One pot synthesis of 3,5-alkylated acetophenone and methyl benzoate derivatives via an anionic domino process

Article abstract of DOI:10.1039/b500846h

The reaction of primary 1,3-dinitroalkanes with 2-ene-1,4-dione or 2-ene-4-oxo ester derivatives in acetonitrile with DBU as base, allow the one pot synthesis of 3,5-alkylated acetophenones and methyl benzoate derivatives respectively via an anionic domin

Full text of DOI:10.1039/b500846h

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One pot synthesis of 3,5-alkylated acetophenone and methyl benzoate
derivatives via an anionic domino process{
Roberto Ballini,* Luciano Barboni,* Dennis Fiorini, Guido Giarlo and Alessandro Palmieri
Received (in Cambridge, UK) 20th January 2005, Accepted 30th March 2005
First published as an Advance Article on the web 12th April 2005
DOI: 10.1039/b500846h
preparation of the title compounds. In fact, the reaction in
acetonitrile of 1 with 2 (Scheme 1) using DBU as base, proceeds as
a tandem process in which a regioselective Michael addition
(yielding 3) is presumably followed by the elimination of nitrous
acid, to give the corresponding nitro-enone derivatives 4.
The latter compounds are prone to an intramolecular nitroaldol
(Henry) reaction, yielding the nitrocyclohexenols 5 in less than 1 h.
The formation of 5 can be easily observed in situ by TLC.
Treatment of 5 with 4M hydrochloric acid favours the elimination
of water and a further molecule of nitrous acid, thus allowing the
one pot synthesis of target molecules 6 in 42–77% yield (Table 1).
When 1-phenyl-2-penten-1,4-dione was used as the Michael
acceptor (Table 1, Entries b, e and i), only the listed regioisomers
were formed, the structures of which were determined from their
MS spectra (CH3CO+ at m/z 5 43).
The reaction of primary 1,3-dinitroalkanes with 2-ene-1,4-dione
or 2-ene-4-oxo ester derivatives in acetonitrile with DBU as
base, allow the one pot synthesis of 3,5-alkylated acetophe-
nones and methyl benzoate derivatives respectively via an
anionic domino process.
The synthesis of complex molecules is traditionally performed by a
chain of separate steps, each of which requires its own conditions,
reagents, solvent and catalyst. After each reaction is complete, the
solvent and the waste products are removed and discarded, and
the intermediate product is separated and purified. Environmental
and economic pressures are now forcing the chemical community
to search for more efficient ways of performing chemical
transformations.1 These issues can be addressed by the develop-
ment of new synthetic methods that, by bringing together simple
components, can generate complex structures in one pot, in much
the same way as occurs in nature. In this context the anionic
domino transformations are of great interest.2
Our procedure for the one pot preparation of aromatic systems
from open chain compounds therefore formally includes five
different transformations: (i) Michael addition, (ii) nitrous acid
elimination, (iii) intramolecular nitroaldol reaction, (iv) water
elimination, and (v) elimination of a further molecule of nitrous
acid.
Aromatic compounds are important reagents in organic
synthesis.3,4 In particular, 3,5-alkylated acetophenones and methyl
benzoate derivatives are key building blocks in the synthesis of
retinoic acids, which have potent anti-proliferative activity in
cervical cancer cells,4a HIV-protease activity inhibitors,4b tyrosine
kinase inhibitors,4c HIV-1 integrase inhibitors,4d NMDA receptor
antagonists,4e and a variety of other important targets.4f,g
Aromatization of acyclic precursors is undoubtedly a useful
reaction in the synthesis of highly substituted aromatic rings,5 and
several methods are known for this purpose.6 We now wish to
report an unprecedented, one pot aromatization of 1,3-dinitroalk-
anes through their reaction with enediones. In fact, the
nucleophilicity of nitroalkanes and the ability of the nitro
functionality to act as a leaving group7 makes it possible to
usefully synthesise a variety of acetophenone and methyl benzoate
derivatives using an anionic domino process.
It is important to note the key role of the dinitro compounds 1,
whereby their nitro functionalities act both as good electron-
withdrawing groups and good leaving groups. This makes it
possible to generate two carbon–carbon double bonds, and so
strongly promote the drive to aromatize the ring system. Several
In the last few years we have reported the direct formation of
carbon–carbon double bonds under basic conditions (1,8-diazabi-
cyclo[5.4.0]undec-7-ene, DBU) through the conjugate addition of
primary or secondary nitroalkanes leading to electron-poor
alkenes bearing two electron withdrawing groups in the a- and
b-positions.8 The application of this strategy to the reaction of 1,3-
dinitroalkanes 1,9 with conjugate enediones 2, allows the one pot
{ Electronic Supplementary Information (ESI) available: General proce-
dure for the preparation of type 6 compounds, analytical data of
compounds 6a–o and their 13C NMR spectra as criterion of purity. See
http://www.rsc.org/suppdata/cc/b5/b500846h/
*roberto.ballini@unicam.it (Roberto Ballini)
luciano.barboni@unicam.it (Luciano Barboni)
Scheme 1
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2633–2634 | 2633

View Article Online
Roberto Ballini,* Luciano Barboni,* Dennis Fiorini, Guido Giarlo and
Alessandro Palmieri
Dipartimento di Scienze Chimiche dell’Universita`, Via S. Agostino 1,
62032, Camerino, Italy. E-mail: roberto.ballini@unicam.it;
luciano.barboni@unicam.it; Fax: +390737402297; Tel: +390737402270
Table 1 A summary of compounds of type 6 prepared
Entry
R
R1
R2
Yield of 6 (%)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
a
CH3(CH2)4
CH3(CH2)4
CH3(CH2)7
PhCH2CH2
CH3(CH2)7
CH3(CH2)4
PhCH2CH2
m-CF3C6H4
p-MeOC6H4
m-CF3C6H4
p-MeOC6H4
p-MeOC6H4
m-NO2C6H4
Ph
CH3
Ph
CH3
CH3
Ph
CH3
CH3
CH3
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
55
62
58
57
61
60
59
58
61
60
77
66
42
76
43
Notes and references
CH3
1 N. Hall, Science (Washington D. C.), 1994, 266, 32–34.
2 J. Rodriguez, Synlett, 1999, 505–518.
CH3O
CH3O
CH3
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CH3
CH3O
CH3O
CH3
CH3O
CH3O
CH3O
2-Py
Yield of pure, isolated product.
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Scheme 2
advantages can be seen in our approach, such as the avoidance of
ortho–meta–para mixture formation, common in conventional
aromatic synthesis. In fact, our regiodefined preparation method
for acetophenone and benzoate derivatives is very difficult to
undertake by the electrophilic substitution of benzenes. In this
context, a significant example is our synthesis of compound 6n (i.e.
Table 1, Entry n), a key building block in the preparation of a
farnesyl-protein tranferase inhibitor. This has previously been
prepared in eight steps from orcinol in only 3% overall yield
(Scheme 2),10 while we obtained the same compound via our one
pot method in 76% isolated yield, starting from 1 (R 5 Ph) and 2
(R1 5 CH3, R2 5 CH3O).
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6 R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH,
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7 See for example: (a) P. Areces, M. V. Gil, F. J. Higes, E. Roma´n and
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and G. Giarlo, Synthesis, 2001, 2003–2006; (g) R. Ballini, G. Bosica,
D. Fiorini and P. Righi, Synthesis, 2002, 681–685; (h) R. Ballini,
D. Fiorini, M. V. Gil, A. Palmieri, E. Roma´n and J. A. Serrano,
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3608.
Moreover, in our method, by making an appropriate choice of
starting 1,3-dinitroalkane and/or the enedione, the opportunity is
offered to predict the relative nature and positions of the
substituents in the products. It also consents to the insertion of
several n-alkyl groups without the isomerization problems typical
of classical Friedel–Crafts alkylation. Finally, the possibility of one
pot introduction of aromatic (compounds 6h–n) and heteroaro-
matic (compound 6o) substituents avoids the need for the cross-
coupling reactions that are usually employed in the preparation of
biphenyl systems.11
8 (a) R. Ballini, D. Fiorini, M. V. Gil and A. Palmieri, Tetrahedron Lett.,
2003, 44, 9033–9034; (b) R. Ballini and A. Rinaldi, Tetrahedron Lett.,
1994, 35, 9247–9250; (c) R. Ballini and G. Bosica, Tetrahedron, 1995, 51,
4213–4222; (d) R. Ballini, G. Bosica, D. Fiorini, M. V. Gil and
M. Petrini, Org. Lett., 2001, 3, 1265–1267.
9 Compounds of type 1 can be easily prepared in one pot by the reaction
of aldehydes with an excess of nitromethane in the presence of basic
alumina as a solid catalyst: R. Ballini, G. Bosica, D. Fiorini and
A. Palmieri, Synthesis, 2004, 1938–1940.
10 F. T. Boyle, G. M. Davies, J. M. Wardleworth and J. C. Arnould,
Imidazolyl Compounds as Inhibitors of Farnesyl-Protein Transferase,
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In conclusion, we have developed the first one pot synthesis of
the title compounds with satisfactory to good yields by the
aromatization of simple, low cost starting materials through
an anionic domino process, promoted by highly versatile
nitroalkanes.
Support by the University of Camerino-Italy and by MIUR-
Italy (Project ‘‘Il Mezzo Acquoso nelle Applicazioni Sintetiche dei
Nitrocomposti Alifatici’’) is gratefully acknowledged.
2634 | Chem. Commun., 2005, 2633–2634
This journal is ß The Royal Society of Chemistry 2005