A Fast Way to Fluorescence: A Fourfold Domino Reaction to Condensed Polycyclic Compounds

Article abstract of DOI:10.1002/chem.201402961

A fast and efficient palladium-catalyzed fourfold domino Sonogashira/double-carbopalladation/C H-activation reaction that converts simple aromatic systems into complex polycyclic hydrocarbons has been developed. A number of substituted products has thus been prepared in yields up to 89 %. The structural assignment has been confirmed by using single-crystal X-ray crystallography. The products show intriguing fluorescence activity and thus might serve as chemical sensors or fluorescent imaging dyes.

Full text of DOI:10.1002/chem.201402961

DOI: 10.1002/chem.201402961
Full Paper
&
Domino Reactions
A Fast Way to Fluorescence: A Fourfold Domino Reaction to
Condensed Polycyclic Compounds
Lutz F. Tietze,*[a] Christoph Eichhorst,[a] Tim Hungerland,[a] and Markus Steinert[b]
Dedicated to Professor Alan Battersby on the occasion of his 90th birthday
Abstract: A fast and efficient palladium-catalyzed fourfold
domino
yields up to 89%. The structural assignment has been con-
firmed by using single-crystal X-ray crystallography. The
products show intriguing fluorescence activity and thus
might serve as chemical sensors or fluorescent imaging
dyes.
Sonogashira/double-carbopalladation/CꢀH-activa-
tion reaction that converts simple aromatic systems into
complex polycyclic hydrocarbons has been developed. A
number of substituted products has thus been prepared in
Introduction
A quick and straightforward synthetic route that leads to
either natural products or functional materials is the aim of
every organic synthesis. To comply with these requirements, it
is essential to develop facile reactions that easily transfer
simple molecules into the desired complex structures in pref-
erably few synthetic steps. Domino reactions fulfill these terms
as they allow the incorporation of several reaction steps into
one process without any intermediate purification.[1] Palladium-
catalyzed domino reactions in particular have been in the
focus of several recent publications.[2]
In a program aimed at the development and application of
efficient palladium-catalyzed domino reactions, our group re-
cently reported the synthesis of the natural products (+)- and
(ꢀ)-linoxepin,[3a] (ꢀ)-diversonol,[3b] (ꢀ)-blennoide A,[3c] (ꢀ)-blen-
nolide C,[3d] and (ꢀ)-gonytolide,[3d] as well as synthetic routes to
tetrasubstituted helical alkenes as potential optical switches.[4]
Thus, a threefold domino Sonogashira/carbopalladation/CꢀH-
activation of 1 and 2 furnished alkene 3 in yields of up to 96%
(Scheme 1).[4–7]
Scheme 1. Palladium-catalyzed domino reactions for the synthesis of func-
tional materials.
tions, and one CꢀH-activation beginning with substrates 4 and
5.
Results and Discussion
Herein we report the synthesis of condensed polycyclic com-
pounds of type 6 by means of a fourfold two-component
domino process using a diyne as one of the starting materials.
The process includes a Sonogashira reaction, two carbopallada-
The fourfold domino Sonogashira/double-carbopalladation/Cꢀ
H activation reaction was optimized by employing iodide 4a
and dialkyne 5a as substrates, and the best results were ob-
tained using a 1:5 catalyst-to-ligand ratio that consisted of
1 mol% of [Pd(OAc)2] and 5 mol% of PPh3 with tetrabutylam-
monium acetate as base (see Table 1).
[a] Prof. Dr. L. F. Tietze, C. Eichhorst, Dr. T. Hungerland
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax: (+49)551-39-9476
The condensed pentacyclic compound 6a was obtained in
a yield of 73% (Table 1, entry 1). A reduction of the catalyst
loading was not advantageous, since 0.5 mol% of [Pd(OAc)2]
furnished only 58% of 6a (Table 1, entry 2). Interestingly, in-
creasing the catalyst loading of [Pd(OAc)2] from 1 to 5 and
10 mol% resulted in a decrease in the isolated yield from 73 to
66 and 62%, respectively (Table 1, entries 3 and 4). However,
a catalyst/ligand ratio of 1:5 seems to be necessary. Neither
E-mail: ltietze@gwdg.de
[b] M. Steinert
Institut fꢀr Anorganische Chemie, Georg-August-Universitꢁt Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402961.
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Table 1. Optimization of the reaction conditions.[a]
Entry [Pd(OAc)2] [mol%] Ligand
Ligand [mol%] Yield [%][b]
1
2
3
4
5
6
7
8
9
1
0.5
5
10
1
PPh3
PPh3
PPh3
PPh3
PPh3
–
5
2.5
25
50
2
73
58
66
62
66
28
11
11
20
57
45
40
1
–
10
10
10
10
10
1
[P(tBu)4][HBF4] 50
PCy3
IPr·HCl
P(4-Cl-Ph)3
PPh3
50
50
50
50
5
10
11[c]
12[d]
Figure 1. Molecular structure of 6a. Hydrogen atoms have been omitted for
clarity.
PPh3
domino reaction of 4b and 5a gave 89% yield of 6b when
using 1 mol% of [Pd(OAc)2]. Good results with 67% of 6c were
also obtained by reaction of 4a and 5b. The yields of the four-
fold domino reactions of the other substrates to give
6d–i were somewhat lower and reached 40 to 22% yield; we
therefore slightly changed the protocol. We thus isolated the
products of the initial Sonogashira reaction, which was then
followed by a threefold domino double-carbopalladation/CꢀH-
activation process. Consequently, the dialkyne substrates
5b–i and 4a–c were transformed into the Sonogashira prod-
ucts 7b–i in 65 to 96% yield, which then led to 6b–i through
a Pd-catalyzed threefold domino reaction. Although the four-
fold domino reaction gave better results than the threefold
domino process for 6b and 6c, in all other cases the threefold
domino process was superior. A striking example is the forma-
tion of 6i when using 1 mol% [Pd(OAc)2], whereby the three-
fold domino process gave almost quantitative yield, whereas
the fourfold reaction led to 6i in only 37% yield under other-
wise identical reaction conditions.
[a] Compound 4a (1.1 equiv), 5a (1.0 equiv), [Pd(OAc)2], ligand,
(nBu)4NOAc (5 equiv), DMF, 1008C, 14.5–21 h. [b] Isolated yields following
flash column chromatography. [c] As in entry 1, but 4a (1.0 equiv), 5a
(1.4 equiv), (nBu)4NOAc (6 equiv). [d] As in entry 1, but on a 1.1 mmol
scale instead of 0.11 mmol.
a ratio of 1:2 (Table 1, entry 5) nor the use of [Pd(OAc)2] with-
out any ligand (Table 1, entry 6) led to better results, as 66 and
28% yield were obtained, respectively. To further improve the
reaction, the use of other ligands was also surveyed. Ionic
ligand [P(tBu)4][HBF4] led to 6a in only 11% yield (Table 1,
entry 7), which is equivalent to the result with the electron-rich
PCy3 ligand furnishing 6a also in only 11% yield (Table 1,
entry 8). An N-heterocyclic carbene (NHC) ligand was also used
but gave a low yield of 20% (Table 1, entry 9). Electron-poor
P(4-ClꢀPh)3, which is structurally similar to PPh3, gave 6a in an
acceptable but slightly decreased yield of 57% (Table 1,
entry 10). Thus, the results show that simple PPh3 seems to be
the best ligand for this transformation, which is consistent
with previous investigations.[2e,5] Finally, experiments with dif-
ferent ratios of the two substrates, aryl iodide 4a and dialkyne
5a, revealed that the initially used 1.1:1 ratio gives the best re-
sults, considering that employing an inverse ratio of 4a and
5a of 1:1.4 delivered 6a in only 45% yield (Table 1, entry 11).
The optimized conditions used in entry 1 of Table 1 were also
applied for a larger-scale synthesis of 6a. However, the yields
dropped, and only 40% of 6a were isolated on a 1.1 mmol
scale, compared to the 73% obtained on a 0.11 mmol scale
(Table 1, entry 12).
In general, the results show that a broad range of different
substrates can be transformed to polycylic compounds 6 in
good yields by using either the four- or threefold protocol.
Even heterocycles can be incorporated, as shown with the
preparation of substrate 6b, which contains a pyridine ring.
The proposed mechanism of the fourfold and the corre-
sponding threefold domino reactions of aryl halides 4 and dia-
lkynes 5, shown for 4a and 5a, begins with a Sonogashira re-
action to give 7a (Scheme 3). After an oxidative addition, a car-
bopalladation takes place to form 8a containing a new CꢀC
single bond and a vinyl–Pd species. The second carbopallada-
tion again leads to the formation of a single bond and a vinyl–
Pd species with concomitant formation of an aliphatic five-
membered ring. At this point an E/Z isomerization from dia-
lkene 9a gives rise to the isomeric vinyl–Pd species 10a, which
can undergo formation of a single bond by means of a CꢀH-
activation; in this transformation an acetate molecule might be
involved. During the last step, both double bonds furnished in
the domino process are incorporated into an aromatic system,
thereby driving the reaction to completion.
Molecule 6a was crystallized for structure elucidation
through X-ray spectroscopy by dissolving 6a in Et2O and
slowly evaporating the solvent in an n-hexane atmosphere.
The crystallographic data show that in the single crystal of 6a
two molecules are included in a triclinic elementary cell
(Figure 1).[8]
We then turned to investigating the scope of the reaction
by introducing both electron-donating and electron-accepting
groups in starting materials 4 and 5. What’s more, we also
used substituted pyridines such as 4b (Scheme 2). The fourfold
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as a temperature of 578C led to
reasonably sharp coalescent sig-
nals, the signals are less well re-
solved at 258C. In contrast, at
ꢀ378C the peaks of both iso-
mers are resolved properly.
To determine the energy barri-
er of the isomerization process,
2D nuclear Overhauser effect
spectroscopy (NOESY) experi-
ments of 6a were conducted at
different mixing times (10ꢀ2 ms
(reference time); 125, 250, 500,
1000 ms). The amplitudes of the
diagonal and cross peaks at d=
1.6 and 2.1 ppm were deter-
mined and the Exsycalc program
by Mestrelab Research was used
to calculate the corresponding
reaction rate constants (k). By
using the Eyring equation, the
¼
corresponding DG values were
determined
(Table 2).
The
measurements revealed an aver-
¼
age value of DG =(69.7ꢁ
2.3) kJmolꢀ1.
Another interesting aspect is
the fluorescence activity of the
formed products 6. Fluorescence
markers are of interest for imag-
ing experiments in biology and
as chemical sensors.[11] Com-
pound 6a absorbs at a wave-
length of 394 nm with an emis-
sion at 481 nm in acetonitrile
(Figure 3).[12]
Conclusion
Highly productive and efficient
fourfold and threefold domino
reactions that consist of a Sono-
gashira reaction, two carbopalla-
dations, and
a
CꢀH-activation
process have been established
that lead to condensed polycylic
compounds that show strong
fluorescence activity.
Scheme 2. Products and corresponding yields for the fourfold and threefold domino reaction.
Experimental Section
Owing to the rotation around the biphenyl axis in 6a that
connects the E to the G ring (compare with Scheme 2), the
molecule showed dynamic effects in the NMR spectra. The
structural lability led to temperature-dependent signal acuity
Synthesis of 6a: General procedure for the fourfold domino
reaction
A mixture of alkyne 5a (29.1 mg, 112 mmol, 1.00 equiv), aryl iodide
4a (50.0 mg, 118 mmol, 1.05 equiv), [Pd(OAc)2] (251 mg, 1.12 mmol,
0.01 equiv), PPh3 (1.47 mg, 5.60 mmol, 0.05 equiv), and (nBu)4NOAc
1
1
in the H NMR spectrum. Figure 2 shows the H NMR spectrum
of the aromatic region of 6a at different temperatures. Where-
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¼
Table 2. Calculation of DG of the rotation around the biphenyl axis in
6a by means of Exsycalc at 295 K.
¼
Entry
Mixing time [ms]
k [sꢀ1
]
DG [kJmolꢀ1
]
1
2
3
4
1000
500
250
125
0.74
1.88
4.41
9.06
72.9
70.6
68.5
66.8
Figure 3. Fluorescence spectrum of 6a.
CH2Cl2 5:1) yielded the domino product 6a (38.9 mg, 81.6 mmol,
73%) as a yellow solid. Rf =0.48 (n-pentane/CH2Cl2 5:1); 1H NMR
(600 MHz, C2D2Cl4, 1008C, TMS): d=1.92 (brs, 2H), 2.73 (brs, 2H),
2.84 (dd, 3J(H,H)=6.7, 4.0 Hz, 2H), 6.79 (d, 3J(H,H)=7.7 Hz, 2H),
Scheme 3. Proposed mechanism for the domino Sonogashira/double-carbo-
palladation/CꢀH-activation reaction of 4a and 5a. Ligands have been omit-
ted for clarity.
3
3
6.93 (t, J(H,H)=7.5 Hz, 1H), 6.96 (d, J(H,H)=7.6 Hz, 1H), 7.09–7.16
(m, 3H), 7.19 (d, 3J(H,H)=8.1 Hz, 1H), 7.25 (mC, 1H), 7.31 (t,
3J(H,H)=7.5 Hz, 1H), 7.37 (dd, 3J(H,H)=8.8, 1.7 Hz, 1H), 7.40–7.49
3
3
(m, 3H), 7.52 (dd, J(H,H)=8.6, 6.7 Hz, 1H), 7.73 (d, J(H,H)=8.5 Hz,
1H), 7.82 (dd, 3J(H,H)=8.8, 1.5 Hz, 1H), 7.85 ppm (d, 3J(H,H)=
8.0 Hz, 1H); 13C NMR (126 MHz, C2D2Cl4, 508C, TMS): d=26.5, 32.6,
36.5, 74.0, 106.7, 115.7, 116.8, 117.6, 118.5, 121.8, 122.7, 123.5,
124.2, 124.6, 125.1, 125.5, 125.5, 127.8, 128.1, 128.7,
129.1, 129.3, 129.7, 130.1, 130.8, 132.1, 133.0, 135.5,
145.7, 150.6, 153.3, 155.0 ppm; IR (ATR): n˜ =1572, 1481,
1444, 1432, 1383, 1373, 1251, 1263, 1251, 1236, 1217,
810, 747, 735, 690 cmꢀ1; UV/Vis (CH3CN): lmax (loge)=
214 (4.8856), 266 (4.4164), 326 (3.9797), 353 (3.8447),
397 nm (3.9685); MS (ESI): m/z (%): 476.2 (100) [M]+,
499.2 (76) [M+Na]+; HRMS (ESI): m/z calcd for C35H24O2:
476.1771; found: 476.1767 [M+Na]+.
(169 mg, 560 mmol, 5.00 equiv) in degassed DMF (3 mL) was stirred
at 1008C for 14.5 h. After cooling to RT, the solution was filtered
through silica gel and the solvent of the filtrate was removed
under vacuum. Column chromatography (silica gel, n-pentane/
Synthesis of 6i: General procedure for the three-
fold domino reaction
A
mixture of 7i (21.9 mg, 35.7 mmol, 1.00 equiv),
[Pd(OAc)2] (80.1 mg, 3.57 mmol, 0.01 equiv), PPh3 (468 mg,
17.9 mmol, 0.05 equiv), and (nBu)4NOAc (53.7 mg,
178 mmol, 3.00 equiv) in degassed DMF (3 mL) was
stirred at 1008C for 26.5 h. After cooling to RT, the reac-
tion mixture was filtered through silica gel, flushed with
EtOAc, and the solvent of the filtrate was removed
under vacuum. Column chromatography (silica gel, n-
Figure 2. 1H NMR spectrum of 6a (aromatic region) at 57, 25, and ꢀ378C in CDCl3.
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3
3
2H), 2.74 (brs, 2H), 2.84 (t, J(H,H)=6.8 Hz, 2H), 6.73 (d, J(H,H)=
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3
3
1H), 7.15 (d, J(H,H)=8.7 Hz, 1H), 7.20 (d, J(H,H)=8.1 Hz, 1H), 7.26
(t, 3J(H,H)=8.0 Hz, 1H), 7.30 (t, 3J(H,H)=7.4 Hz, 1H), 7.38 (d,
3J(H,H)=8.7 Hz, 1H), 7.41–7.48 (m, 3H), 7.53 (t, 3J(H,H)=7.6 Hz,
1H), 7.77 (d, 3J(H,H)=8.4 Hz, 1H), 7.82 (d, 3J(H,H)=8.7 Hz, 1H),
7.86 ppm (d, 3J(H,H)=8.0 Hz, 1H); 13C NMR (126 MHz, C2D2Cl4,
508C, TMS): d=26.5, 31.2, 32.6, 33.8, 36.6, 74.0, 106.7, 115.7, 116.9,
117.7, 118.3, 119.1, 121.8, 123.2, 124.2, 124.6, 125.0, 125.5, 125.5,
125.8, 127.8, 128.3, 128.7, 129.4, 129.7, 130.0, 130.8, 132.0, 133.0,
135.5, 145.7, 145.8, 150.6, 153.3, 154.5, 155.5 ppm; IR (ATR): n˜ =
3344, 3057, 2956, 2925, 2866, 1621, 1600, 1574, 1506, 1481, 1458,
1445, 1433, 1373, 1264, 1237, 1171, 1141, 1109, 1098, 1070, 1049,
1032, 1013, 1003, 982, 948, 923, 900, 877, 846, 832, 812, 784, 751,
736, 702, 665, 648, 637, 629, 606, 546 cmꢀ1; UV/Vis (CH3CN): lmax
(loge)=194 (5.2866), 213 (4.6149), 267 (4.1242), 326 (3.7003),
397 nm (3.6590); MS (ESI): m/z (%): 532.2 (100) [M+H]+; HRMS
(ESI): m/z calcd for C39H32O2: 532.2397; found: 532.2402 [M+H]+.
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[8] X-ray crystallography: X-ray data were collected by using a STOE IPDS II
diffractometer (graphite-monochromated MoKa radiation, l=0.71073 ꢄ)
by use of w scans at ꢀ1408C. The structure was solved by direct meth-
ods (SHELXS) and refined on F2 using all reflections with SHELXL-97.1;
see Ref. [9]. Non-hydrogen atoms were refined anisotropically. Hydro-
gen atoms were placed in calculated positions and assigned to isotrop-
ic displacement parameters of 1.2/1.5Ueq(C). Face-indexed absorption
corrections were performed numerically with the X-RED 2 program; see
Ref. [10]. Experimental procedure: Compound 6a (5 mg) was dissolved
in Et2O (5 mL) and stored in an n-hexane atmosphere. The method
could be reproduced. Empirical formula: C35H24O2, Mr: 476.54, crystal
Acknowledgements
We thank the Bundesland Niedersachsen, the Deutsche For-
schungsgemeinschaft, and the Volkswagen-Stiftung for their
generous support.
Keywords: CꢀH-activation
·
domino reactions
·
dyes/
pigments · luminescence · palladium
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¯
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99.404(4)8; T=133(2) K, l=0.71073 ꢄ; V=2383.9(2) ꢄ3; Z=4; 1calcd
=
1.328 Mgmꢀ3
; ; F(000)=1000; crystal size: 0.500ꢅ
e=0.081 mmꢀ1
0.450ꢅ0.240 mm3; q range for data collection: 1.219–26.0998; index
ranges: ꢀ11 ꢂhꢂ11, ꢀ19ꢂkꢂ18, ꢀ22ꢂlꢂ22; reflections collected:
44852; independent reflections: 44852; completeness to q=25.2428:
99.9%; absorption correction: numerical; max/min transmission:
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data/restraints/parameters: 44852/0/668; GoF on F2: 0.965; final R indi-
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0.1429; extinction coefficient: n/a; largest diff. peak/hole: 0.229/
ꢀ0.149 eꢄꢀ3
.
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Full Paper
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[12] Fluorescence spectrum: The spectrum was recorded by using an FP
6500 fluorimeter by JASCO. Light source: 150 W Xe lamp; photometric
system: monochromatic light; monochromator: signal-to-noise ratio
(Raman band of water, 350 nm excitation wavelength, 2 s response
time, 5 nm bandwidth) of 200:1 (excitation and emission monochroma-
tor), measuring wavelength range: zero order, 220–750 nm; resolution:
1 nm (excitation and emission), wavelength accuracy: +/ꢀ1.5 nm (exci-
tation and emission); wavelength reproducibility: +/ꢀ0.3 nm (excita-
tion and emission); detector: photomultiplier tube (excitation and emis-
sion). Experimental procedure: Compound 6a (980 mg) was dissolved in
acetonitrile (6 mL; c=3.43ꢅ10ꢀ4 molLꢀ1).
Received: April 4, 2014
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Fast Domino: We report a facile synthe-
sis that converts simple molecules into
polycyclic fluorescent dyes. The synthet-
ic route entails a fourfold Pd-catalyzed
domino Sonogashira/double-carbopalla-
dation/CꢀH-activation process that ena-
bles efficient transformation of alkyne
precursors into the desired products.
These products exhibit strong fluores-
cence radiation in the blue spectral
region (see figure).
&
Domino Reactions
L. F. Tietze,* C. Eichhorst, T. Hungerland,
M. Steinert
&& – &&
A Fast Way to Fluorescence: A
Fourfold Domino Reaction to
Condensed Polycyclic Compounds
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ