters
Letter
Scheme 1. Synthesis of HTIs with 4-Fold Substituted Double-
Bonds
Scheme 2. Synthesis of Chlorinated HTIs 10 to 14
a
Prepared according to ref 22. All yields are isolated yields.
replaces the bromine with the thiol group and provides the
corresponding thioethers in excellent yields. In this reaction, the
first substituent (R1) is introduced and can be varied between
aliphatic or aromatic character. Addition of NaOAc in DMF leads
to facile ring closure and formation of the corresponding 3-
hydroxybenzothiophenyl-ketone, a reaction that has been
described before for related benzothiophenyl-ketones.20 Reac-
tion with thionyl chloride readily establishes the HTI
chromophore structure with a chloride as the fourth substituent
at the double-bond, again in excellent yields. Interestingly, the
corresponding regioisomer with the chloride at the benzothio-
phene ring is not observed under these conditions. These two
steps can also be realized in a one-pot reaction without the need
to isolate the benzothiophenyl-ketone products while maintain-
ing high yields of the products (e.g., 92% for 10). The chlorinated
HTIs are stable and easy to handle compounds and were, to the
best of our knowledge, not described so far. The only related
structures bear a carboxylic acid or ester function as R1 group and
could only be obtained under low yielding and harsh reaction
conditions.21
Figure 2. Prepared substituted HTIs 15−39. Conditions: (a) 10,
various boronic acids, Pd(PPh3)4, K2CO3, dioxane/H2O, 80 °C; (b) 10,
MeLi, CuI, THF, −78 → 23 °C; (c) 10, (triisopropylsilyl)acetylene,
CuI, PdCl2(PPh3)2, NEt3, THF, 60 °C; (d) 11, various boronic acids,
Pd(PPh3)4, K2CO3, dioxane/H2O, 80 °C; (e) 11, 4-(tributylstannyl)-
pyridine, Pd(PPh3)4, CsF, CuI, dioxane, 100 °C; (f) 11,
(triisopropylsilyl)acetylene, CuI, PdCl2(PPh3)2, NEt3, THF, 60 °C;
(g) 11, MeLi, CuI, THF, −78 → 23 °C; (h) 12, various boronic acids,
Pd(PPh3)4, K2CO3, dioxane/H2O, 80 °C; (i) 12, (triisopropylsilyl)-
acetylene, CuI, PdCl2(PPh3)2, NEt3, THF, 60 °C; (j) 12, MeLi, CuI,
THF, −78 → 23 °C; (k) 13, potassium (3,5-dimethoxyphenyl)-
trifluoroborate, APhos Pd G3, dioxane/H2O, 80 °C; (l) 14, various
boronic acids, Pd(PPh3)4, K2CO3, dioxane/H2O, 80 °C; (m) 14,
(triisopropylsilyl)acetylene, CuI, PdCl2(PPh3)2, NEt3, THF, 60 °C. All
reported yields are isolated yields.
With chloride as the fourth substituent at the double-bond, the
HTIs are now set up for introduction of various substituents R2
via nucleophilic substitution reactions or cross-coupling
chemistry. We exemplify the broad scope of this step by
installing a variety of aliphatic, aromatic, acetylenic, or
heterocyclic substituents with different electronic and steric
character using Suzuki, Sonogashira, or Stille cross-coupling
reactions (Figure 2).
As can be seen in Figure 2, these palladium-catalyzed reactions
give very high yields, usually beyond 90%, without interference of
the particular electronics at the metalated species. Typically
mixtures of E and Z isomers are obtained, which are most likely a
result of the thermal- and light-induced isomerizability. Thus,
pharmaceutically interesting heterocycle motives such as
pyridines (HTIs 29, 32, 33, 34, and 35), indole (HTI 22), or
furane (HTI 23) can be introduced as well as ordinary aromatics
bearing nitriles (HTIs 17, 26, 32, and 37), amines (HTIs 18, 27,
33, and 38), or methoxy groups (HTIs 21, 28, and 36). Of
special interest is the straightforward introduction of protected
carboxylic acid and amine functionalities (HTIs 19 and 20) as
they can be used directly for further peptide coupling or other
bioconjugation chemistry. Substitution with silyl-protected
acetylene (HTIs 25, 30, 34, and 39) provides a different
possibility for further functional group elaboration via, e.g., click-
chemistry or cross-coupling reactions. Another interesting aspect
is the selectivity of cross-coupling reactions as exemplified by the
high yielding introduction of a brominated aromatic substituent
in HTI 16. Apparently the chlorinated precursor HTI 10 is a
considerably better electrophile and undergoes oxidative
addition faster than the bromide-bearing coupling partner.
This allows introducing another halogen functional group with
reactivity orthogonal to amide chemistry for further and late-
stage cross-coupling chemistry. For chlorinated HTI 10 as well as
B
DOI: 10.1021/acs.orglett.7b03574
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HTIs 19, 29, 33, and 37, crystal structures were obtained (shown
and 33 in toluene as example). First, trends can be established: all
HTIs bearing strong electron donating substituents show
pronounced red shifts of their absorptions and typically
considerable photochromism. If both substituents are electron
withdrawing, then photoswitching is not efficient because of the
strongly reduced photochromism. Heteroatom substituents also
seem to inhibit photoisomerization in most cases.
in Figure 4a) facilitating assignment of the double-bond
1
configuration in solution by extrapolating H NMR shifts (see
Supporting Information). Introduction of aliphatic groups is also
straightforward starting from the HTI chlorides by reacting them
with, e.g., methyl-cuprates. The corresponding methyl-substi-
tuted derivatives are obtained in good yields (HTIs 24, 31, and
35 in Figure 2). For the introduction of heteroatom-substituents
at the double-bond, the HTI chlorides can be reacted with
amines (HTIs 40, 43, and 44 in Figure 3), alcohols (HTI 41 in
In summary, we present a novel, concise, and highly efficient
method to synthesize HTI photoswitches with 4-fold substituted
double-bonds. This method possesses a very broad substrate
scope and delivered more than 30 new photoswitches with very
different structures and electronic properties. Incorporation of
aromatic, heterocyclic, aliphatic, or acetylenic carbon based
substituents is similarly straightforward as the introduction of
nitrogen, oxygen, or sulfur based residues as the fourth
substituent. We also provide a variety of prefunctionalized
HTIs for further synthetic elaboration, i.e., brominated and
acetylene-substituted derivatives for late stage cross-coupling or
click-chemistry reactions and aminated as well as carboxylated
derivatives for amide formation or peptide conjugation
chemistry. The photoswitching properties under visible light
irradiations were examined for all derivatives showing that
efficient photoisomerizations take place in almost all cases. A full
photophysical and -chemical assessment of these structures is
currently underway in our laboratory.
Figure 3. Prepared heteroatom substituted HTIs 40−44. Conditions:
(a) 11, pyrrolidine, dioxane, 23 °C; (b) 11, NaOEt, EtOH, 23 °C; (c)
11, pyridine-4-thiol, K2CO3, THF, 23 °C; (d) 12, pyrrolidine, dioxane,
23 °C; (e) 13, pyrrolidine, dioxane, 23 °C. All yields are isolated yields.
ASSOCIATED CONTENT
Figure 3), or thiols (HTI 42 in Figure 3). In each case, high yields
of the corresponding products are obtained. Crystal structural
data were obtained for HTIs 40, 42, and 44 (Figure 4a).
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03574.
Synthetic procedures as well as a full set of characterization
1
data including melting points, H NMR, 13C NMR, IR,
and (HR)MS, structural analysis in solution and in the
crystal, and photophysical data including extinction
coefficients and absorption changes during light irradi-
ation (PDF)
Accession Codes
CCDC 1586002−1586010 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: heduch@cup.uni-muenchen.de.
ORCID
Figure 4. (a) Structures in the crystalline state of HTIs Z-10, Z-19, E-19,
E-29, E-33, E-37, E-40, E-42, and Z-44. (b) Absorption changes at
different time points during photoisomerization of HTIs 10, 18, 19, 21,
30, and 33 in toluene solution.
Henry Dube: 0000-0002-5055-9924
Notes
The authors declare no competing financial interest.
To showcase the potential of this method to generate actual
photoswitches, we have examined the photoswitching properties
of all HTIs presented in this work. Apart from a few exceptions
(HTIs 23, 24, 35, 40, 43, and 44), all derivatives show good
photoswitching properties in the visible part of the spectrum.
This can be clearly seen by the spectral changes upon
photoirradiation and the clean isosbestic points that are observed
(see Figure 4b for the photoswitching of HTIs 10, 18, 19, 21, 30,
ACKNOWLEDGMENTS
■
H.D. thanks the “Fonds der Chemischen Industrie” for a Liebig
fellowship and the DFG for an Emmy−Noether fellowship. We
further thank the collaborative research center SFB749 and the
Cluster of Excellence “Center for Integrated Protein Science
Munich (CiPSM)” for financial support.
C
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