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Cite this: DOI: 10.1039/c9cc04012a
Received 24th May 2019,
Accepted 12th June 2019

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Connecting a carbonyl and a p-conjugated groupthrough a p-phenylene linker by (5+1) benzene
ring formation†
Tatsuya Morofuji,* Hanae Kinoshita and Naokazu Kano*

DOI: 10.1039/c9cc04012a
rsc.li/chemcomm

A benzene ring was formed to connect a carbonyl group of various
methyl ketones with a p-conjugated group through a p-phenylene
linker. Methyl ketones and streptocyanines were used as the C1 andC5 sources, respectively, in the (5+1) annulation, which could form
donor–p–acceptor molecules.

Connecting two diﬀerent molecules with a linker is a fundamental design principle of functional organic molecules such asorganic devices,1 supramolecular materials,2 bioactive compounds,3and ligands for metal–organic frameworks.4 The p-phenylene groupis one of the most widely used linkers for the following reasons:(1) the rigid structure of the benzene ring defines the relative
position of two substituents on the benzene ring,5 and (2) the
p-phenylene group can connect two substituents with p-conjugation,
which affects the electronic state of the molecule.6 Compared witho- or m-phenylene groups, (3) the p-phenylene group can extend
p-conjugation more effectively because of steric or electronic
reasons, and (4) the planar structure and p-electrons of thebenzene ring induce p–p stacking, which can affect the secondary
structure of the molecules.7
Utilizing these characteristics, various p-phenylene-containing
molecules were designed and synthesized as functional organic
molecules. Particularly, carbonyl-p-phenylene-p molecules (Fig. 1a)are used for a wide range of applications such as receptor
antagonists,8 aggregation-induced emission luminogens,9 andphotoinitiators for free radical polymerization.10 In addition,
when a p-conjugated substituent acts as a donor, such a carbonyl-pphenylene-p molecule could be regarded as a donor–acceptor
molecule, which is an important core structure of thermally activated delayed fluorescent emitters11 and photocatalysts mediating
proton-coupled electron transfer.12
One approach to synthesizing carbonyl-p-phenylene-p molecules is the introduction of a p-conjugated substituent to a
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro,
Toshima-ku, Tokyo 171-8588, Japan. E-mail: tatsuya.morofuji@gakushuin.ac.jp,
naokazu.Kano@gakushuin.ac.jp; Tel: +81-3-5904-9394† Electronic supplementary information (ESI) available: Experimental procedures
and NMR data. See DOI: 10.1039/c9cc04012a

This journal is © The Royal Society of Chemistry 2019

Fig. 1Strategies for synthesis of carbonyl-p-phenylene-p molecules.

benzene ring bearing a carbonyl group via cross-coupling
reactions13 (Fig. 1b). Another method is the connection of acarbonyl group to a benzene ring to form a ketone (Fig. 1c). The
most popular classical approach with respect to the lattermethod is the Friedel–Crafts reaction of acid chlorides andelectron-rich aromatic compounds.14 The reaction of theWeinreb amide or its analogues with organometallic reagentsis an alternative method for ketone formation.15 Transitionmetal-catalyzed ketone formation is also popular.16 These
approaches are valuable, but the scope of the Friedel–Crafts
reaction is limited and some aromatic substrates show undesired
regioselectivity.
The introduction of a p-conjugated group needs to use botharyl halides and arylmetal reagents that require multistep
preparation in most cases. A more convenient regiospecificChem. Commun.

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method for synthesizing carbonyl-p-phenylene-p molecules isstill highly desired.
Benzene ring formation would be an alternative approach tosynthesize benzene-containing molecules. Various approaches
for [2+2+2] and [4+2] benzene ring formation have been developedin the past up to the present.17 However, it is diﬃcult to synthesize
carbonyl-p-phenylene-p molecules using the [2+2+2] and [4+2]annulation because of their inherent 1,4-disubstitution pattern.
In contrast, (5+1) benzene ring formation18,19 could be expected togive 1,4-disubstituted benzene derivatives regioselectively.
Based on this background, we envisioned that (5+1) benzene
ring formation using a methyl ketone 1 as the C1 source and a
C5 source bearing a p-conjugated substituent would be an
attractive approach to obtaining carbonyl-p-phenylene-p molecules because starting methyl ketone 1 is readily available(Fig. 1d). This approach would give the p-phenylene-linked
products regiospecifically. In relation to the approach, conversion of an acetyl group into an unsubstituted benzoyl groupusing a conjugated methine compound (streptocyanine) as a C5
source was reported by Jutz.20 However, the mere formation ofan unsubstituted phenyl group, which restricted applicability ofthis reaction, has not been applied to connecting two fragments
through the benzene ring formed. We report here a new
method for connecting a carbonyl and a p-conjugated groupthrough a p-phenylene linker by benzene ring formation using
a methyl ketone as the C1 source and a streptocyanine bearinga p-conjugated substituent as the C5 source (eqn (1)).

(1)

A working hypothesis is that the (5+1) annulation proceeds
following a pathway such as that shown in Scheme 1. The
enolate generated from methyl ketone 1 and a base attacks an
iminium group in streptocyanines 2, and following the elimination of an amine gives triene intermediate 3. Triene 3 could
be converted thermally to E/Z isomer 4 because of the push–pull
electronic structure.21 Then, 6p electrocyclization22 of 4 gives
cyclohexadiene 5, and following the second elimination of theamine produces the desired carbonyl-p-phenylene-p molecule 6.
It follows that the base, nitrogen substituents, and reaction
temperature could be critical for the successful (5+1) annulation.
We first optimized the reaction conditions for the (5+1)
annulation using streptocyanines bearing no internal substituent(Table 1).20 Acetophenone (1a), streptocyanine 2, and KOtBu weremixed and stirred in THF at 80 1C for 10 h in a pressure tube togive benzophenone (6a) in a 30% yield (entry 1). Higher reaction
temperatures increased the yield of the product (entries 2 and 3).
The nitrogen substituent in streptocyanine 2 was found to aﬀect
the yield, and the piperidinyl substituent turned out to be the best
(entries 3–5). The use of NaOtBu instead of KOtBu as a base gave
the product in an almost quantitative yield (entry 6). The (5+1)

Chem. Commun.

Scheme 1

Proposed reaction mechanism of (5+1) benzene ring formation.

Table 1

Optimization of the reaction conditionsa

Entry

R0, R0Base

Temp. (1C)

Yieldb (%)

1
2
3
4
5
6

Me, MeMe, MeMe, Me–(CH2)2O(CH2)2––(CH2)5––(CH2)5–

KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu

80
100
120
120
120
120

30
53
84
29
89
99 (94)ca
Acetophenone (1a) (0.2 mmol), streptocyanine 2 (1.5 equiv.), and base(1.5 equiv.) were stirred at the indicated temperature in THF (4 mL)
for 10 h. b Yield of the products was determined by 1H NMR analysis
using 1,1,2,2-tetrachloroethane as an internal standard. c Isolated yield.

benzene ring formation was achieved in one pot without isolatingintermediates 3.
Next, we prepared streptocyanines bearing a p-conjugatedsubstituent at the 3-position, 2, for the (5+1) annulation
synthesizing carbonyl-p-phenylene-p molecules. The procedure
for synthesizing streptocyanines 2 is illustrated in Fig. 2.23
N-Arylation of 4-substituted pyridine 7 with 2,5-dinitrochlorobenzene gave the corresponding N-arylpyridinium salt 8 (Fig. 2, A).
The resulting N-arylpyridinium 8 was treated with piperidine,and following salt exchange gave the desired streptocyanine 2(Fig. 2, B). Streptocyanines bearing a p-conjugated substituent
such as a phenyl group, a biphenyl group, a naphthyl group,a benzothiophenyl group, and a pyrenyl group were prepared(2b–2f). Streptocyanines bearing a diphenylamino group, a carbazolyl group, and a tert-butyl group were also synthesized in theThis journal is © The Royal Society of Chemistry 2019

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Fig. 2 Synthesis of streptocyanines bearing a substituent. a NH4PF6 wasused. b KPF6 was used. c NaSbF6 was used.

same manner (2g–2i). It should be noted that streptocyanines
2a–2i could be purified by filtration and washing and did not
require purification by column chromatography.
The synthesized streptocyanines 2 were used for (5+1) annulation under the optimized reaction conditions described inTable 1. Some of the scope of the reaction is shown in Fig. 3.
The functional group compatibility of the present transformationis remarkable. Acetophenones bearing an electron-donating group
and an electron-withdrawing group gave the corresponding
products (6b–6h) in excellent to moderate yields. Particularly,
iodo- or bromo-substituted products (6e, 6f) are valuable
because further transformation of the products is easy using
a transition-metal catalyst. Additionally, benzylacetone, which
is an aliphatic ketone, could also be used for (5+1) annulation
to give the corresponding product 6i.
This annulation reaction was applied to the synthesis ofcarbonyl-p-phenylene-p molecules. Reactions of acetophenone(1a) with streptocyanines bearing a phenyl substituent 2b gavecorresponding product 6j in excellent yield. The reaction also
worked well on a gram scale. Sterically hindered o-methylacetophenone was also a good substrate for (5+1) annulation (6k).
Heteroaryl methyl ketones such as 2-acetyl thiophene and 1-methyl3-acetylindole gave the corresponding heteroaryl–carbonyl-pphenylene-p molecules (6l, 6m).
(5+1) benzene ring formation using acetophenone andstreptocyanines bearing various p-conjugated substituents wasThis journal is © The Royal Society of Chemistry 2019

Fig. 3 Scope of (5+1) benzene ring formation. Aryl methyl ketone 1(0.5 mmol), streptocyanine 2 (1.5–6 equiv.), and NaOtBu (1.5–18 equiv.)
were stirred at 120 1C in THF for 10 h. a Reaction run on 0.2 mmol scale.
b
Reaction run on a gram scale (12 mmol scale). See ESI† for details.

carried out. Biphenyl-, naphthyl-, and 2-benzothiophenylsubstituted streptocyanines were found to be good substrates
for the annulation (6n–6p). Use of pyrenyl-substituted streptocyanine 2f gave corresponding product 6q, which was used as aphotoinitiator.10 Using diphenylamino- or carbazolyl-substituted
streptocyanines (2g, 2h), the present method could be applied
to the synthesis of carbonyl-p-phenylene-donor molecules (6r, 6s,
respectively). The reaction of acetophenone with tert-butylsubstituted streptocyanine 2i gave p-tert-butylphenyl phenyl
ketone (6t).
An advantage of this method is the availability of versatileacetyl compounds as a counterpart to streptocyanines. Evendi- or tri-acetyl-substituted compounds are also readily available.
By using such compounds as a starting material, we applied
this method to the synthesis of symmetric molecules bearing
p-phenylene groups connecting the triphenylamine moiety as
the donor and carbonyl groups as the acceptor. C2h symmetricChem. Commun.

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donor–acceptor molecule 6u was synthesized from 4,4 0 -diacetylbiphenyl and 2g via double (5+1) benzene ring formation. Using
4,4 0 ,400 -triacetyltriphenylamine and 2b as starting materials, triplep-phenylene group formation was achieved to give the corresponding C3 symmetric donor–acceptor molecule 6v. The reactionof 1,3,5-triacetylbenzene with 2g also gave the C3 symmetric
donor–acceptor molecule 6w.
In conclusion, we have developed an eﬃcient method forsynthesizing carbonyl-p-phenylene-p molecules from readily available methyl ketones and easily synthesized streptocyanines in one
pot. This convenient method was applied to the synthesis ofsymmetric donor–acceptor molecules that have two or three suchlinkages.
This research was partially supported by the MEXT-supported
program for the Strategic Research Foundation at Private
Universities and the Moritani Scholarship Foundation.

Conflicts of interest
There are no conflicts to declare.

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