Synthesis of novel photochromic pyrans via palladium-mediated reactions

Article abstract of DOI:10.3762/bjoc.5.25

Photochromic pyrans for applications in material and life sciences were synthesized via palladium-mediated cyanation, carbonylation and Sonogashira cross-coupling starting from bromo-substituted naphthopyran 1 and benzopyrans 2a/b. A novel photoswitchable benzopyran-based ?-amino acid 6 for Fmoc-based solid-phase peptide synthesis is presented. The photochromic behaviour of the 3-cyano-substituted benzopyran 5a was investigated by time-resolved absorption spectroscopy in the picosecond time domain.

Full text of DOI:10.3762/bjoc.5.25

Synthesis of novel photochromic pyrans via
palladium-mediated reactions
Christoph Böttcher1, Gehad Zeyat1, Saleh A. Ahmed1,3, Elisabeth Irran1,
Thorben Cordes2, Cord Elsner2, Wolfgang Zinth2 and Karola Rueck-Braun*,1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
1Institut für Chemie, Technische Universität Berlin, Straße des 17.
Juni 135, 10623 Berlin, Germany, 2Lehrstuhl für BioMolekulare Optik,
Department für Physik, Ludwig-Maximilians-Universität München,
Oettigenstraße 67, 80538 München, Germany and 3Permanent
address: Chemistry Department, Faculty of Science, Assiut University,
71516 Assiut, Egypt
doi:10.3762/bjoc.5.25
Received: 27 February 2009
Accepted: 05 May 2009
Published: 27 May 2009
Associate Editor: H. Ritter
Email:
Karola Rueck-Braun* - karola.rueck-braun@tu-berlin.de
© 2009 Böttcher et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
benzopyrans; chromenes; naphthopyrans; palladium-mediated
coupling reactions; photochromism
Abstract
Photochromic pyrans for applications in material and life sciences were synthesized via palladium-mediated cyanation, carbonyla-
tion and Sonogashira cross-coupling starting from bromo-substituted naphthopyran 1 and benzopyrans 2a/b. A novel photoswitch-
able benzopyran-based ω-amino acid 6 for Fmoc-based solid-phase peptide synthesis is presented. The photochromic behaviour of
the 3-cyano-substituted benzopyran 5a was investigated by time-resolved absorption spectroscopy in the picosecond time domain.
Introduction
Interest in photoswitchable chromophores for the material and photo-controlling the structure and function of complex
life sciences has increased dramatically over the past decade biomolecules [6-12]. In this regard also a broad range of
[1]. In the past, naphthopyrans were primarily commercialized photoswitchable functionalized pyrans and spiropyrans seem to
as components for photochromic ophthalmic eyeware [2-5]. be promising candidates [13,14], but they are in addition inter-
Nowadays, basic research in material sciences tries to imple- esting optical probes for fluorescence-based imaging technolo-
ment photoswitchable pyrans and related chromophores as gies [15,16].
functional parts in organo-electronic devices, e.g. as logic gates
[1]. In the life sciences, functionalized azobenzenes [6], hemi- UV light-illumination of naphtho- and benzopyrans (closed
thioindigos [7,8] and fulgimides [9,10] among other classes of forms), also referred to as chromenes, leads to the formation of
photoswitches, have already proven to be valuable tools for interconverting photoisomers of the open merocyanine-type
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Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
(quinoidal, zwitterionic and hybrid forms and their stereoi-
somers), depending upon the substitution pattern of the parent
pyrans and the conditions employed (Scheme 1). Typically the
thermal reversion of the open forms is very fast [17-20].
Quite recently, the formation of allene intermediates at low
temperatures was also reported in the literature. They originate
from open merocyanine isomers and are formed via a 1,5-
hydrogen shift reaction [21,22]. However, these allene interme-
diates can be avoided by the replacement of hydrogen in the
immediate vicinity of the two aryl residues (3-position of 2H-1-
benzopyrans and 2-position of 3H-naphtho[2,1-b]pyrans).
Thereby, the photochromism of benzo- and naphthopyrans is
expected to be simplified for biological applications and also in
material sciences.
The design of the novel functionalized naphtho- and benzo-
pyrans 3 and 5 presented herein is based on the substitution of
the hydrogen in the neighbourhood of the two aryl residues by a
cyano group, and additionally on fluoro-substituted aryl
moieties (Scheme 2).
Scheme 1: Photochromism of 2H-chromenes.
This substitution pattern permits detailed nitrile and fluorine
spectroscopic probing of the photochromism in solution and on
surfaces over a broad temperature range. Furthermore, the
closed form of the benzopyran-based ω-amino acid 6 (Scheme
2) might be an ideal photoswitchable β-turn mimetic. Optical
stimulation generates a flexible C3–C4 single bond within the
open merocyanine forms in place of the former double bond of
the pyran ring (Scheme 1), resulting in a significant structural
alteration of the β-turn scaffold.
Herein we describe the synthesis of functionalized photo-
chromic pyrans by palladium-catalyzed transformations of the
bromo-substituted naphthopyran 1 and the benzopyrans 2a/b
(Scheme 2). A variety of transformations for the synthesis of
4-substituted benzopyrans of pharmacological interest
(potassium channel openers), starting from triflate and bromo
precursors, is well documented in the literature [23,24]. In
comparison, reported transformations for 3-bromo-benzopyrans
and bromo-substituted naphthopyrans are still rare. One reason
could be the well documented anionic cleavage of 3-bromo-
substituted benzopyrans upon metal halogen exchange,
resulting in the formation of allenes and subsequent rearrange-
ment reactions [25].
Scheme 2: Synthesis of functionalized pyrans from 2-bromo-3H-
naphtho[2,1-b]pyrans and 3-bromo-2H-1-benzopyrans by palladium-
mediated transformations.
Fmoc protecting group for the direct synthesis of ω-amino acid
6. Also, a Sonogashira reaction was conducted towards the
synthesis of naphthopyran precursor 4, which is suitable for
attachment to tripodal linker systems for the immobilization on
surfaces [26].
Since nitriles are important intermediates in the synthesis of
carboxylic acids and derivatives, and for the introduction of
aminomethyl substituents, we started our studies with palla-
dium-catalyzed cyanation reactions. The studies were then
extended towards a Heck carbonylation in the presence of an
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Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
Results and Discussion
be improved by activation of the zinc powder using TMSCl or
The starting materials, propargyl alcohol 9 and the phenol 8b, iodine, whereas bromine was less efficient (Table 1).
were prepared essentially by following literature procedures
(Scheme 3). Synthesis of the pyran precursors 10 and 12a/b was When using iodine, 56% conversion was determined by
accomplished by using PPTS and trimethyl orthoformate in RP-HPLC (Table 1, entry 3). Under related reaction conditions
DCE in a standard protocol developed by Carreira [27] for the with a selection of other ligands (PEPPSI, dppf, dpppe) the
Claisen-type rearrangement of propargyl aryl ethers in situ transformation could not be further enhanced.
formed. All attempts to optimize the yield of 12a/b failed,
because of the decomposition reactions observed over For complete conversion the concentration of the reaction
prolonged reaction times and the difficulties encountered during mixture was raised from 0.03 M to 0.5 M, 1.1 equiv Zn(CN)2
the separation of the byproducts by flash chromatography. was applied and the reaction time was doubled. Thereby,
Treatment of 10 and 12a/b with NBS in wet DMSO furnished compound 3 could be isolated in 83% yield after work up and
the bromohydrin intermediates 11 and 13a/b in good to excel- flash chromatography. In other solvents, the reaction either did
lent yields. The bromo-substituted fused pyrans 1 and 2a/b were not proceed (toluene, THF) or was less efficient (DMF).
obtained in high yields by using TsOH in toluene for the
subsequent elimination of water [25].
The cyanation of vinyl bromide 1 was also investigated by
using K4[Fe(CN)6] in the presence of Pd(OAc)/dppf and
Since arenenitriles are important for the fine chemical industry, Na2CO3 in NMP at 120 °C for 44 h (Scheme 4) [28]. However,
a variety of methods have been developed recently for the effi- only the rearranged and hydrodehalogenated benzofuran 14 was
cient cyanation of aryl halides under mild conditions. By isolated in 65% yield after flash chromatography.
applying electron-rich phosphanes and either Zn(CN)2 or
K4[Fe(CN)6], the transformation of chlorides to nitriles was Formation of the benzofuran can be rationalized by cleavage of
successfully achieved under fairly mild conditions. However, the benzopyran ring and a subsequent rearrangement reaction
protocols for vinyl systems are still rare.
[29,30]. However, by using standard Sonogashira conditions in
THF, (trimethylsilyl)acetylene was reacted with 1 for 45 h to
When using Zn(CN)2 (0.6 equiv) in the presence of yield 4 in 53% after work-up and purification by flash chroma-
Pd(dba)2/[(t-Bu)3PH]BF4 with Zn (0.05 equiv) as additive in tography (Scheme 5).
wet NMP (0.2% water, 0.03 M) at 45 °C, no conversion of the
bromo-substituted naphthopyran 1 was observed after 17 h. The Zn(CN)2-based cyanation protocol was also successfully
Additional experiments showed that the conversion of 1 could utilized in the transformation of the sterically demanding vinyl
Scheme 3: Synthesis of the 2-bromo-3H-naphtho[2,1-b]pyran 1 and the 3-bromo-2H-1-benzopyrans 2a/b.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
Table 1: Optimization of palladium catalyzed cyanation reactions with Zn(CN)2.
entry
concn (M)
Zn(CN)2 (equiv)
additive (equiv)
time (h)
conversiona (%)
yielda,b,c (%)
1
2
3
4
0.03
0.03
0.03
0.50d
0.6
0.6
0.6
1.1
0.2 Br2
0.2 TMSCl
0.2 I2
18
19
17
41
7
5
29
56
100
23
54
97e
0.2 I2
aDetermined by RP-HPLC at 210 nm. bHPLC-based yield. c2–5% of a byproduct, that was not further characterized, were observed by HPLC. d8% [(t-
Bu)3PH]BF4 were used. eIsolated yield after purification by flash-chromatography: 83%.
Scheme 4: Ring contraction observed during the cyanation approach
towards the synthesis of 3.
Scheme 6: Palladium-catalyzed cyanation and carbonylation of
3-bromo-2H-1-benzopyrans 2a/b.
Heck carbonylations are known, only a few report neutral reac-
tion conditions, necessary here because of the sensitivity of the
Fmoc protecting group. However, in a procedure published by
Urata et al. [31] the use of molecular sieve instead of base was
successful. The reaction outcome was dependent on the
molecular sieves type, since the pore diameter must correspond
Scheme 5: Palladium-catalyzed Sonogashira-coupling of 2-bromo-3H-
naphtho[2,1-b]pyran 1.
to the ion size of the halides used. We were pleased to isolate
200 mg of the ω-amino acid 6 starting from a 2.3 mmol reac-
tion scale of 2b, when using water in THF for 72 h at 100 °C
bromides 2a/b, affording 5a and 5b in good to excellent yields and 50 atm CO in the presence of PdCl2(PPh3)2 and 4 Å
(Scheme 6).
molecular sieves. The low yield of 14% could be attributed to
decomposition of starting material and product under the harsh
Starting from the bromo-substituted pyran 2b a final carbonyla- reaction conditions. All attempts to use MeOH in THF under
tion step (Scheme 6) would directly complete the synthesis of similar conditions failed to produce detectable amounts of the
an Fmoc-protected ω-amino acid. Though many protocols for desired methyl ester.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
Photochemistry of benzopyrans: Compound
structure with these time constants. The coloured “open” forms
5a
appear on a longer time-scale (τ = 31 ps) related with the rise of
Photophysical properties of the novel pyrans are exemplified an intense band centered at ~460 nm (Figure 1a/b). The spec-
with compound 5a: in stationary measurements no indications tral signature of this band allows an assignment to the open
for the formation of the open form, i.e. appearance of a visible forms with a more planar structure due to the sp2-hybridization
absorption band after UV-illumination, were found. Therefore at the formerly sp3-hybridized carbon carrying the aryl residues.
spectroscopic techniques with much higher time-resolution The π-system now extends over a considerable fraction of the
were applied to record the reaction dynamics of 5a and to molecule.
search for its “ring-opened” forms. The photoreaction was initi-
ated by short light-pulses at 340 nm. The corresponding tran- The time constant for the formation of the open form (31 ps) is
sient absorption changes (375–650 nm) as a function of the slower than the reaction dynamics recorded for other benzo-
delay-time between pump and probe are shown in Figure 1a. An pyrans [20,32]. The slow reaction speed may be related to the
inspection of the data at early delay-times (0.2 ps) reveals a cyano substituent at the 3-position in the benzopyran moiety
broad and unstructured induced absorption in the complete (compare Scheme 2). A detailed publication comparing
spectral range. This feature vanishes on fast timescales < 1 ps substances with and without substituents in this position is in
and leads to a weak absorption increase in the 400 nm range. preparation.
On the time scale of 30 ps a pronounced absorption band in the
visible appears, which peaks at ~460 nm.
The results given in Figure 1a/b clearly demonstrate that the
ring-opening reaction proceeds on a picosecond timescale.
This spectral and temporal behaviour is already known from Since the stationary measurements do not reveal a change of
other naphtho- and benzopyrans as well as for spiropyrans [20, absorption under light exposure, the open intermediate should
32]. The initial transients are assigned to the first excited singlet be short-lived. The laser-flash experiments of Figure 1c show
state [32]. Global fitting of the data set reveals a bi-exponential the kinetics of the back reaction. The band of the open form
decay of the excited state absorption with the time constants (e.g. Figure 1a, tD = 1000 ps) vanishes mono-exponentially with
0.15 ps and 0.9 ps. The low absorption and the spectral position a time-constant of 12 μs (Figure 1c). Similar lifetimes were
(~400 nm) of the band observed subsequently point to the form- found for related systems [20].
ation of ring-opened molecules with a distorted non-planar
Figure 1: Data from time-resolved measurements of compound 5a. a) and b): Results from fs-pump-probe-spectroscopy. Please note the linear time-
scale from −1 ps to 1 ps and the logarithmic scale thereafter. a) Two-dimensional overview plot of the transient absorbance changes in false colour
coding. a.u. = arbitrary units. b) Temporal behaviour of the absorbance changes at a detection wavelength of 470 nm. c) Results from laser-flash
photolysis. The transient was recorded at 470 nm (black) and is shown together with a single-exponential fit (red) yielding a decay time of 12 μs.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 25.
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This paper is dedicated to Professor Hans-Ulrich Reißig on the
occasion of his 60th birthday. This work was supported by the
Volkswagen Foundation, the Deutsche Forschungsge-
meinschaft (SFB 658, SFB 749, Cluster of Excellence 314 and
Munich-Centre for Advanced Photonics) and the Fonds der
Chemischen Industrie. We thank Prof. Dr. M. Beller, Leibniz-
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for the use of his autoclave equipment. Part of this work was
supported by the Alexander von Humboldt-Stiftung through a
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