Base-Promoted Tandem Cyclization for the Synthesis of Benzonitriles by C?C Bond Construction

Article abstract of DOI:10.1002/adsc.201701329

A facile synthesis of benzonitriles via a base-promoted tandem cyclization reaction of α,β-unsaturated enones having electron-withdrawing group (EWG) and 2-acyl-acrylonitriles was developed. This new synthetic method to access benzonitriles is suitable for a wide range of substrates. A plausible reaction mechanism is proposed on the basis of previous literature and our own investigations. (Figure presented.).

Full text of DOI:10.1002/adsc.201701329

Title: Base-Promoted Tandem Cyclization for the Synthesis of
Benzonitriles by C–C Bond Construction
Authors: Cheng-Zhi Zhu, Yin Wei, and Min Shi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701329
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10.1002/adsc.201701329
Advanced Synthesis & Catalysis
.
UPDATES
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Base-Promoted Tandem Cyclization for the Synthesis of Benzonitriles
by C–C Bond Construction
Cheng-Zhi Zhu,a Yin Wei,*c Min Shi*a,b,c
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237 China.
b State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China.
c State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai
200032 China.
Fax: (+86)-21-6416-6128; e-mail: weiyin@sioc.ac.cn, mshi@mail.sioc.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
harsh reaction conditions and heavy metal wastes.[7] In recent
Abstract. A facile synthesis of benzonitriles via a base-
promoted tandem cyclization reaction of α,β-unsaturated enones
having electron-withdrawing group (EWG) and 2-acyl-
acrylonitriles was developed. This new synthetic method to
access benzonitriles is suitable for a wide range of substrates. A
plausible reaction mechanism is proposed on the basis of
previous literature and our own investigations.
years, the N-heterocyclic carbene (NHC)-catalyzed rapid
construction of benzene framework has been independently
developed by Ye and Wang to overcome these drawbacks.[8a-c]
They established a completely different synthetic strategy to
access benzonitrile via a C-C bond formation reaction to achieve
alternative benzene framework construction using readily
available starting materials other than toxic cyanide sources
(Scheme 1, eq 2). As an interesting improvement, herein, we
wish to report a base-promoted tandem cyclization reaction of
α,β-unsaturated enones having EWG (electron-withdrawing group)
and 2-acyl-acrylonitriles under mild conditions, affording a wide
range of benzonitriles, which is a novel synthetic strategy for
benzonitrile framework from readily available starting
materials based on a different C-C bond formation reaction
(Scheme 1, eq 3).
Keywords: C−C bond construction; cyclization; base-
promoted; benzonitrile;
Tandem reactions have witnessed significant progress and
have been developed as powerful synthetic methods to access
highly intricate molecular frameworks in only few synthetic
steps.[1] Among them, base-promoted tandem reactions attracted
much attention on account of mild reaction conditions and
simple operability.
A general reaction pattern of base-
promoted tandem reaction can be described as shown in
Scheme 1, eq 1. Deprotonation of the nucleophile precursor by
base leads to a Michael donor, which then attacks a Michael
acceptor to complete the subsequent reaction through two or
more consecutive steps.[2] Easily available electron-deficient
alkenes have been frequently adopted in many different
Michael addition reactions for the C−C bond construction.[3]
Aromatic nitrile scaffolds have been often found in many
biologically active compounds, such as pharmaceuticals,
agrochemicals, and natural products.[4] Development of
efficient methods for the incorporation of a cyano group into
aromatic rings is still a challenge in synthetic chemistry.[5] In
the last decades, many organic chemists have explored facile and
efficient synthetic protocols for the construction of benzonitrile
cores. Although syntheses of various substituted benzonitriles
have been achieved by different synthetic methods,[6] the use of
toxic cyanide sources or the stoichiometric amount of toxic
wastes generally become a serious limitation for the these
synthetic methods. For example, the traditional SN2 reaction can
be utilized to incorporate a cyano group into the aromatic system
through a C−C bond forming process, but it often suffers from
Scheme 1. Previous background and our work.
On the basis of our previous studies,[9] we initially
investigated the reaction of ene-yne ketone 1j and 2-acyl-
acrylonitrile 2a in the presence of Cs2CO3, and found that
benzonitrile 3ja was isolated as a sole product. Its structure had
been unambiguously confirmed by X-ray diffraction.[10] The
1
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10.1002/adsc.201701329
Advanced Synthesis & Catalysis
ORTEP drawing is shown in Table 1 and the corresponding
CIF data have been indicated in the Supporting Information.
The further examination of the reaction conditions revealed that
no reaction occurred if using PPh3 as a promoter (Table 1, entry
1). Cs2CO3 was essential for the reaction proceeding to give the
desired product 3ja in 70% yield (Table 1, entry 2). After
examination of other bases, we realized that Cs2CO3 was an
appropriate choice to produce 3ja in a desirable yield because the
use of organic bases such as DBU and DABCO as well as
Na2CO3 and KtOBu could not promote the reaction and the
employ of K2CO3, NaOH and KOH gave 3ja in lower yields
(Table 1, entries 2-9).[11] Decreasing the amount of Cs2CO3
reduced the yield of the desired product (Table 1, entry 10). Using
1.0, 1.5 or 2.0 equiv of Cs2CO3 as a base promoter did not affect
the yield of 3ja significantly (Table 1, entries 11-13). Raising the
reaction temperature to 60 or 80 oC, no significant
improvements on the reaction outcomes were observed, but
the reaction time could be significantly shortened (Table 1,
entries 14-15). A quick solvent screening demonstrated that no
apparent solvent effect was realized in this reaction; DCE was
identified as the solvent’s choice in order to facilitate the
purification process (Table 1, entries 16-19).
yield. Biphenyl substrate was also compatible to produce the
desired product 3ia in 65% yield. Then, we evaluated a series
of ene-yne ketones, and found that the reactions also proceeded
smoothly to afford the products 3ja-3oa in satisfactory yields;
thus, the electronic nature of alkyne moiety did not influence
the reaction outcome significantly. However, alkene-
containing substrate only gave trace amount of 3pa along with
other complex product mixtures. This result could be
explained by the fact that 1,4-addition from carbanion A to 1p
could also cause a series of side reactions, leading to a
complicated reaction system (see Scheme 3).
Table 2. Reaction scope of α,β-unsaturated enones for the
synthesis of 3.[a]
Table 1. Optimization of the reaction conditions of ene-yne
ketone 1j and 2-acyl-acrylonitrile 2a toward the synthesis of
3ja.[a]
Next, we investigated the reaction scope with respect to a
series of 2-acyl-acrylonitriles 2. As shown in Table 3, when R2
= Me and Et, the reactions took place smoothly to afford the
desired products 3ab and 3ac in 63% and 65% yields,
respectively. For various 2-acyl-acrylonitriles 2d-2g having
either electron-donating or electron-withdrawing groups on the
aromatic rings, the reactions all went through efficiently,
giving the desired products 3ad-3ag in 62-75% yields. A
meta-substituted phenyl ring had little influence to the reaction
proceeding, affording the desired product 3ah in 74% yield.
However, trace of the desired product 3ai was obtained in the
case of ortho-substituted phenyl ring containing substrate
because of the steric bulkiness. When R3 = 3,4-Me2C6H3 and 2-
naphthalen, the reactions also proceeded smoothly to afford
the corresponding products 3aj and 3ak in 72% and 67%
yields, respectively. It was also encouraging to note that the 2-
acyl-acrylonitrile 2 containing a 2-thiophene or a 2-furan
moiety could react with 1a smoothly to give the desired
product 3al or 3am in reasonable yield under the standard
conditions. Subsequently, we further investigated the reaction
of ene-yne ketone 1j with several variants of 2-acyl-acrylonitriles
2 and the results are indicated in Table 4. As expected, the
corresponding products 3jc-3jl were obtained in 65-73%
yields. It should be mentioned here that in all these cases, the
2-acyl-acrylonitriles 2 were used as an E and Z-isomeric mixture.
With the optimized reaction conditions in hand, we next
investigated the substrate scope with respect to the α,β-
unsaturated enones 1 and the results are shown in Table 2.
Enone 1a reacted smoothly with 2-acyl-acrylonitrile 2a (R1 = Ph)
to afford the corresponding product 3aa in 75% yield.
Different electronic properties of R1 group (e.g. electron-rich,
-neutral, or -deficient) as for these methyl-, methoxyl-,
trifluoromethyl-, or halogen-substituted benzene ring did not
significantly impact the reaction outcome, affording the
corresponding products 3ba-3fa in moderate to good yields.
However, when R1 group was an ortho-substituted phenyl
group, the yield of the corresponding product 3ga decreased to
41%, probably due to the steric hindrance. Hetero-aromatic
ring was also tolerated, giving the desired product 3ha in 55%
2
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10.1002/adsc.201701329
Advanced Synthesis & Catalysis
Table 3. Reaction scope of 1a and 2-acyl-acrylonitriles 2 toward
the synthesis of 3.[a]
carbonyl group, which undergoes a benzoate anion elimination
to afford the cyclohexadiene intermediate H via an intermediate
G. After washed with 10% aq. HCl, the benzoic acid was
detected by GC-MS in the reaction mixture of 1a and 2a,
which clearly gave an evidence for the step from G to H
(Scheme 4, see SI for detailed information). Upon oxidation
with air, the aromatization of intermediate H takes place to
give the corresponding product 3aa.
Table 4. Reaction scope of ene-yne ketone 1j and 2-acyl-
acrylonitriles 2 toward the synthesis of 3.[a]
Scheme 3. A proposed mechanism for the tandem cyclization
reaction.
In order to clarify whether the configuration of 2-acyl-
acrylonitriles 2 affected the reaction outcome of this interesting
tandem cyclization reaction, the E and Z-isomeric mixture of 2l
was separated and they were used to react with 1a under the
standard conditions, respectively. The similar results were
obtained, indicating that the configuration of 2-acyl-
acrylonitrile 2 has no influence on the reaction result (Scheme 2).
Scheme 4. GC-MS data of [PhCOOH] in the reaction mixture.
For the sake of further expanding the substrate scope of
the reaction, we utilized α-nitro-β-methylenone 4 and 1a to
process the reaction under the standard conditions.
Unfortunately, the corresponding nitrobenzene containing
product was not obtained, presumably due to the steric hindrance
of nitro group (Scheme 5, eq 1). The substrate 5 without phenyl
group at the β-position did not undergo the reaction to give the
desired product either, probably due to the instability of the
corresponding carbanion A shown in Scheme 3 (Scheme 5, eq
2). The use of substrate 6 in the reaction with 2a did not give the
desired product. This may be due to that propionyl group has a
larger steric bulkiness than that of acetyl group and it could be
difficult to generate the corresponding cyclized intermediate E
or F shown in Scheme 3 (Scheme 5, eq 3). Employing the α-
ester enone 7 as a substrate, the reaction with 2a went
Scheme 2. Control experiments toward the synthesis of 3al.
On the basis of our experimental results and the previous
reports, a plausible reaction mechanism has been outlined in
Scheme 3, using 1a and 2a as the model substrates. In the
presence of
a base, 2-acyl-acrylonitrile 2a undergoes a
deprotonation to generate a carbanion A. Then, the carbanion A
attacks to the alkenyl moiety of 1a, giving the corresponding
intermediate B. After a subsequent 1,3-proton shift and an
isomerization, an α-cyano carbanion D is formed via an
intermediate C, which attacks to the carbonyl group, affording
the cyclized intermediate E. Next, an intermediate F containing
smoothly to give the desired product
8 in 66% yield,
suggesting that some enones with one acyl and another
electron-withdrawing group were also suitable for this type of
reaction (Scheme 5, eq 4).
A synthetic transformation was performed by subjecting 3da
a
four-membered ring can be generated through an
o
into DIBAL-H in THF at 0 C, affording the reduction product
intramolecular nucleophilic attack of oxo anion (O-) to the
9 in 80% yield (Scheme 6).
3
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10.1002/adsc.201701329
Advanced Synthesis & Catalysis
General Procedure for Synthesis of 3
Under an air atmosphere, compound 1 (1.5 mmol), 2 (1.0 mmol)
and Cs2CO3 (487 mg, 1.5 mmol) were weighed into a Schlenk
tube. DCE (3.0 mL) was added via a syringe and the reaction
mixture was stirred at room temperature until compound 2 was
consumed completely. The reaction mixture was filtered through
Celite. The filtrate was concentrated under reduced pressure and
the residue was purified by silica gel column flash
chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1)
to afford product 3.
Supporting Information Available
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are presented in
the Supporting Information. CCDC 1523308 (3ja) contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 5. Further examination of the reaction scope.
Acknowledgements
We are grateful for the financial support from the National Basic
Research Program of China (973)-2015CB856603, the Strategic
Priority Research Program of the Chinese Academy of Sciences,
Grant No. XDB20000000, the National Natural Science
Foundation of China (20472096, 21372241, 21572052, 20672127,
21421091, 21372250, 21121062, 21302203, 20732008, 21772037
and 21772226), and the Fundamental Research Funds for the
Central Universities 222201717003.
Scheme 6. Synthetic transformation.
Furthermore, since many aromatic hydrocarbons have been
proven to have good emission properties,[12] compounds 3ad and
3ak were selected for studying their photonic properties. As
shown in Figure 1, 3ak showed a better fluorescence emission
than 3ad when they were excited at λ = 264 nm,[13] presumably
due to 3ak containing the electron-rich naphthalene moiety.
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In summary, we have developed a novel, useful and facile
synthesis of benzonitriles using α,β-unsaturated enones and 2-
acyl-acrylonitriles as substrates via a base-promoted tandem
cyclization reaction under mild conditions. The reaction has a
broad substrate scope and excellent functional group tolerance. A
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literature and our own examinations. Further investigations on
application of this new reaction to synthesize biologically active
substances and interesting photonic materials are underway in our
laboratory.
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10.1002/adsc.201701329
Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
UPDATES
Base-Promoted Tandem Cyclization for the
Synthesis of Benzonitriles by C–C Bond
Construction
Adv. Synth. Catal. Year, Volume, Page – Page
Cheng-Zhi Zhu, Yin Wei,* Min Shi*
6
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