Facile synthesis of 2-nitromethyl aromatic ketones by insertion of benzynes into the C-C bond of α-nitroketones

Article abstract of DOI:10.1080/00397911.2018.1563794

A facile method to synthesize 2-nitromethyl aromatic ketones was developed. In the method, benzyne was generated in situ for the insertion to α-Nitroketones in one pot to achieve 2-nitromethyl aromatic ketones under mild conditions. Aromatic and aliphatic α-nitroketones were applied in the reaction, and the results show that aliphatic α-nitroketones gave excellent yields (up to 96%), while aromatic α-nitroketones gave moderate yields. The synthesized 2-nitromethyl aromatic ketones could be potential substrates to synthesize isoindoles.

Full text of DOI:10.1080/00397911.2018.1563794

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile synthesis of 2-nitromethyl aromatic ketones
by insertion of benzynes into the C-C bond of α-
nitroketones
Ji-Hong Hu & Hong-Jie Zheng
To cite this article: Ji-Hong Hu & Hong-Jie Zheng (2019): Facile synthesis of 2-nitromethyl
aromatic ketones by insertion of benzynes into the C-C bond of α-nitroketones, Synthetic
Communications, DOI: 10.1080/00397911.2018.1563794
To link to this article: https://doi.org/10.1080/00397911.2018.1563794
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https://doi.org/10.1080/00397911.2018.1563794
Facile synthesis of 2-nitromethyl aromatic ketones by
insertion of benzynes into the C-C bond of a-nitroketones
Ji-Hong Hua and Hong-Jie Zhengb
aDepartment of Food and Wine, Sichuan Technology and Business College, Chengdu, P. R. China;
bChengdu R&D Center, Porton Fine Chemical Ltd., Chengdu, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 31 July 2018
A facile method to synthesize 2-nitromethyl aromatic ketones was
developed. In the method, benzyne was generated in situ for the
insertion to a-Nitroketones in one pot to achieve 2-nitromethyl
aromatic ketones under mild conditions. Aromatic and aliphatic
a-nitroketones were applied in the reaction, and the results show
that aliphatic a-nitroketones gave excellent yields (up to 96%), while
aromatic a-nitroketones gave moderate yields. The synthesized
2-nitromethyl aromatic ketones could be potential substrates to
synthesize isoindoles.
KEYWORDS
2-Nitromethyl aromatic
ketone; a-nitroketone;
benzyne; inserion
GRAPHICAL ABSTRACT
Introduction
Arynes are highly strained and kinetically unstable molecules that have been recognized
as useful reactive intermediates in organic synthesis.[1] Insertion of arynes into an elem-
ent-element r-bond has high synthetic significance, because both elements can be intro-
duced into the adjacent positions of aromatic skeletons simultaneously, leading to the
formation of polysubstituted arenes, which are otherwise difficult to prepare.[2] Many
works for insertion of arynes into a heteroatom-carbon r-bond under mild conditions
had been reported,[3] while examples of arynes insertion into a carbon-carbon r-bond
are rare. In 2005, Tamber and Stoltz reported the first example of acyl-alkylation of
arynes with b-ketoesters, which is an efficient method for the generation of interesting
ortho-disubstituted arenes and benzannulated carbocycles.[4] Afterwards, they applied
CONTACT Hong-Jie Zheng
scucioc0205@163.com
Chengdu R&D Center, Porton Fine Chemical Ltd., Room 701,
Building B7, No. 88, Keyuan South Road, High-Teck Zone, Chengdu, Sichuan Province, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
J.-H. HU AND H.-J. ZHENG
Table 1. Screening of insertion conditions.
Entrya
Fluoride salt
Temperature
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
CsF
[Bu4N]F
NaF
KF
KF
KF
KF
KF
KF
20 ꢀC
20 ꢀC
80 ꢀC
20 ꢀC
40 ꢀC
60 ꢀC
80 ꢀC
20 ꢀC
60 ꢀC
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Complicated mixtures
Complicated mixtures
No reaction
No reaction
No reaction
36
71
No reaction
Complicated mixtures
THF
aReaction conditions: 0.4 mmol a-nitroketones, 1.25 equiv of benzyne precursor and 2.5 equiv of flouride in 4 ml of solv-
ent at selected temperature for 8 h.
bIsolated yield.
this technology for the synthesis of natural product (þ)-amurensinine successfully.[5]
Subsequently, Kunai et al. disclosed that the carbon-carbon r-bond of b-dicarbonyl
compounds also readily added to arynes to form two carbon-carbon r-bonds in one
step, which enables direct introduction of different carbon functional groups into adja-
cent positions of the aromatic skeleton, and provides diverse polysubstituted arenes
straightforwardly[6].
Herein, we report the insertion of benzynes into carbon-carbon r-bond of a-nitroke-
tones, which is a straightforward method for the synthesis of various 2-nitromethyl-
phenyl ketones that could be potential substrates to prepare isoindoles.
Results and discussion
The reaction of 2-nitro-2-phenylethanone 2a with benzyne was invstigated, in which,
ortho-(trimethylsilyl) phenyl triflate 1a was used as benzyne precursor. The reaction was
carried out in acetonitrile or THF, and various fluoride salts were screened to generate
benzyne in situ. The results show that KF was the most suitable reagent among
[Bu4N]F, NaF, CsF and KF (Table 1, entries 1–7), and acetonitrile is better solvent than
THF (Table 1, entries 6 and 8).
With the optimized conditions, the scope and the limitation of this reaction was
examined. The results shown in Table 2 demonstrate that the reaction could proceed
smoothly with wide range ketones. Alkylketones (2g–2i) added to benzyne afforded
insertion products in excellent yields (Table 2, entries 7-9). Arylketones (2a–2f) added
to benzyne in moderate to good yields. Unsubstituted aryl ketones (2a, 2f) gave good
yields (Table 2, entries 1 and 6), while substituted aryl ketones (2b–2e) provided rela-
tively low yields (Table 2, entries 2–5). Furthermore, substituted benzyne could also
insert into a-nitroketones. When 4, 5-dimethyl-1-(trimethylsilyl) phenyl triflate 1b was
selected as substrate to react with ketones 2g, 2h and 2i, the insertion products 3bg,
3bh and 3bi were obtained in good yields (Table 2, entries 10, 11 and 12).

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Table 2. Reaction of benzynes with a-nitroketones.
Entrya
R(1)
R1(2)
Ph (2a)
3
Yield (%)b
1
2
3
4
5
6
7
8
H (1a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
71
59
33
61
31
75
95
93
96
84
83
80
H
H
H
H
H
H
H
H
m-BrC6H4(2b)
o-BrC6H4 (2c)
p-FC6H4 (2d)
p-MeOC6H4 (2e)
2-Furanyl (2f)
Ethyl (2g)
n-Pr (2h)
Cyclohexyl (2i)
Ethyl (2g)
9
10
11
12
Me (1b)
Me
Me
3bg
3bh
3bi
n-Pr (2h)
Cyclohexyl (2i)
aReaction conditions: 0.4 mmol a-nitroketones, 1.25 equiv of benzyne precursor and 2.5 equiv of KF in 4 mL of CH3CN
at 80 ꢀC for 8 h.
bIsolated yield.
Scheme 1. A proposed method for the synthesis of isoindole derivatines.
Scheme 2. A plausible mechanism for the reaction of benzyne with a-nitroketones.
The produced 2-nitromethylated phenylketones 3 could be very useful building
blocks. As depicted in Scheme 1, via selective reduction nitro group of nitro ketones[7]
and intramolecular condensation[8] respectively, which would afford a new method for
the synthesis of isoindole derivatives.
A plausible mechanism of the insertion is described in Scheme 2. Firstly, nucleophilic
attack of an enolate 4 to the benzyne occurs to produce an aryl anion 5, which then
undergoes intramolecular nucleophilic attack to the carbonyl moiety, giving the benzo-
cyclobutane 6. Ring opening of the resulting benzocyclobutane 6 affords benzyl anion 7
and a proton abstraction by 7 from water gives the product 3.

4
J.-H. HU AND H.-J. ZHENG
Conclusion
We have demonstrated that the carbon-carbon r-bond of various a-nitroketones can be
readily cleaved and added to the carbon-carbon triple bond of benzynes under mild
conditions. The transformation results in the formation of 2-nitromethyl aromatic
ketones directly that would otherwise be difficult to obtain. A further study on convert-
ing the insertion products 3 to isoindoles is proceeding.
Experimental
Commercial reagents were used as received. Benzyne precursor ortho-(trimethylsilyl)
phenyl triflate 1a was purchased from the Sigma-Aldrich Chemical Company.
Substituted benzyne precursor 4, 5-dimethyl-1-(trimethylsilyl) phenyl triflate 1b was
prepared according to literature procedures.[9] Preparation of a-nitroketones (2a–2i)
1
could be found in supporting information. CH3CN was distilled from CaH2. H NMR
spectra were recorded on a Brucker Avance 300MHz. 1H and 13C NMR (300 and
1
75MHz, respectively) spectra were recorded in CDCl3. H NMR chemical shifts are
reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance
employed as the internal standard (CDCl3, d ¼ 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s ¼ singlet, brs ¼ broad singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet), coupling constants (Hz) and integration. 13C NMR chemical
shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as
the internal standard (CDCl3, d ¼ 77.00 ppm). High resolution mass spectra were
recorded on Aligent 6230 TOF LC/MS.
General procedure for the insertion reaction
To a flame-dried sealed tube was charged with anhydrous acetonitrile (4 mL), a-nitroke-
tone 2 (0.4 mmol), benzyne precursor 1a or 1b (0.5 mmol, 1.25 equiv) and potassium
fluoride (75 mg, 1.0 mmol, 2.5 equiv) sequentially. The mixture was then heated at 80 ꢀC
till benzyne precursor 1a or 1b was consumed completely. After completion of the reac-
tion, the mixture was quenched with brine (4 mL). The aqueous layer was extracted
with ethyl acetate (3 ꢁ 5 mL). The organic phases were combined, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to give crude product, which
was subjected to flash chromatography for further purification.
Funding
The authors thank the financial support by Education Department of Sichuan Provincial
[No. 14ZA0349].
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