Benzannulation of substituted 3-alkoxycarbonylhex-3-en-5-ynoic acids: A new route to 4-substituted 3,5-dihydroxybenzoic acids derivatives

Article abstract of DOI:10.1055/s-2002-34212

A new regioselective pathway to 4-substituted 3,5-dihydroxybenzoic acids derivatives is described here. According to this procedure substituted propargylic aldehydes are converted into substituted 3-alkoxycarbonylhex-3-en-5-ynoic acids, which are in turn, treated with acetic anhydride in the presence of sodium acetate to give the substituted benzoic acids derivatives. The aromatic moiety constructed using the latter benzannulation reaction is formed in regioselective fashion and a range of substituents are tolerated.

Full text of DOI:10.1055/s-2002-34212

LETTER
1661
Benzannulation of Substituted 3-Alkoxycarbonylhex-3-en-5-ynoic Acids:
A New Route to 4-Substituted 3,5-Dihydroxybenzoic Acids Derivatives
A
New Route
t
to 4-Su
e
bstituted 3,
f
5-Dihyd
a
roxybenzoi
n
c
A
cids
D
eri
o
vatives Serra,* Claudio Fuganti
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘Adolfo Quilico’ presso Dipatimento di Chimica, Materiali ed
Ingegneria Chimica ‘Giulio Natta’ del Politecnico, Via Mancinelli 7, 20133 Milano, Italy
Fax +39(2)23993080; E-mail: stefano.serra@polimi.it
Received 1 August 2002
R'
COOR'''
R'
COOR'''
R''
3-alkoxycarbonyl-
3,5-hexadienoic
acids
Abstract: A new regioselective pathway to 4-substituted 3,5-dihy-
droxybenzoic acids derivatives is described here. According to this
procedure substituted propargylic aldehydes are converted into sub-
stituted 3-alkoxycarbonylhex-3-en-5-ynoic acids, which are in turn,
treated with acetic anhydride in the presence of sodium acetate to
give the substituted benzoic acids derivatives. The aromatic moiety
constructed using the latter benzannulation reaction is formed in
regioselective fashion and a range of substituents are tolerated.
R
R''
R
C
O
1
OH
O-
Nu-
Nu
R
COOR'
COOR'
3-alkoxycarbonylhex-
3-en-5-ynoic acids
R
C
O
2
Key words: annulations, cyclizations, phenols, regioselectivity,
biaryls
Scheme 1
Polysubstituted phenols are relevant compounds in organ-
ic synthesis. Though a wide range of methods devoted to
their preparation have been developed in the past, the
main general approach to these compounds still involves
the introduction of a substituent to a pre-existing arene.
Since the activating or deactivating and orienting effects
of the substituents are the main restriction to this route, an
increasing interest is therefore arising around some new
approaches which are able to build up the aromatic moiety
starting from acyclic precursors.
aldehydes 4a–i. These latter compounds were obtained by
oxidation7 of related propargylic alcohol 3a–i (Scheme 2)
which were themselves easily prepared by known meth-
ods.8
P3P
COOEt
5
OH
O
a
b
COOH
R
R
R
4a-i
3a-i
AcO
R
COOEt
COOEt
COOH
c
In this context, we have developed a method of benzannu-
lation which allows the construction of substituted-3-hy-
droxy-benzoic acid derivatives by cyclization of
substituted 3-alkoxycarbonyl-3,5-hexadienoic acids. The
latter process was successfully used in the preparation of
many kinds of compounds, such as oligoaryls,1 naphtha-
lenes,2 chiral tetrahydronaphthalenes,3 ring fused hetero-
cycles,4 C-aryl-glycosides,5 and many natural products of
different structure.6 We believe that the key steps of this
annulation process are the conversion of the substituted 3-
alkoxycarbonyl-3,5-hexadienoic acids to the dienylketene
intermediates 1 (Scheme 1) which then cyclized through a
1,6-electrocyclic reaction.
6a-i
7a-i
OAc
Scheme 2 Reagents and Conditions: a) MnO2, CH2Cl2, 2–6 h at r.t.
or CrO3, H2SO4, 0 °C; b) 4a–i + 5, toluene, r.t, 2–4 h; c) Ac2O, 10
equiv and NaOAc, 2 equiv, hydroquinone, 0.05 equiv, then heating 2
h at reflux.
The following Wittig olefination of 4a–i with triphenyl-
( -ethoxycarbonyl- -carboxyethyl)phosphonium ylide9
smoothly afforded the substituted 3-alkoxycarbonylhex-
3-en-5-ynoic acids 6a–i. This reaction proceeded with
complete regioselectivity for all substrates and the acids
were isolated as a single E-isomers10 in a yields ranging
from 57% to 90% (Table).
We envisaged that the structurally related 3-alkoxycarbo-
nylhex-3-en-5-ynoic acids are possible precursors of yne-
nylketene 2 which may be cyclized to give a phenolic
compound by electrophilic attack and nucleophilic addi-
tion to the triple bond.
In order to assay the feasibility of the conversion of 6a–i
into benzannulated phenols and to simplify the products
distribution, we selected the acetic anhydride–sodium
acetate system as the activating agent. Thanks to the use
of these reagents, the mixed anhydride of acids 6a–i was
formed first. We believe that the basic sodium acetate then
promoted the elimination of acetic acid with production of
the ynenylketene 2. Electrophilic attack on the triple bond,
the nucleophilic addition of acetate anion, and the esteri-
fication of the phenolic moiety give the diacetates 7a–i
Herein is documented the successful accomplishment of
this plan starting from a variety of substituted propargylic
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1661,1664,ftx,en;G17002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1662
S. Serra, C. Fuganti
LETTER
(Scheme 3). Therefore, we treated11acids 6a–i with an ex-
cess of acetic anhydride (10 equiv) in the presence of so-
dium acetate (2 equiv) and hydroquinone (0.05 equiv)
heating at reflux for a few hours. The diacetates 7a–i12
were obtained in regioselective fashion and in moderate to
good yields (Table 1).
AcO-
CO2Et
OAc
CO2Et
Ac2O
7a-i
H
H
R
R
C
O
AcO-
O
Scheme 3
Table 1 Synthesis of Acids 6 and Phenols 7 from Aldehydes 4
Entry
Aldehydes 4
Wittig
Acids 6
Benzanulla-
Phenols 7
(yields)a
tion (yields)a
a
57%b
74%c
83%b
56%
COOEt
COOH
AcO
COOEt
O
OAc
AcO
b
c
62%
85%
COOEt
COOEt
O
COOH
OAc
COOEt
COOEt
AcO
O
COOH
OAc
d
e
f
90%b
78%b
81%b
89%b
88%
68%
81%
76%
AcO
COOEt
COOEt
O
COOH
OAc
COOEt
F
F
F
COOEt
AcO
O
COOH
Cl
OAc
Cl
Cl
COOEt
AcO
AcO
AcO
COOEt
O
O
MeO
MeO
MeO
MeO
MeO
MeO
COOH
OAc
OAc
g
COOEt
COOH
COOEt
COOEt
O2N
O2N
O2N
h
i
82%b
73%b
90%
83%
COOEt
COOH
O
OAc
COOEt
COOH
AcO
COOEt
O
S
S
S
OAc
a After chromatography and/or crystallisation.
b 2 hours.
c 6 hours.
Synlett 2002, No. 10, 1661–1664 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route to 4-Substituted 3,5-Dihydroxybenzoic Acids Derivatives
1663
alcohol accordingly to the following reference: Sonogashira,
K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
(b) Alcohols 3d–g and 3i were prepared by palladium
mediated coupling of propargyl alcohol with 1-bromo-4-
fluorobenzene, 1-bromo-2-chlorobenzene, 4-
The examination of the substitution pattern of the acids
6a–i shows the flexibility of this synthetic method. The
substituent groups may be hydrogen, alkyl, aryl, vinyl and
heteroaryl as show in entries a,b,c–g,h and i, respectively.
Moreover, other functional groups as an halo, alkoxy, ni-
tro, in positions ortho, meta and para of the aryl substitu-
ents (entries d–g) were unaffected in the reaction
conditions in order to give the related biaryls in good
yields.
bromoveratrole, 4-nitro-1-iodobenzene and 3-
bromothiophene, respectively; this method of preparation
has been performed by a small modification of the method
described in the following reference: Bleicher, L. S.;
Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.; McDonald,
I. A. J. Org. Chem. 1998, 63, 1109.
Only few methods devoted to the preparation of 4-substi-
tuted-3,5-dihydroxybenzoic acids derivatives are de-
scribed in the literature and most of them are based on
aromatic substitution which is performed either with elec-
trophilic reagents,13 nucleophilic organometallic
reagents14 or chemical rearrangement.15 Since these pub-
lished approaches are not completely regioselective and a
narrow set of substituents is allowed, we believe that our
present method holds some advantages over these classi-
cal routes.
(9) For the preparation of this ylide see: Hudson, R. F.; Chopard,
P. A. Helv. Chim. Acta 1963, 46, 2178.
(10) The Wittig reaction of ylide 5 with the aldehydes affords the
3-(E)-alkylidene-succinic acid monoalkyl esters in a highly
stereoselective way; for previous studies on this reaction
see: (a) Paquette, L. A.; Schulze, M. M.; Bolin, D. J. Org.
Chem. 1994, 59, 2043. (b) Röder, E.; Krauss, H. Liebigs
Ann. Chem. 1992, 177.
(11) General procedure for the benzannulation of acids 6a–i to
give phenols 7a–i:
Acids 6a–i (50 mmoles)were dissolved in acetic anhydride
(48 mL, 0.5 mol). To this solution, anhyd sodium acetate
(8.2 g, 0.1 mol) and hydroquinone (275 mg, 2.5 mmol) were
added in one portion. The obtained heterogeneous mixture
was heated at reflux for 2 h under a nitrogen atmosphere.
After cooling to r.t., the acetic anhydride was removed in
vacuo and the residue was treated with ethyl acetate (200
mL) and water (100 mL). The organic phase was separated,
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by chromatography and
In conclusion, we have developed a new preparative
method for access to 4-substituted-3,5-dihydroxybenzoic
acids derivatives. This procedure is experimentally sim-
ple, the starting materials are easily available and yields
are comparable to or higher than those reported from the
known methods.
Further studies to expand the applicability of our method
also to asymmetrical 3,4,5-trisubstituted benzoic acids de-
rivative are still in progress and will be reported in due
course.
crystallisation to give phenols derivatives 7a–i.
(12) All new compounds were fully characterised. Selected
analytical data:
6f: Anal. Calcd for C17H18O6: C, 64.14; H, 5.70. Found: C,
63.98; H, 5.72. Mp 135–136 °C (ethyl acetate); 1H NMR
(250 MHz, CDCl3) 1.30 (3 H, t, J = 7.2 Hz), 3.70 (2 H, s),
3.88 (3 H, s), 3.90 (3 H, s), 4.25 (2 H, q, J = 7.2 Hz), 6.82 (1
H, d, J = 8.5 Hz), 6.95 (1 H, d, J = 1.7 Hz), 7.04 (1 H, s), 7.10
(1 H, dd, J = 8.5, 1.7 Hz); EI-MS m/z 319 (M+ + 1), 318 (M+),
289, 273, 259, 245, 229, 217, 214, 201, 185, 151, 128, 88;
FT-IR(nujol): (cm–1) 766, 807, 860, 1036, 1054, 1212, 1247,
1281, 1515, 1594, 1618, 1702, 2187.
6i: Anal. Calcd for C13H12O4S: C, 59.08; H, 4.58; S, 12.13.
Found: C, 59.15; H, 4.60; S, 12.20. Mp 92 °C (hexane–ethyl
acetate); 1H NMR (250 MHz, CDCl3) 1.30 (3 H, t, J = 7.1
Hz), 3.68 (2 H, s), 4.25 (2 H, q, J = 7.1 Hz), 7.02 (1 H, s),
7.14 (1 H, dd, J = 5, 1 Hz), 7.30 (1 H, dd, J = 5, 3 Hz), 7.56
(1 H, dd, J = 3, 1 Hz); EI-MS m/z 264 (M+), 220, 205, 191,
163, 147, 135, 111, 83; FT-IR(nujol): (cm–1) 763, 811, 1041,
1203, 1288, 1421, 1619, 1709, 2195.
Acknowledgement
We thank MURST for partial financial support.
References
(1) (a) Serra, S.; Fuganti, C.; Moro, A. J. Org. Chem. 2001, 66,
7883. (b) Brenna, E.; Fuganti, C.; Serra, S. J. Chem. Soc.,
Perkin Trans. 1 1998, 901. (c) Brenna, E.; Fuganti, C.;
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62.90; H, 5.55. Mp 109–110 °C (hexane–ethyl acetate);
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in CH2Cl2 at r.t.
(8) (a) Propargylic alcohols 3a and 3b are commercially
available. Alcohol 3c was prepared from phenylacetylene by
treatment with butyllithium followed by addition of
formaldehyde. Alcohol 3h was prepared by palladium
mediated coupling of (E)- -bromostyrene with propargyl
Synlett 2002, No. 10, 1661–1664 ISSN 0936-5214 © Thieme Stuttgart · New York

1664
S. Serra, C. Fuganti
LETTER
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Synlett 2002, No. 10, 1661–1664 ISSN 0936-5214 © Thieme Stuttgart · New York