A new method to prepare 3-alkyl-2-hydroxy-1,4-naphthoquinones: Synthesis of lapachol and phthiocol

Article abstract of DOI:10.1055/s-0030-1260771

In this article a mild, simple, safe, and chemoselective synthesis and reduction of o-quinone methides to the corresponding 3-alkyl-2-hydroxy-1,4- naphthoquinones, compounds with interesting biological activity, mediated by the formic acid-water system is described. This new one-pot methodology was applied to the synthesis of lapachol and constitutes an efficient and inexpensive alternative for the preparation of this natural bioactive compound Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260771

LETTER
1551
A New Method to Prepare 3-Alkyl-2-hydroxy-1,4-naphthoquinones:
Synthesis of Lapachol and Phthiocol
A
N
ew Metho
a
d to Prepar
b
3-Alkyl-2-h
r
ydroxy-
i
1,4-nap
n
hthoquinone
a
s
Baptista Ferreira,a David Rodrigues da Rocha,b José Walkimar M. Carneiro,c Wilson Costa Santos,d
Vitor Francisco Ferreira*b
a
Universidade Federal do Rio de Janeiro, Instituto de Química, 27930-560 Macáe, Rio de Janeiro, Brazil
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, 24020-141 Niterói, Rio de Janeiro, Brazil
Fax +55(21)26292362; E-mail: cegvito@vm.uff.br
b
c
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Inorgânica, 24020-141 Niterói, Rio de Janeiro, Brazil
d
Universidade Federal Fluminense, Faculdade de Farmácia, Departamento de Farmácia e Administração Farmacêutica,
24241-000 Niterói, Rio de Janeiro, Brazil
Received 24 January 2011
logues, with b-lapachone (4) being one of the main lapa-
chol derivatives. b-Lapachone (4) is currently being tested
in a clinical phase II trial, under the code ARQ501, in
combination with gemcitabine in a formulation with hy-
Abstract: In this article a mild, simple, safe, and chemoselective
synthesis and reduction of o-quinone methides to the corresponding
3-alkyl-2-hydroxy-1,4-naphthoquinones, compounds with interest-
ing biological activity, mediated by the formic acid–water system is
described. This new one-pot methodology was applied to the syn- droxypropyl-b-cyclodextrin (HPbCD) for the treatment of
pancreatic cancer.8a,b
thesis of lapachol and constitutes an efficient and inexpensive alter-
native for the preparation of this natural bioactive compound
Key words: reduction, quinones, alkylation, lapachol, phthiocol
O
OH
Alkyl-1,4-naphthoquinones constitute an important group
O
of compounds that present some types of biological activ-
HO
O
O
O
ity. 3-Substituted-2-hydroxy-1,4-naphthoquinones such
as lapachol (1) exhibit a broad spectrum of activities.1
Some 3-substituted-2- hydroxy-1,4-naphthoquinones 1–3
reported in the literature that highlight the importance of
this class of compounds are presented in Figure 1.
lapachol (1)
O
O
O
O
The most prominent member of this group is lapachol (1)2
which has inspired the synthesis of many compounds such
as atovaquone (3). Lapachol (1) is a naturally occurring
naphthoquinone found as a constituent of various plant
families, including the Bignoniaceae, Leguminosae, Sa-
potaceae, Scrophulariaceae, Verbenaceae, Malvaceae,
and Proteaceae and exhibits an impressive list of biolog-
ical activities.3 Its occurrence is prominent in the Bignon-
iaceae family, particularly in the genus Tabebuia
(Tecoma). Lapachol was first isolated in 1882 from the
Tabebuia species avellanedae.4 These trees are common-
ly known in South America as Ipês, Lapacho, Pau d’Arco,
purple and lapacho Taheebo.5
HO
O
O
O
OH
conocurvone (2)
O
O
Cl
O
atovaquone (3)
O
β-lapachone (4)
Since the discovery of the activity of 1 against Walker car-
cinoma 256,6 several structural modifications have been
introduced into the compound’s structure to obtain new
bioactive compounds against several pathogens.7a–e
Figure 1 Natural and synthetic bioactive 3-substituted 1,4-naphtho-
quinones
For this reason, the isolation, structure elucidation, and
synthesis of 2-hydroxy-3-alkyl-1,4-naphthoquinones, es-
pecially lapachol, has attracted a lot of attention. This ex-
plains the fact that C–C bond-forming reactions providing
lawsone (5) have become of great interest and have long
been studied in the literature. In view of these facts, sev-
eral methodologies have been described like coupling of
Lapachol (1) has a prominent biological action and is
widely used by the scientific community as a raw material
for the synthesis of various bioactive derivatives and ana-
SYNLETT 2011, No. 11, pp 1551–1554
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260771; Art ID: S00411ST
© Georg Thieme Verlag Stuttgart · New York

1552
S. B. Ferreira et al.
LETTER
lawsone phenyliodonium ylide with activated arenes and
aromatic aldehydes9 and other coupling reactions10,11 or
different direct methods of alkylation, involving coupling
of lawsone (5) with diazonium salts,12 alkylation with tri-
alkylboranes,13 or addition of other alkylating agents to
lawsone (5) and analogues.14–16 One of the oldest methods
was reported by Fieser;17 this method performs the alky-
lation of the silver salt of lawsone (5) with 1-bromo-3-
Table 1 Reduction of o-Quinone Methides to the Corresponding 3-
Alkyl-2-hydroxy-1,4-naphthoquinones under Optimized Reaction
Conditions
Product
6a23
R
Time (h)
Yield (%)
H
3
2
3
3
3
3
3
3
89
90
85
64
78
45
60
78
6b15
4-O2NC6H4
Ph
methyl-2-butene. Fieser also produced a panel of naphtho- 6c9
quinones possessing antimalarial activity by the reaction
6d24
4-MeOC6H4
CHMe2
COMe
(CH2)3CHO
CH=CMe2
of diacyl peroxides with lawsone (5).18
6e25
6f26
6g
The limitations of the above methodologies and our inter-
est in the development of new synthetic approaches to
prepare 2-hydroxy-1,4-naphthoquinones with important
biological properties prompted us to explore the reduction
of o-quinone methides (o-QM)19a,b generated in situ via
the Knoevenagel condensation reaction between lawsone
(5) and aldehydes (Scheme 1).
127
the possibility of formation o-alkylated byproducts, one of
the major problems encountered when alkylating 2-hy-
droxyquinones.
O
O
O
O
R
OH
OH
R
RCHO
This protocol was used with different aldehydes to verify
the versatility of the reaction; these aldehydes included
those that contained aliphatic or benzyl substitutions with
electron-withdrawing and electron-donor groups. The
best yield was obtained for 6b, which uses p-nitrobenzal-
dehyde, which contains a strong electron-withdrawing
group, NO2, that favors the condensation step. More inter-
estingly, the use of a dialdehyde led selectively to the for-
mation of 6g in moderate yield without reduction of the
terminal aldehydes.
HCOOH
EtOH–H2O (1:1)
200 °C, 2–3 h
O
O
O
5
(o-QM)
1, 6a–g
Scheme 1 Synthesis of 1,4-naphthoquinones 1 and 6a–g
As in other methodologies, lawsone (5) was used as the
starting material, and it reacted with various aldehydes,
followed by reduction of the o-QM formed in situ with
formic acid at high temperature. Using this protocol, it
was possible to prepare in moderate to excellent yields
several 3-alkyl derivatives of 2-hydroxy-1,4-naphtho-
quinone 6a–g, including lapachol (1), which are described
in Table 1.
The structures of compounds 1 and 6a–g were confirmed
1
by spectroscopic techniques, such as H NMR and 13C
NMR and infrared (IR) spectroscopy, and these structures
were identical to those reported in the literature.
To experimentally prove the need for water in the reduc-
tion of o-QM formed in situ, the reactions were performed
in ethanol as the solvent (Scheme 2). The formation of the
desired alkylated product was not observed in any of these
reactions, and the starting material lawsone (5) was recov-
ered.
The condensation and reduction reactions were performed
in a closed steel reactor vessel in ethanol–water (1:1) us-
ing formic acid as reduction agent. Initially, the one-pot
reaction was performed with formaldehyde, leading to the
formation of 6a, a commercial product known as phthio-
col that is described as having molluscicidal activity.20 It
is worth noting that under these experimental conditions,
if formaldehyde is used in excess, it can be oxidized by the
oxygen in the air present inside the reactor vessel to for-
mic acid,21,22 which can then perform the reduction of the
o-QM intermediate. The use of aldehydes as reagents and
proreducing agents can only be applied for the preparation
of 6a or other naphthoquinones with a methyl group at po-
sition 3.
As noted above, water participates actively in the course
of this reaction, and this hypothesis is supported by previ-
ous reports in literature, which consider the participation
of water on this reducing mechanism.22
To gain additional insight into the reaction mechanism,
we carried out a set of DFT calculations for the reduction
of the o-quinone methide by formic acid. After full opti-
mization of a transition structure, we calculated an activa-
tion enthalpy of 17.8 kcal mol–1. As the experimental
results suggested a powerful effect of water on the reac-
tion yield, we additionally optimized a transition structure
in which one water molecule actively participates in the
reduction process (see Figure 2 for both transition struc-
tures). The activation enthalpy in this case was reduced to
8.4 kcal mol–1, therefore reinforcing the experimental ev-
idence that the presence of water helps to reduce the acti-
We next examined the formation and reduction of o-QM
generated from other aldehydes, leading to substituted
hydroxyl-naphthoquinones 1, 6b–g. The results indicated
that we have developed a simple method for the reduction
of o-quinone methides and an effective alternative to per-
form selective alkylation of lawsone (5). This methodolo-
gy is interesting because it could be employed to obtain 2-
hydroxy-3-alkyl naphthoquinones in good yields without
Synlett 2011, No. 11, 1551–1554 © Thieme Stuttgart · New York

LETTER
A New Method to Prepare 3-Alkyl-2-hydroxy-1,4-naphthoquinones
1553
O
O
O
OH
H
O
O
EtOH
H
H
O
H
H
+
H
+
+
– H2O
O
H
O
O
OH
H
O
O
H
O
O
O
H
O
OH
+ CO2 + H2O
H
O
O
Scheme 2 Proposed mechanism for the reduction of o-quinone methide by formic acid in water
vation energy. In summary, the DFT calculations Acknowledgment
provided further evidence for the reduction of quinone
methides by formic acid, preferentially with one interven-
ing water molecule.
Thanks are due to the CNPQ (National Council of Research of Bra-
zil), CAPES and FAPERJ-PRONEX (E-26/171.512.2010), for fun-
ding this work. S. B. Ferreira and D. R. da Rocha thanks FAPERJ
for their doctoral fellowship.
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LETTER
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Synlett 2011, No. 11, 1551–1554 © Thieme Stuttgart · New York