Three-step synthesis of highly substituted phenols from 1,3-dinitropropanes

Article abstract of DOI:10.1055/s-2006-944231

Reaction of 1,3-dinitropropanes with acrolein under heterogeneous conditions (neat Al₂O₃) gives dinitrocyclohexanols, which, by treatment with potassium carbonate followed by acidic work-up, allow access to nitrocyclohexenone derivat

Full text of DOI:10.1055/s-2006-944231

1956
LETTER
Three-Step Synthesis of Highly Substituted Phenols from 1,3-Dinitropropanes
T
hree-Step Synth
o
esis of High
b
ly
S
ubstituted
e
P
henols from 1,3-
t
D
initro
o
propanes Ballini,* Luciano Barboni,* Guido Giarlo, Alessandro Palmieri
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 63032 Camerino, Italy
Fax +39(0737)402297; E-mail: roberto.ballini@unicam.it
Received 13 February 2006
During the course of our studies on the chemistry of ni-
Abstract: Reaction of 1,3-dinitropropanes with acrolein under het-
erogeneous conditions (neat Al2O3) gives dinitrocyclohexanols,
which, by treatment with potassium carbonate followed by acidic
work-up, allow access to nitrocyclohexenone derivatives. The lat-
troalkanes,9 we reported the one-pot synthesis of a new
class of nitrocyclohexanols 2 obtained by treatment of
1,3-dinitroalkanes 1 with acrolein, under basic conditions
ter, by reaction with phenyltrimethylammonium tribromide, con- (basic Al2O3, neat), through tandem Michael/nitroaldol
(Henry) reactions.10 These results prompted us to explore
the feasibility of the construction of a substituted phenolic
ring relying upon the utilization of 1,3-dinitropropanes as
key precursors. Thus, we wish to report herein a new,
three-step synthesis of polyfunctionalized phenols by aro-
matization of 1 (Scheme 1).
cludes
satisfactory yields.
a three-step synthesis of nitro-dibromophenols in
Key words: bromophenols, aromatization, 1,3-dinitroalkanes, Nef
reaction, nitrocyclohexanols
The regiospecific preparation of polyfunctionalized aro-
matic compounds represents a major challenge in organic
synthesis.1 Classical approaches are based on the modifi-
cation of arenes, and rely heavily on conventional electro-
philic or nucleophilic substitutions, catalyzed coupling
reactions, and metallation–functionalization reactions.
However, these synthetic routes suffer from long multi-
step reaction sequences, low yields of target products,
and, in particular, serious regiochemical ambiguities due
to the activating/deactivating and orienting effects of the
substituents. Alternatively, aromatization of acyclic pre-
cursors is undoubtedly a useful reaction in the synthesis of
highly substituted aromatic rings, and several methods are
known for this purpose. In this context, nitroalkane deriv-
atives have emerged, over recent years, as versatile pre-
cursors for the one-pot synthesis of a variety of aromatic
structures, such as polyalkylated acetophenones2,3 and
benzoates.3
R
NO2
NO2
O2N
HO
NO2
CHO
3
6
2
1
4
5
R
Al2O3
neat, r.t.
68–88%
1a–g
2a–g
1) K2CO3, H2O–MeOH
15 min., r.t.
2) HCl, 30 min
1) PhNMe3Br⋅Br2
CH2Cl2, overnight
2) DBU, 1 h
O
HO
R
Br
R
Br
37–68% overall
yields from 2
NO2
NO2
4a–g
3a–g
Scheme 1 Three-step synthesis of 4.
Reaction of 1,3-dinitroalkanes 1 with acrolein, under
Al2O3 catalysis, affords nitrocyclohexanols 2 in one pot.
Treatment of compounds 2 with potassium carbonate,
followed by acidic work up, transforms them via water
elimination from C1–C2 and nitro to carbonyl conversion
(Nef reaction)11 at C4 to nitrocyclohexenones. Reaction of
the crude nitrocyclohexenones 3 with phenyltrimethylam-
monium tribromide (a well-known a-keto brominating
agent12) allows the direct synthesis of nitro dibromophe-
nols 4. All the reactions proceeded smoothly to afford the
corresponding substituted phenols 4 in satisfactory yields
(Tables 1, 37–68% overall yield from 2).13
Phenols are of great interest in organic synthesis since
they are found in a large number of biologically active
compounds and/or are employed as key building blocks
for the preparation of important targets.4 Of particular in-
terest are the polyfunctionalized derivatives such as nitro-
phenol derivatives that possess a range of versatile
applications as functional materials such as dyes,5 phar-
maceutical agents or their synthetic intermediates,6 and
bromophenols which are present in algae, such as Polysi-
phonia lanosa, where they are thought to be responsible
for the cytotoxic activity against human colon adenocarci-
noma.7
Although we have no clear evidence of the mechanism for
the conversion of 3 to 4, a possible hypothesis could be
that reported in Scheme 2. Nitrocyclohexenone 3, after
both bromination and HBr elimination, is converted into
the structure B in equilibrium with its enol form C. Sub-
sequent bromination of C allows the one-pot synthesis
(from 3) of the target phenol derivatives 4.
However, the synthesis of both of these classes of com-
pounds suffers, in general, from low regioselectivity and/
or rearrangements that make the introduction of alkyl
groups, longer than an ethyl group, difficult.8
SYNLETT 2006, No. 12, pp 1956–1958
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-944231; Art ID: D04306ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Three-Step Synthesis of Highly Substituted Phenols from 1,3-Dinitropropanes
1957
Table 1 Preparation of Nitrodibromophenols 4
Acknowledgment
This work was supported by the University of Camerino, Italy and
by MIUR-Italy.
R
Yields (%)a of 2
(reaction time, h)
Yields (%)a
of 4
a
b
c
d
e
f
Me(CH2)4
Ph(CH2)2
Ph
88 (8)
74 (6)
71 (4)
76 (18)
70 (20)
68 (48)
71 (6)
44
46
51
37
68
54
47
References and Notes
(1) (a) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH:
Weinheim, 2002. (b) The Chemistry of Phenols; Rappoport,
Z., Ed.; Wiley-VCH: New York, 2003.
(2) Ballini, R.; Barboni, L.; Bosica, G. J. Org. Chem. 2000, 65,
6261.
p-MeOC6H4
p-CNC6H4
m-NO2C6H4
o-Py
(3) Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo, G.; Palmieri, A.
Chem. Commun. 2005, 2633.
(4) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical
Synthesis; John Wiley and Sons: New York, 1989. (b) Ho,
T.-L. Tactics of Organic Synthesis; Academic Press Inc.:
New York, 1994. (c) Nicolaou, K. C.; Sorensen, E. J.
Classics in Total Synthesis; VCH: Weinheim, 1996.
(5) (a) Osterby, B. R.; McKelvey, R. D. J. Chem. Educ. 1996,
73, 260. (b) Reichardt, C.; Eschner, M. Liebigs Ann. Chem.
1991, 1003. (c) Kessler, M. A.; Wolfbeis, O. S. Synthesis
1988, 635.
g
a Yield of pure, isolated product.
3
1) PhN(Me)3Br·Br2
CH2Cl2, overnight
(6) (a) Fujimoto, K.; Asai, F. Jpn. Kokai Tokkyo Koho JP
2003002832, 2003; Chem. Abstr. 2003, 138, 66685.
(b) Selassie, C. D.; Verma, R. P.; Kapur, S.; Shusterman, A.
J.; Hanasch, C. J. Chem. Soc., Perkin Trans. 2 2002, 1112.
(c) Butera, J. A.; Caufield, C. E.; Graceffa, R. F.; Greenfield,
A.; Gunderson, E. G.; Havran, L. M.; Katz, A. H.; Lennox,
J. R.; Mayer, S. C.; McDevitt, R. E. U.S. Patent 01/018525,
2001; Chem. Abstr. 2001, 134, 280608.
Br
O
HO
R
O
DBU
– HBr
R
R
NO2
NO2
NO2
A
C
B
(7) Shoeib, N. A.; Bibby, M. C.; Blunden, G.; Linley, P. A.;
Swaine, D. J.; Wheelhouse, R. T.; Wright, C. W. J. Nat.
Prod. 2004, 67, 1445.
(8) (a) Nakaike, Y.; Kamijo, Y.; Mori, S.; Tamura, M.;
Nishiwaki, N.; Ariga, M. J. Org. Chem. 2005, 70, 10169;
and references cited therein. (b) de Rege, F. M. G.;
Buchwald, S. L. Tetrahedron 1995, 51, 4291.
(9) (a) Rosini, G.; Ballini, R. Synthesis 1988, 833. (b) Ballini,
R. In Studies in Natural Products Chemistry, 19; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1997, 117. (c) Ballini,
R. Synlett 1999, 1009. (d) Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
(e) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.
Tetrahedron 2005, 61, 8971.
PhN(Me)3Br⋅Br2
CH2Cl2, overnight
(via enolisation–
bromination)
4
Scheme 2 Hypothesis of the mechanism for the conversion of
3 to 4.
Whatever the details of the mechanism, the reaction rep-
resents an unprecedented, reproducible, and useful meth-
od for the preparation of a variety of polyfunctionalized
phenol derivatives from acyclic precursors. Additionally,
in our procedure, by choosing the appropriate starting 1,3-
dinitroalkane 1, a multiplicity of groups in the ortho-posi-
tion can be easily introduced, comprising aryls and het-
eroaryls. The specific features of our approach, include,
the preparation of tetrasubstituted phenols with the avoid-
ance of ortho-meta-para mixtures common in conven-
tional aromatic synthesis. In fact, our method appears as a
regiodefined synthesis of 2-alkyl-4,5-dibromo-3-nitro-
phenols, which are very difficult to obtain by other means.
It should be noted that the synthesis of substituted bi-
phenyls (compounds 4c–f) can also be accomplished, and
the reaction conditions allow the survival of other func-
tionalities such as methoxy and nitrile.
(10) Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo, G.; Palmieri, A.
Green Chem. 2005, 7, 828.
(11) (a) Nef, J. U. Liebigs Ann. Chem. 1894, 280, 263.
(b) Pinnick, H. W. Org. React. (N.Y.) 1990, 38, 655.
(c) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
(12) See for example: Miranda Moreno, M. J. S.; Sá e Melo, M.
L.; Campos Neves, A. S. Synlett 1994, 651.
(13) Preparation of Nitrodibromophenols 4; General
Procedure
To a stirred mixture of dinitroalkane 1 (2 mmol) and acrolein
(2.6 mmol, 0.174 mL) was added, at 0 °C, basic Al2O3 (2 g,
activity I). The resulting mixture was stirred at the same
temperature for 15 min, then at r.t. for the appropriate
reaction time (Table 1). The heterogeneous mixture was
directly charged onto a chromatography column (EtOAc–
hexane) giving the pure compound 2.13 To a solution of 2
(1 mmol) in H2O–MeOH (1:1, 10 mL), K2CO3 (0.2 g, 2
mmol) was added at r.t. After stirring for 15 min, the solution
was acidified with 4 N HCl (pH 2–3) and left at r.t. for 30
min. The organic solution was washed with NaHCO3 (3 × 5
mL), brine (1 × 10 mL), and then evaporated. The residue
was dissolved in CH2Cl2 (20 mL), followed by the addition
In summary, the letter reports a novel synthetic strategy
for the preparation of highly functionalized phenols from
acyclic precursors. The simplicity of execution, ready
availability of substrates, and the variety of potential
products make this procedure very attractive and practi-
cal.
Synlett 2006, No. 12, 1956–1958 © Thieme Stuttgart · New York

1958
R. Ballini et al.
LETTER
H, 3.66; N, 3.69. Compound 4e: 1H NMR (CDCl3, 200
of PhN(CH3)3Br·Br2 (0.38 g, 1 mmol). The solution obtained
after stirring overnight at r.t. was treated with DBU until the
color changed, and the reaction was left to proceed for 1 h.
The mixture was washed with H2O (2 × 5 mL), brine (10
mL), and the organic layer was dried (MgSO4),
MHz): d = 7.22 (d, 2 H, J = 8.2 Hz), 7.51 (d, 2 H, J = 8.2
Hz), 7.64 (s, 1 H), 9.38 (br s, 1 H). 13C NMR (CDCl3, 50
MHz) d = 101.9, 112.6, 114.5, 118.2, 123.0, 130.4, 132.1,
136.0, 136.1, 150.7. GC-MS (70 eV): m/z = 398 [M+]. Anal.
Calcd for C13H6Br2N2O3: C, 39.23; H, 1.52; N, 7.04. Found:
C, 39.45; H, 1.61; N, 6.89. Compound 4g: 1H NMR (CDCl3,
200 MHz): d = 7.37 (m, 2 H), 7.80 (td, 1 H, J = 7.8, 2.0 Hz),
8.27 (s, 1 H), 8.65 (d, 1 H, J = 4.3 Hz). 13C NMR (CDCl3, 50
MHz): d = 110.2, 123.1, 123.7, 124.3, 129.0, 131.0 (2 C),
137.2, 150.0, 150.5, 150.7. GC-MS (70 eV): m/z = 294
[M+ – Br]. Anal. Calcd for C11H6Br2N2O3: C, 35.33; H, 1.62;
N, 7.49. Found: C, 35.54; H, 1.73; N, 7.28.
concentrated, and purified by flash chromatography (SiO2,
hexane–EtOAc) giving pure compounds 4.
Compound 4a: 1H NMR (CDCl3, 200 MHz): d = 0.89 (m, 3
H), 1.32 (m, 4 H), 1.58 (m, 2 H), 2.59 (m, 2 H), 5.90 (br s, 1
H), 7.63 (s, 1 H). 13C NMR (CDCl3, 50 MHz) d = 14.1, 22.4,
27.8, 28.9, 31.9, 103.0, 112.3, 124.8, 132.97, 132.98, 105.8.
GC-MS (70 eV): m/z = 367 [M+]. Anal. Calcd for
C11H13Br2NO3: C, 36.0; H, 3.57; N, 3.82. Found: C, 36.31;
Synlett 2006, No. 12, 1956–1958 © Thieme Stuttgart · New York