2-Ethynylperylene and improved synthesis of 3-ethynylperylene

Article abstract of DOI:10.1016/j.tetlet.2016.01.067

3-Ethynylperylene 1, an important precursor for fluorescent dyes, fluorescent nucleosides, and potent nucleoside-based antivirals, has been prepared from perylene on a multigram scale (3 steps, 55% overall yield). A simple synthesis of 2-ethynylperylene 2 from perylene (5 steps, 20% yield) has been developed. UV and fluorescence spectra of the ethynylperylenes 1 and 2 are compared to those of perylene.

Full text of DOI:10.1016/j.tetlet.2016.01.067

Accepted Manuscript
2
-Ethynylperylene and improved synthesis of 3-ethynylperylene
Alexey A. Chistov, Sergey V. Kutyakov, Alexey V. Ustinov, Ilya O. Aparin,
Anton V. Glybin, Irina V. Mikhura, Vladimir A. Korshun
PII:
S0040-4039(16)30066-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.067
TETL 47231
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 December 2015
15 January 2016
19 January 2016
Please cite this article as: Chistov, A.A., Kutyakov, S.V., Ustinov, A.V., Aparin, I.O., Glybin, A.V., Mikhura, I.V.,
Korshun, V.A., 2-Ethynylperylene and improved synthesis of 3-ethynylperylene, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.01.067
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Graphical Abstract
2
3
-Ethynylperylene and improved synthesis of
-ethynylperylene
Alexey A. Chistov, Sergey V. Kutyakov, Alexey V. Ustinov, Ilya O. Aparin, Anton V. Glybin, Irina V. Mikhura
and Vladimir A. Korshun*

1
Tetrahedron Letters
2
-Ethynylperylene and improved synthesis of 3-ethynylperylene
Alexey A. Chistov, Sergey V. Kutyakov, Alexey V. Ustinov, Ilya O. Aparin, Anton V. Glybin,
Irina V. Mikhura and Vladimir A. Korshun
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3-Ethynylperylene 1, an important precursor for fluorescent dyes, fluorescent nucleosides, and
potent nucleoside-based antivirals, has been prepared from perylene on a multigram scale (3
steps, 55% overall yield). A simple synthesis of 2-ethynylperylene 2 from perylene (5 steps,
20% yield) has been developed. UV and fluorescence spectra of the ethynylperylenes 1 and 2 are
compared to those of perylene.
Available online
2
016 Elsevier Ltd. All rights reserved.
Keywords:
Perylene
Ethynylperylenes
Friedel–Crafts acylation
Vilsmeyer–Haak–Arnold formylation
Fluorescence
Introduction
Results and discussion
The most convenient procedure for scale-up appeared to be
3-Ethynylperylene 1, initially studied as a suicide inhibitor of
1
7a
P450 metabolic enzymes; later was used in syntheses of the
bright emitting unit of light harvesting systems, ferrocene-
derived artificial receptor for nucleobases, BODIPY and other
that already used by our research group; the three-stage
synthesis of 1 starting from perylene 3 (Scheme 1). The first step
is the simple Friedel–Crafts acylation to afford ketone 4. This
transformation was initially reported in 1966 by Zieger in 54%
2
3
4
5
6
fluorescent dyes, and fluorescent nucleosides. Moreover, 5-
perylen-3-yl-ethynyl) uracil nucleosides, produced from 3-
9
10
11
(
yield and later reproduced in 40% and 56% yields. In our
attempts to increase the conversion of the starting perylene we
obtained considerable amounts of undesired bis-acetylated
product (non-separable mixture of 3,9- and 3,10-
ethynylperylene via Sonogashira coupling, were recognized as
7
antivirals. However, reported procedures for the synthesis of
2b,3,5c,7a,7d,8
1
were performed on a small scale, probably due to the
limited solubility of perylene derivatives in organic solvents. 2-
Ethynylperylene 2 was not previously reported.
3
diacetylperylenes). However, the addition of AlCl catalyst as a
solution in nitromethane to perylene and acetyl chloride
dissolved in chlorobenzene gave clean mono-acetylation and
9
(
1% yield of 4. The reaction was easily performed on 100 mmol
25 g) scale. Apparently, nitromethane controls the reactivity of
AlCl and favors formation of the mono-acylated product.
3
The next two steps, 4→5→1 (Scheme 1), were previously
performed on a 1.7 g scale (81% yield) and 200 mg scale (91%
7a
yield), respectively. However, yields decreased dramatically
upon scale up. Nevertheless, the modification of the isolation
step in the Vilsmeyer–Haak–Arnold 4→5 transformation allowed
us to obtain an acceptable 66% isolated yield on a 107 mmol
In our studies of antiviral nucleosides we required multigram
(31.5 g) scale. For the Bodendorf fragmentation 5→1 we
quantities of 1 for the synthesis of amphipathic compounds
7b–e
succeeded in keeping the high yield through replacement of the
solvent: a toluene–isopropanol mixture was used instead of
dioxane. The reaction was performed on a 22 mmol (7.5 g) scale
and gave a 92% yield of 1 (5.6 g). Thus, we report herein the
multigram synthesis of 3-ethynylperylene 1 from perylene
dUY11 and aUY11, potent inhibitors
of enveloped viruses
with non-nucleoside mechanism of action. Therefore, our first
aim was to develop a reliable and scalable synthetic procedure
for 1. We were also interested in the isomer 2 in light of its
fluorescence properties and the potential antiviral activity of its
nucleoside derivatives.
—
——

Corresponding author. Tel./fax: +7-499-724-6715; e-mail: korshun@ibch.ru

2
Tetrahedron
Scheme 1. Synthesis of 3- and 2-ethynylperylenes. Reagents and Conditions: (a) AcCl, AlCl
3
/CH
, CH
3
NO
2 3
, chlorobenzene, 40 °C; (b) POCl ,
; (f) DDQ, toluene, reflux.
2
DMF, r.t.; (c) KOH, isopropanol/toluene, reflux; (d) H , 10% Pd/C, 17 bar, 60 °C; (e) AcCl, AlCl
3
2
Cl
2
using inexpensive reagents and solvents.
Perylene ex.
Perylene em.
1
000
800
600
400
200
0
For the preparation of 2-ethynylperylene 2 we used a similar
approach (Scheme 1). Transformations 3→6→7 were already
2
-Ethynylperylene ex.
-Ethynylperylene em.
2
9
reported by Zieger. Perylene hydrogenation was performed
3-Ethynylperylene ex.
3-Ethynylperylene em.
using 10% Pd/C catalyst and gave a similar yield 9 of
hexahydroperylene 6 to that obtained using copper chromite or
12
2 8
Co (CO) .
Acylation of 6 in dichloromethane gave 87% of
ketone 7 vs. 64% by acylation in chlorobenzene as reported
9
earlier. Aromatization of 7 with DDQ (2,3-dichloro-5,6-dicyano-
1
,4-benzoquinone) gave 2-acetylperylene 8 in 62% yield.
Surprisingly, the compound was not reported previously. The
ketone was successively transformed to aldehyde
remarkably, isolated as a single E-stereoisomer) and alkyne 2
8
9
(
using conditions similar to those used in the synthesis of the 3-
isomer. The approach based on hydrogenation–acylation–
aromatization followed by Vilsmeyer–Haak–Arnold formylation
and Bodendorf fragmentation has already been used in the
300
350
400
450
500
550
Wavelength (nm)
Figure 2. Normalized fluorescence spectra (excitation and emission)
of perylene, 2- and 3-ethynylperylene in cyclohexane. Excitation
wavelengths: 385 nm (perylene), 380 nm (2), and 420 nm (1).
1
3
convenient synthesis of 2- and 4-ethynylpyrenes.
Interestingly, the long-wavelength absorbance of 2-
ethynylperylene is rather similar to that of parent hydrocarbon. In
contrast, the absorbance of 3-ethynylperylene is red shifted by
Excitation and emission spectra of 2 are very similar to those
of perylene, while 1 shows some red shift in both spectra (Fig. 2).
Similar effects of differential conjugation was observed on 2- vs.
16–18 nm (Fig. 1).
1
3,14
1
(4)-phenylethynyl derivatives of pyrene.
Stokes shifts for
Perylene
-Ethynylperylene
3-Ethynylperylene
perylene and both ethynylperylenes are about 2 nm.
2
30000
20000
10000
0
Conclusion
To conclude, we report a simple and convenient multigram
procedure for the three step transformation of perylene to 3-
ethynylperylene 1. The previously unknown 2-ethynylperylene 2
has been prepared from perylene in five steps and 20% total
yield. The use of 2 in amphipathic antiviral nucleoside synthesis
and click chemistry applications will be reported elsewhere.
Acknowledgments
The research has been supported by the Russian Science
Foundation (project no. 15-15-00053). We thank Philip
Streshnev, Stanislav Khramyshev and Igor Prokhorenko for
helpful advice.
250
300
350
400
450
500
Wavelength (nm)
Figure 1. UV spectra of perylene, 2- and 3-ethynylperylene in
cyclohexane.

3
Supplementary data
6.
(a)
Korshun, V. A.;
Manasova, E. V.;
Sokolova, T. A.;
Balakin, K. V.;
Berlin, Y. A.
Malakhov, A. D.;
Perepelov, A. V.;
Nucleosides Nucleotides 1998, 17, 1809–1812; (b) Skorobogatyj, M. V.;
Pchelintseva, A. A.; Ustinov, A. V.; Korshun, V. A.; Malakhov, A. D.
Nucleosides Nucleotides Nucleic Acids 2005, 24, 931–934; (c)
Skorobogatyi, M. V.; Malakhov, A. D.; Pchelintseva, A. A.; Turban, A. A.;
Bondarev, S. L.; Korshun, V. A. ChemBioChem 2006, 7, 810–816; (d)
Kumar, P.; Østergaard, M. E.; Baral, B.; Anderson, B. A.; Guenther, D. C.;
Kaura, M.; Raible, D. J.; Sharma, P. K.; Hrdlicka, P. J. J. Org. Chem. 2014,
Supplementary data (synthetic procedures, HRMS, NMR
spectra) associated with this article can be found in the online
version at http://dx.doi.org/10.1016/j.tetlet
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