Facile synthesis of cyanoarenes from quinones by reductive aromatization of cyanohydrin intermediates

Article abstract of DOI:10.1055/s-0034-1380150

A novel synthesis of cyanoarenes from quinones by using PCl₃ as the reagent for reductive aromatization of cyanohydrin intermediates is reported. In situ IR spectroscopic measurements were conducted to monitor the reactions and to develop a convenient one-pot protocol. 1,4-Dicyanobenzene and 9,10-dicyanoanthracene were prepared by the new procedure.

Full text of DOI:10.1055/s-0034-1380150

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Georg Thieme Verlag Stuttgart · New York
2015, 26, 950–952
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letter
Synlett
F. Glöcklhofer et al.
Letter
Facile Synthesis of Cyanoarenes from Quinones by Reductive
Aromatization of Cyanohydrin Intermediates
Florian Glöcklhofer*
N
N
Markus Lunzer
O
TMS
TMS-CN, CsF
O
Johannes Fröhlich
PCl3, DMF
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Getreidemarkt 9/163, 1060 Vienna, Austria
florian.gloecklhofer@tuwien.ac.at
O
O
TMS
N
N
Received: 18.12.2014
Accepted after revision: 14.01.2015
Published online: 19.02.2015
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R
DOI: 10.1055/s-0034-1380150; Art ID: st-2014-d1040-l
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M(X)
SnCl2
Abstract A novel synthesis of cyanoarenes from quinones by using
PCl as the reagent for reductive aromatization of cyanohydrin interme-
3
diates is reported. In situ IR spectroscopic measurements were con-
ducted to monitor the reactions and to develop a convenient one-pot
protocol. 1,4-Dicyanobenzene and 9,10-dicyanoanthracene were pre-
pared by the new procedure.
a
b
OH
N
O
R
R
N
Key words arenes, cyanohydrins, nitriles, quinones, reduction
O
TMS
O
Quinones, and in particular 1,4-benzoquinones, are fre-
quently used as building blocks in organic synthesis due to
their widespread availability and their modifiability by nu-
i
ii
1
merous reactions. In recent years, modification by nucleo-
O
TMS
philic attack of acetylides at the carbonyl functionalities of
quinones and subsequent reductive aromatization (mostly)
N
N
2
1
a cis isomer
1b trans isomer
155 mg, 30% (one-pot)
53 mg, 30% (stepwise)
1
using SnCl (Scheme 1, a) has gained significant attention in
2
organic synthesis, particularly in the field of organic func-
tional materials. TIPS-pentacene, to name just one of the
Scheme 1 (a) Well-established synthesis of ethynyl-substituted aro-
matic compounds. (b) Novel synthesis of cyanated aromatic com-
pounds: nucleophilic attack (i): TMSCN, CsF, MeCN, 0 °C, 10 min;
2
most prominent compounds synthesized by this approach,
is a frequently used and well-investigated material for or-
reductive aromatization (ii): PCl , DMF, MeCN, 0 °C to r.t., 1.5 h.
3
3
ganic field-effect transistors.
The corresponding introduction of cyanides instead of
acetylides has not been described in the literature, although
theoretical calculations suggest that cyano substituents in-
crease the electron affinity, reduce the internal reorganiza-
tion energy and promote the π-stacking of molecules.4
These properties render cyanoarenes particularly promis-
ing for (n-type) organic semiconductors. The development
of a facile and cheap synthesis of these compounds from
quinones therefore represents a major benefit to a broad
field of organic chemistry. Using quinones as reactants en-
ables the preparation of many compounds from available
substrates; on the other hand, it allows for substitution pat-
terns that are difficult to realize using alternative methods.
5
Unlike lithium acetylides, cyanides favor 1,4-addition to
benzoquinones over 1,2-addition. This problem can be
overcome by the application of trimethylsilyl cyanide (TMSCN)
for the synthesis of stable (silylated) cyanohydrins. Follow-
ing a protocol for the mild and efficient preparation of cy-
6
anohydrins in acetonitrile using CsF as catalyst, but carry-
ing out the reaction at lower temperatures of 0 °C, resulted
in a 1:1 cis/trans isomeric mixture of 1a,b (Scheme 1, b).
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The isomer ratio was determined by H NMR spectroscopy
chlorinated dicyanobenzene based on GC–MS measure-
ments. We assume chlorination (substitution of an O-TMS
group) followed by a similar elimination–rearrangement
step as described for the reaction of 3,6-dimethoxy-3,6-di-
methyl-1,4-cyclohexadiene to methoxyxylenes10 to be re-
sponsible for the formation of this by-product.
1
after evaporation of the solvent. The H NMR signals of the
trans isomer 1b were published recently in a crystallo-
graphic report, which allowed assignment of the signals to
7
the respective isomers.
The rapid reaction using 3 equivalents of TMSCN and 20
mol% CsF was monitored by in situ IR spectroscopic mea-
surements (Figure 1, top left). To follow the conversion of
the starting material, the carbonyl vibrational bands were
integrated in a range of 1730 cm to 1628 cm . Cyanohy-
drin formation was monitored by plotting the area of a
Based on these results and due to the reducing proper-
ties of PCl3,11 we tested it as a reagent for reductive aromati-
zation. Indeed, addition of PCl to a solution of crude 1a,b in
3
–1
–1
acetonitrile afforded 2 if two small drops of DMF were add-
ed (153 mg, 30% yield). Only a very small amount of the
aforementioned by-product was observed (larger amounts
of DMF resulted in increased by-product formation). Con-
version was again monitored by in situ IR spectroscopic
measurements (Figure 1, top right). The lower peak area at
the starting point of the reaction is explained by precipita-
tion of the intermediate product when the reaction was
–1
–1
newly appearing peak at 1138 cm to 1100 cm (interme-
diate peak).
cooled to 0 °C for addition of DMF and PCl . The reaction
3
was then allowed to warm to room temperature, resulting
in increased solubility and, thus, in an increased intermedi-
ate product peak area in the early stage of the aromatiza-
tion reaction.
As the reaction progressed, precipitation at the IR probe
was observed, which led to a deviation of the measured val-
ues (Figure 1, grey lines) from the expected results (Figure
1, dotted lines). However, an estimation of the reaction
time as 90 minutes turned out to be consistent with GC–MS
measurements.
Furthermore, we were able to synthesize 2 in a conve-
nient one-pot reaction without isolating the intermediate
compounds 1a,b. TMSCN was added only until the carbonyl
vibrational bands disappeared completely, thus 2.0 equiva-
lents TMSCN was added, followed by another two additions
of 0.1 equivalent each (Figure 1, bottom). After stirring for
1
0 minutes, two drops of DMF and 1.0 equivalent of PCl3
Figure 1 In situ IR spectroscopic measurements of the reactions to-
ward 1a,b (i) and 2 (ii): stepwise (top) and one-pot reaction (bottom);
were added and the reaction was allowed to warm to room
temperature. After 1.5 hours, the reaction was diluted with
dichloromethane and filtered directly through a pad of sili-
ca using dichloromethane as eluent. Evaporation of the sol-
–
1
–1
peaks integrated from 1730 cm to 1628 cm (carbonyl vibrational
bands), 1138 cm–1 to 1100 cm (intermediate peak); solid lines: mea-
sured values, dotted lines: expected values (deviation attributed to pre-
cipitation at the IR probe).
–1
12
vent afforded 1,4-dicyanobenzene (2) in a yield of 30%.
A greater excess of TMSCN turned out to inhibit aroma-
tization in one-pot reactions. However, if the solvent and
excessive TMSCN were evaporated in vacuo, the reaction
not only proceeded in acetonitrile, but also in dichloro-
methane and in THF. Application of other reducing agents
such as phosphorous acid, diethyl phosphite, trimethyl
phosphite, sodium metabisulfite and sodium sulfite instead
Direct reductive aromatization of 1a,b towards target
compound 2 (Scheme 1, b) using SnCl (or Zn) proved to be
2
impossible. This reaction yields 4-cyanophenol, as was pre-
viously described when applying SmI as reducing agent in
2
8
a similar reaction. Deprotection of 1a,b and following re-
ductive aromatization may appear to be a suitable solution
to this problem, but results in the back-formation of 1,4-
benzoquinone.
of PCl did not result in any product formation.
3
To investigate the applicability of the reaction condi-
tions to larger and less soluble substrates, we synthesized
9,10-dicyanoanthracene (3) from 9,10-anthraquinone
(Scheme 2). In situ IR spectroscopic measurements were
not suitable for monitoring the reaction progress due to the
above-mentioned low solubility. However, according to GC–
MS measurements, cyanohydrin formation was complete
9
Inspired by the work of Yamaguchi et al, we applied
POCl3 in anhydrous pyridine for aromatization toward 2,
and product formation was indeed observed. However, we
obtained a significant amount of aromatic by-product that
we were not able to separate efficiently from 2 using col-
umn chromatography. This by-product was attributed to a
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F. Glöcklhofer et al.
Letter
after five hours and aromatization was complete overnight.
Yields of 27% were achieved after workup. Larger amounts
of DMF (0.5 equiv) were added to allow for a one-pot syn-
thesis despite a larger excess of TMSCN (1.0 equiv excess).
This is possible in the synthesis of 3, since by-product for-
mation by rearrangement as for 2 is not feasible.
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2
43 mg, 27% (one-pot)
Scheme 2 One-pot synthesis of 9,10-dicyanoanthracene (3) from
,10-anthraquinone: nucleophilic attack (i): TMSCN, CsF, MeCN, 0 °C, 5 h;
2
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3
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In conclusion, the developed protocol is notable due to
its convenience and straightforwardness. For the first time,
reductive aromatization of cyanohydrins to dicyanoarenes
has been demonstrated. One-pot conversion to the respec-
tive arenes has also been demonstrated for both 1,4-benzo-
quinone, which is prone to 1,4-addition and rearrange-
ments, and for 9,10-anthraquinone, which is characterized
by low solubility in acetonitrile.
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Acknowledgment
We thank Brigitte Holzer, Paul Kautny and Philipp Skrinjar for NMR
experiments. Esther Knittl and Felix Biegger are acknowledged for
support with solid-phase ATR-IR measurements.
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including complete experimental and instrumental details for the
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and
characterization
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http://dx.doi.org/10.1055/s-0034-1380150.
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(
12) General Procedure (One-Pot): 1,4-Benzoquinone (1.0 equiv)
References and Notes
was dissolved in MeCN (1 M) and added to a suspension of CsF
(
0.2 equiv) in MeCN (0.2 M) at 0 °C. The reaction was carefully
(
1) (a) The Chemistry of the Quinonoid Compounds; Vol. 2; Patai, S.;
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purged with argon and TMSCN (2.0 equiv) was added dropwise,
followed by another two additions after 4 min (0.1 equiv) and 6
min (0.1 equiv). After 10 min of total stirring time, DMF (2 small
drops) and PCl3 (1.0 equiv) were added. The reaction was
allowed to warm to r.t. and stirred for 90 min. The resulting sus-
pension was diluted with CH Cl and filtered through a pad of
22, 385.
2
2
(2) (a) Lin, Y.-Z.; Huang, C. H.; Chang, Y. J.; Yeh, C.-W.; Chin, T.-M.;
silica using CH Cl as the eluent. Evaporation of the solvent
afforded 1,4-dicyanobenzene (2) as a white solid (30% yield).
2
2
Chi, K.-M.; Chou, P.-T.; Watanabe, M.; Chow, T. J. Tetrahedron
2014, 70, 262. (b) Ghosh, K. R.; Saha, S. K.; Gao, J. P.; Wang, Z. Y.
Chem. Commun. 2014, 50, 716. (c) Glöcklhofer, F.; Lumpi, D.;
©
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