Synthesis of Acyl Terphenyls and Higher Polyaromatics via Base-Promoted C-H Functionalization of Acetylarenes with Arylacetylenes

Article abstract of DOI:10.1021/acs.orglett.6b00782

KO^tBu/DMSO-promoted C-H functionalization of acetylarenes with arylacetylenes (100°C, 30 min), generating β,γ-ethylenic ketones, triggers upon further heating (100°C, 4 h, with or without acidifying additive) the cascade assembly of acyl terphenyls and higher polyaromatics in good yields.

Full text of DOI:10.1021/acs.orglett.6b00782

Letter
pubs.acs.org/OrgLett
Synthesis of Acyl Terphenyls and Higher Polyaromatics via Base-
Promoted C−H Functionalization of Acetylarenes with
Arylacetylenes
Elena Yu. Schmidt, Elena V. Ivanova, Inna V. Tatarinova, Igor’ A. Ushakov, Nadezhda V. Semenova,
Alexander V. Vashchenko, and Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia
S
* Supporting Information
ABSTRACT: KOtBu/DMSO-promoted C−H functionaliza-
tion of acetylarenes with arylacetylenes (100 °C, 30 min),
generating β,γ-ethylenic ketones, triggers upon further heating
(100 °C, 4 h, with or without acidifying additive) the cascade
assembly of acyl terphenyls and higher polyaromatics in good
yields.
Table 1. Optimization of the Reaction Conditions for the
Synthesis of Terphenyl 4a
he search for straightforward and efficient methods to
Tassemble complex molecular scaffolds, especially carbo-
and heterocycles, from readily accessible precursors is one of the
major and most enduring challenges in synthetic organic
chemistry. In pursuit of this objective, cascade reaction processes
comprising multiple structural transformations in a single
synthetic step are highly attractive, especially those which
proceed with good regio- and stereoselectivity.1 Acetylenes have
become increasingly attractive starting materials for such
processes, due to their ability to simultaneously function as
electrophilic and nucleophilic reagents. In the presence of
superbases (such as alkali metal hydroxide or alkoxide/DMSO),
this dual reactivity of acetylenes is most pronounced.
Combination of these competing processes (acetylene deproto-
nation and nucleophilic addition to the triple bond) provides the
possibility of new reactions, which often represent one-pot
multistep assemblies of intricate structures with involvement of
several molecules in the process.1c
a
temp
time
c
content of 3a
yield of 4a
b
c
d
e
entry additive, equiv
(°C)
(h)
(%)
(%)
1
2
none
100
120
120
120
120
120
100
100
120
120
120
120
4
4
2
3
4
5
2
4
2
4
2
4
15
61
32
11
32
49
53
51
72
67
63
65
66
H2O, 1.00
50
3
NaHCO3, 0.66
NaHCO3, 0.66
NaHCO3, 0.66
NaHCO3, 0.66
MeCO2H, 0.66
MeCO2H, 0.66
MeCO2H, 0.66
MeCO2H, 0.66
MeCO2H, 1.00
MeCO2H, 1.00
65
4
46
5
22
6
none
13
7
8
none
15
9
It is the KOH/DMSO and KOtBu/DMSO systems that have
allowed the stereoselective C−H functionalization of ketones
with acetylenes to be discovered (Scheme 1).2
10
11
12
none
14
none
a
The reaction provides a straightforward entry to the chemistry
of hitherto hardly accessible β,γ-ethylenic ketones 3, which are
promising building blocks for fine organic synthesis,3 and can
also be used in one-pot assemblies (without isolation of β,γ-
ethylenic ketones 3) of pharmaceutically and synthetically
important functionalized carbo-4 and heterocyclic5 compounds.
Reagents and conditions: 1a (0.605 g, 5.0 mmol), 2a (0.510 g, 5.0
mmol), KOtBu (0.561 g, 5.0 mmol), and DMSO (15 mL), 100 °C, 30
b
c
min; additive was introduced. Relative to acetophenone 1a. After
d
heating at 100 °C for 30 min. In the crude product (1H NMR).
e
Isolated yield after column chromatography (Al2O3, eluent hexane/
ethyl ether with gradient from 1:0 to 10:1).
As a further development of this inspiring approach to the
synthesis of valuable cyclic compounds, here, we disclose another
serendipitous finding of the one-pot assembly of acylated
terphenyls and related polyaromatics via the cascade reactions
between readily available acetylarenes 1 and arylacetylenes 2.
Scheme 1. Base-Promoted Addition of Ketones to Acetylenes
Received: March 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope and Product Yields for the Reaction of Acetylarenes 1a−g with Arylacetylenes 2a−d
a
Reagents and conditions: acetylarene 1 (5.0 mmol), arylacetylene 2 (5.0 mmol), KOtBu (0.561 g, 5.0 mmol), DMSO (15 mL), 100 °C, 30 min;
b
MeCO2H (3.3 mmol), 100 °C, 4 h. Isolated yield after column chromatography.
We have revealed that acetophenone 1a, when heated with
phenylacetylene 2a in the KOtBu/DMSO system longer (4 h
instead of 0.5 h) than is required for synthesis of the
corresponding β,γ-unsaturated ketone 3a,2 gave 2-benzoylter-
phenyl 4a as the major reaction product (Table 1). Afterward, we
focused our efforts on optimization of this process, first on the
example of this very reaction. Selected results are presented in
Table 1.
equiv of KOtBu in DMSO, was heated at 100 °C for 4.5 h (entry
1). When acetic acid was added, after the above reaction mixture
was kept at 100 °C for 30 min, and the heating was continued
additionally for 2−5 h, terphenyl 4a was formed in improved
yield along with toluene (as detected by GLC). However, when 1
equiv (relative to 1a) of water was added to the reaction mixture
(entry 2), the yield of 4a was reduced to 32%, even at a higher
temperature (120 °C instead of 100 °C). When NaHCO3 was
incorporated, the yield of 4a was also poor (entries 3−5). The
best yield (72%) was attained using acetic acid as an additive at
The reaction was implemented as follows: a mixture of
acetophenone 1a and phenylacetylene 2a, in the presence of 1
B
DOI: 10.1021/acs.orglett.6b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetophenone 1a, phenylacetylene 2a, and KOtBu (molar ratio of
1a/2a/KOtBu = 1:1:1) were heated for 30 min at 100 °C in
DMSO, and the heating was continued with MeCO2H (0.66
equiv) for 4 h at 100 °C.
Scheme 2. Reaction of Acetophenone 2a with Acetylene 2b
These optimized conditions were applied for the reactions of a
variety of acetylarenes 1 with diverse arylacetylenes 2 (Table 2).
As can be seen from Table 2, the synthesis of acylated
terphenyls and related polyaromatics was efficient for a wide
range of acetylaromatics and also valid for acetyl-condensed
aromatics and heteroaromatics. Various arylacetylenes worked
well in this reaction to give the hitherto inaccessible substituted
polyaromatic ketones in good yields. Both electron-donating and
electron-withdrawing substituents (methyl, phenyl, fluoro, and
chloro) in the acetylarene and arylacetylene partner were well-
tolerated. Note that acetyl thiophene was also a suitable substrate
for this process to provide a product with the combination of two
thiophenes with two benzene rings and a carbonyl moiety all in
one molecule.
Scheme 3. Plausible Pathway for the Cascade Formation of
Terphenyls 4
In accordance with the above observation, in the crude
products, there were always some amounts of β,γ-unsaturated
ketones 3 (Scheme 1), which were easily separated from the
major products by SiO2 column chromatography. Also, like the
formation of toluene during the synthesis of terphenyl 4a, the
analogous methyl aromatics, such as 4-methyl-1,1′-biphenyl 5
(when 4-ethynyl-1,1′-biphenyl 2b was used), were present in the
reaction mixtures, thus indicating this elimination process was a
general one (Scheme 2).
The structure of products 4 was confirmed unambiguously by
X-ray crystallography of one of their representatives, 4b (CCDC
1453334; see Supporting Information).
Possibly, this assembly of the acylated terphenyls 4 involves
the following cascade sequence (Scheme 3). Initially, the enolate
derived from 1 adds onto the aryl(heteroaryl) acetylene to
generate a stabilized vinyl anion that protonates to afford 32 and
re-enolizes to give A. The latter then does an aldol addition to
deliver B. Next, triene B is isomerized into the conjugated triene
C, which undergoes electro- or base-catalyzed cyclization to
dihydrobenzene D. Elimination of methyl aromatics from the
dihydrobenzene moiety leads to its aromatization, with the latter
being the driving force of this elimination.
Scheme 4. Reaction of Propiophenone with Phenylacetylene
2a
As stated above, this elimination of the methyl aromatics at the
final stage of this cascade sequence was confirmed experimen-
tally.
Notably, when propiophenone reacted with phenylacetylene
2a under the above conditions, only an equilibrium mixture of
the isomeric β,γ- and α,β-ethylenic ketones in a 2:1 ratio was
formed (Scheme 4). Evidently, this cascade sequence was
impossible.
To obtain additional robust support for the mechanism of this
transformation, we have implemented the self-condensation of
the preliminarily isolated β,γ-unsaturated ketone intermediates
3a,b, and these afforded the expected terphenyls 4a,b in good
yields (Scheme 5). Thus, unambiguous evidence for the
suggested mechanism was provided.
Scheme 5. Transformation of Intermediate β,γ-Unsaturated
Ketones 3 into Terphenyls 4
To assess the practical value and feasibility of the developed
methodology, we performed the reaction of acetophenone 1a
with phenylacetylene 2a on a larger scale (25 mmol each, 5.575 g
all together). The expected terphenyl 4a was obtained in 77%
yield. This proves the scalability of the process.
It is relevant to note here that functionalized terphenyls are
widely used in materials science as important building blocks for
the preparation of laser dyes, scintillators, heat-resistant
polymeric materials, heat storage, and transfer agents.6 Some
100 °C (entry 8), whereas at 120 °C, the yield of the target
product decreased by 9% (entry 10).
Thus, based on the data of Table 1, the most suitable
conditions for the synthesis of terphenyl 4a were as follows:
C
DOI: 10.1021/acs.orglett.6b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A. I. Adv. Synth. Catal. 2012, 354, 1813. (c) Trofimov, B. A.; Schmidt, E.
Yu.; Ushakov, I. A.; Zorina, N. V.; Skital’tseva, E. V.; Protsuk, N. I.;
Mikhaleva, A. I. Chem. - Eur. J. 2010, 16, 8516.
(3) (a) Iwasaki, M.; Morita, E.; Uemura, M.; Yorimitsu, H.; Oshima, K.
Synlett 2007, 2007, 167. (b) Comprehensive Organic Functional Group
Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier, 2005.
(c) Gohain, M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S. New J. Chem.
2003, 27, 1038. (d) Ohtsuka, Y.; Sasahara, T.; Oishi, T. Chem. Pharm.
Bull. 1982, 30, 1106.
(4) (a) Schmidt, E. Yu.; Trofimov, B. A.; Bidusenko, I. A.;
Cherimichkina, N. A.; Ushakov, I. A.; Protzuk, N. I.; Gatilov, Y. V.
Org. Lett. 2014, 16, 4040. (b) Trofimov, B. A.; Schmidt, E. Yu.;
Skitaltseva, E. V.; Zorina, N. V.; Protsuk, N. I.; Ushakov, I. A.; Mikhaleva,
A. I.; Dyachenko, O. A.; Kazheva, O. N.; Aleksandrov, G. G. Tetrahedron
Lett. 2011, 52, 4285.
(5) (a) Ouyang, L.; Qi, C.; He, H.; Peng, Y.; Xiong, W.; Ren, Y.; Jiang,
H. J. Org. Chem. 2016, 81, 912. (b) Wang, Y.-C.; Wang, H.-S.; Huang,
G.-B.; Huang, F.-P.; Hu, K.; Pan, Y.-M. Tetrahedron 2014, 70, 1621.
(c) Undeela, S.; Ramchandra, J. P.; Menon, R. S. Tetrahedron Lett. 2014,
55, 5667. (d) Schmidt, E. Yu.; Tatarinova, I. V.; Ivanova, E. V.; Zorina,
N. V.; Ushakov, I. A.; Trofimov, B. A. Org. Lett. 2013, 15, 104.
(e) Trofimov, B. A.; Schmidt, E. Yu.; Ushakov, I. A.; Mikhaleva, A. I.;
Zorina, N. V.; Protsuk, N. I.; Senotrusova, E. Yu.; Skital’tseva, E. V.;
Kazheva, O. N.; Alexandrov, G. G.; Dyachenko, O. A. Eur. J. Org. Chem.
2009, 2009, 5142.
terphenyls exhibit significant biological activities, such as
cytotoxic, immunosuppressant, neuroprotective, anti-throm-
botic, and anticoagulant agents.7 This is why terphenyls generate
an ever-increasing research interest.
The classic methods for the synthesis of substituted terphenyls
involve free-radical substitution of an aromatic ring as well as
Ullmann and related reactions and condensations of quinones.7b
Separate substituted terphenyl compounds are prepared by
methods with more limited scope.7b Recently, syntheses of
terphenyls using Pd-catalyzed cross-coupling of bis(triflates) of
dihydrobenzophenones,8 Mn-catalyzed dehydrative [2 + 2 + 2]
coupling of 1,3-dicarbonyl compounds and terminal acetylenes,9
and Au-catalyzed [4 + 2] benzannulation between enynals and
enols10 were published. Therefore, this conceptually new
methodology reported here, which is based on inexpensive
readily available starting materials (acetylarenes and arylacety-
lenes) and a common superbase catalytic system (KOtBu/
DMSO), increases the accessibility and structural variety of
terphenyls and related polyaromatics.
In summary, a new facile and efficient methodology for
construction of acyl terphenyls and higher polyaromatics via a
base-promoted C−H functionalization of acetylarenes with
arylacetylenes was developed.
(6) (a) Lee, C. W.; Lee, J. Y. Dyes Pigm. 2014, 101, 150. (b) Sasabe, H.;
Pu, Y.-J.; Nakayama, K.; Kido, J. Chem. Commun. 2009, 6655.
(c) Electronic Materials: The Oligomer Approach; Muellen, K., Wegner,
G., Eds.; Wiley-VCH: Weinheim, 1998.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) (a) Gonzal
́
ez-Bulnes, L.; Ibanez, I.; Bedoya, L. M.; Beltran, M.;
́
́
̃
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00782.
Catalan, S.; Alcamí, J.; Fustero, S.; Gallego, J. Angew. Chem., Int. Ed.
́
2013, 52, 13405. (b) Liu, J.-K. Chem. Rev. 2006, 106, 2209.
(8) Khera, R. A.; Nawaz, M.; Feist, H.; Villinger, A.; Langer, P. Synthesis
2012, 2012, 219.
1
Experimental procedure, compound characterization, H
and 13C NMR spectra of all compounds, and crystallo-
graphic data (PDF)
(9) Tsuji, H.; Yamagata, K.; Fujimoto, T.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 7792.
(10) (a) Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71, 5249. (b) Asao,
N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: boris_trofimov@irioch.irk.ru.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant from the Russian Scientific
Foundation (Project No. 14-13-00588).
■
REFERENCES
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DOI: 10.1021/acs.orglett.6b00782
Org. Lett. XXXX, XXX, XXX−XXX