Novel thermal and microwave-assisted facile route to naphthalen-2(1 h)-ones via an oxidative alkoxylation-ringopening protocol

Article abstract of DOI:10.1021/ol9008574

Several novel 1,1-disubstituted-8-hydroxynaphthalen-2(1H)-ones have been efficiently synthesized via a two-step sequence from 2-hydroxy1-naphthaldehyde oxime. The methodology involves oxidative ring closure and alkoxylation to 3a-alkoxynaphtho[1,8-de][1,2

Full text of DOI:10.1021/ol9008574

ORGANIC
LETTERS
2009
Vol. 11, No. 14
2964-2967
Novel Thermal and Microwave-Assisted
Facile Route to Naphthalen-2(1H)-ones
via an Oxidative Alkoxylation-Ring-
Opening Protocol
Chrysanthi Dolka,† Kristof Van Hecke,‡ Luc Van Meervelt,‡ Petros G. Tsoungas,§
Erik V. Van der Eycken,*,| and George Varvounis*,†
Department of Chemistry, UniVersity of Ioannina, 45110 Ioannina, Greece, Laboratory
for Organic & MicrowaVe-Assisted Chemistry (LOMAC), Department of Chemistry,
Katholieke UniVersiteit LeuVen, Celestijnenlaan 200F, B-3001 LeuVen, Belgium,
Biomolecular Architecture, Department of Chemistry, Katholieke UniVersiteit LeuVen,
Celestijnenlaan 200F, B-3001, LeuVen, Belgium, and Ministry of DeVelopment,
Department of DeVelopment and Technology, Messogion 14-16, 115 10 Athens, Greece
gVarVoun@cc.uoi.gr; erik.Vandereycken@chem.kuleuVen.be
Received April 19, 2009
ABSTRACT
Several novel 1,1-disubstituted-8-hydroxynaphthalen-2(1H)-ones have been efficiently synthesized via a two-step sequence from 2-hydroxy-
1-naphthaldehyde oxime. The methodology involves oxidative ring closure and alkoxylation to 3a-alkoxynaphtho[1,8-de][1,2]oxazin-4(3aH)-
ones, followed by thermal ring-opening. Both thermal and microwave irradiation conditions were used. A novel one-pot reaction of oxime to
8-isopropoxynaphthalene-1,7-diol using microwave irradiation is also reported.
Naphthalen-2(1H)-ones are an important class of pharmacologi-
cally active compounds. 1-Hydroxy-1,6-dimethylnaphthalen-
2(1H)-ones 1-3 belong to a group of phytoalexines, produced
by the cotton plant Gossypium hirsutum when infected by
bacteria.1a The second member exhibits in vitro chemotactic
activity toward human polymorphonuclear leukocytes.1b Non-
natural compounds such as 4 are HIV-1 reverse transcriptase
inhibitors,1c 5 are inhibitors of genotype 1 hepatitis C virus
(HCV) polymerase,1d,e whereas 6 exhibit prolyl hydroxylase
inhibitory activity.1f A large number of synthetic routes to
1,1-disubstituted naphthalen-2(1H)-ones have been described.
In particular, attention has been paid to the synthesis of 1,1-
difluoronaphthalen-2(1H)-one, useful as a synthetic inter-
mediate and a tool for elucidating biological processes. The
compound is synthesized by fluorination of 2-naphthol,2a-h
2-methoxynaphthalene,3f,g 1-alkoxy-2-fluoronaphthalenes, or
2-(N-acetylamino)naphthalene.2a,b Other 1,1-disubstituted
naphthalen-2(1H)-ones have been synthesized by amination
ofsodium1-methylnaphthalen-2-olate,2i methylationof1-meth-
yl-2-naphthol,2j oxidation of 4-isopropyl-7-methoxy-1,6-
dimethyl-2-naphthol,2k reaction of sodium naphthalen-2-olate
with alkyl halides over supported hexamethylphosphoric
† University of Ioannina.
‡ Biomolecular Architecture, Katholieke Universiteit Leuven.
§ Ministry of Development.
| Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Katholieke Universiteit Leuven.
(1) (a) Krohn, K.; Zimmermann, G. J. Org. Chem. 1998, 63, 4140. (b)
Jeffs, P. W.; Lynn, D. G. J. Org. Chem. 1975, 40, 2985. (c) Alam, M.;
Bechtold, C. M.; Patick, A. K.; Skoog, M. T.; Gant, T. M.; Colonno, R. J.;
Meyers, A. I.; Li, H.; Trimble, J.; Lin, P.-F. AntiViral Res. 1993, 22, 131.
(d) Krueger, A. C.; Madigan, D. L.; Green, B. E.; Hutchinson, D. K.; Jiang,
W. W.; Kati, W. M.; Liu, T.; Maring, C. J.; Masse, S. V.; McDaniel, K. F.;
Middleton, T. R.; Mo, H.; Molla, A.; Montgomery, D. A.; Ng, T. I.; Kempf,
D. J. Bioorg. Med. Chem. Lett. 2007, 17, 2289. (e) Bosse, T. D.; Larson,
D. P.; Wagner, R.; Hutchinson, D. K.; Rockway, T. W.; Kati, W. M.; Liu,
Y.; Masse, S.; Middleton, T.; Mo, H.; Montgomery, D.; Jiang, W.; Koev,
G.; Dale, J.; Kempf, D. J.; Molla, A. Bioorg. Med. Chem. Lett. 2008, 18,
568. (f) Allen, J. R.; Biswas, K.; Bryan, M. C.; Burli, R.; Cao, G.-Q.; Frohn,
M. J.; Golden, J. E.; Mercede, S.; Neira, S.; Peterkin, T.; Pickrell, A. J.;
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10.1021/ol9008574 CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

triamide,2l chlorination of 2-naphthol and decomposition of
1,1,3,4-tetrachlorotetralin-2-one,2m oxidation of 1,1-dimeth-
ylnaphthalene-2(1H)-thione,2n radical-mediated oxidative cy-
clization of 1-(3,5-dimethoxyphenyl)hex-1-ene-3,5-diones,2o
oxidation of 1,1-dimethyl-1,2-dihydronaphthalen-2-ol,2p and
Claisen rearrangement followed by ring-closing metathesis
of 1-allyl-2-(allyloxy)naphthalenes.2q Among the plethora of
microwave-assisted transformations, oxidation with hyper-
valent iodine reagents stands out as the most common green
chemistry protocol that employs solid-supports and benign
reaction media.3a Iodobenzene diacetate has been used in
reactions with solid-supports,3b-e with water as solvent,3f-h
without solvent,3i-l and with common organic solvents3m-q
(Figure 1).
Table 1. Examples of Alkoxynaphthooxazin-4(3aH)-ones 10
Prepared (Scheme 2)a
a Representative procedure. Thermally (T): compound 7 (1.07 mmol),
IBD (2.17 mmol), and appropriate alcohol (15 mL) were stirred at 22 °C
for the indicated time. Microwave-irradiation (MW): compound 7 (1.07
mmol), IBD (2.17 mmol), and appropriate alcohol (15 mL) were irradiated
at a ceiling temperature of 40 °C and a maximum power level of 100 W
for the indicated time. b Isolated yields after column chromatography.
Figure 1. Pharmacologically active naphthalen-2(1H)-ones.
thermal ring-opening. Both conventional and microwave condi-
tions were used and the results are compared. This synthesis
was inspired by an unexpected observation as shown in Scheme
1. On the basis of our previous observation that 2-hydroxy-1-
Herein, we report a novel two-step synthesis of 1,1-disub-
stituted-8-hydroxynaphthalen-2(1H)-ones (1-alkoxy-8-hydroxy-
2-oxo-1,2-dihydronaphthalene-1-carbonitriles) 11a-g (Scheme
2, Table 2) from 2-hydroxy-1-naphthaldehyde oxime 7 via
oxidative ring closure and alkoxylation to 3a-alkoxynaphtho[1,8-
de][1,2]oxazin-4(3aH)-ones 10a-g (Table 1), followed by
Scheme 1
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naphthaldehyde oxime 7 undergoes a one-pot o- and peri-
oxidative cyclization with lead(IV) acetate to give isomeric
naphtho[1,2-d]isoxazole 2-oxide and naphtho[1,8-de][1,2]-
oxazine via a common o-naphthoquinone nitrosomethide in-
termediate 7a,4 we envisaged that the oxidation of compound
7 with iodobenzene diacetate in methanol would lead to reactive
intermediate 7a, followed by fast Michael addition of methanol
to give 7b and/or 7c. When compound 7 was treated with 2
Org. Lett., Vol. 11, No. 14, 2009
2965

Table 2. Examples of Naphthalen-2(1H)-ones 11 Prepared
(Scheme 2)a
Figure 2. X-ray molecular structure of 10d, with atom-labeling
a Representative procedure. Thermally (T): appropriate compound 10
(0.35 mmol) and DMF (5 mL) were heated at 120 °C for the indicated
time. Microwave-irradiation (MW): appropriate compound 10 (0.35 mmol)
and DMF (5 mL) were irradiated at a ceiling temperature of 40 °C and a
maximum power level of 150 W for the indicated time. b Isolated yields
after column chromatography.
scheme. Displacement ellipsoids are drawn at the 50% probability level.
1
equiv of iodobenzene diacetate in methanol, the H and 13C
NMR and mass spectra of the compound isolated did not
account for the expected compounds 7b or 7c or any of their
possible oxidation products (Scheme 1). Structure 10a (Scheme
1, Table 1, entry 1) was tentatively assigned to the product and
later confirmed by comparison with the product from the
reaction of compound 7 with 2 equiv of iodobenzene diacetate
in i-propanol (70 min reaction time). The structure of this
product 10d (Table 1, entry 4) was determined by single crystal
X-ray crystallographic analysis (Figure 2). The X-ray structure
features a chiral center on the C-atom C1. The compound
In our previous work concerning the synthesis of 4-hy-
droxynaphtho[1,8-de][1,2]oxazine, we demonstrated that
upon heating this compound in DMF at 120 °C, ring-opening
occurred to give 2,8-dihydroxynaphthalene-1-carbonitrile.4
Overall this reaction is important because it implies an
intramolecular nuclear hydroxylation. Hydroxylation and
oxygennation are important biological processes.5a,b We
therefore thought that a similar ring-opening of compounds
10a-g would occur. Thus, heating compounds 10a-g in
DMF at 120 °C for 30 min resulted in ring-opening of these
compounds to give the corresponding 1,1-disubstituted-8-
hydroxynaphthalen-2(1H)-ones 11a-g, in 77-82% yields
(Table 2). Application of microwave irradiation to these
reactions required the same temperature but reaction time
was drastically reduced to 4 min. A comparison of the yields
of compounds 11a-g by the conventional and microwave
methods establishes that the yields using microwave irradia-
tion show a small increase of 4-8% and, remarkably, a 2%
decrease in the yield of compound 11d (Table 2).
A plausible mechanistic explanation, for the overall trans-
formation of 7 to the oxidatively alkoxylated naphthooxazinones
10a-g and then thermal ring-opening to the corresponding
alkoxylated naphthalenone-carbonitriles 11a-g, is shown in
Scheme 2. To establish that the first step of the reaction gives
the peri-oxidative cyclization intermediate 8, compound 7 was
treated with 1 equiv of iodobenzene diacetate in methanol to
afford, after chromatographic separation, compound 8 and
starting material 7 in 60 and 32% yields, respectively. Moreover,
treating compound 7 with 2 equiv of iodobenzene diacetate in
t-butanol afforded only compound 8 in 80% yield. It is
reasonable to assume that attack of t-butanol on 9 is sterically
j
crystallized in the centrosymmetric space group P1, hence both
enantiomers are present in the structure. No classic hydrogen
bonds are observed. Stacking interactions occur between the
C5-C10 aromatic ring and the same ring of a symmetry-
equivalent molecule (3.8 Å between the ring centroids).
The reaction of compound 7 with iodobenzene diacetate was
repeated in the presence of other alcohols (Table 1). Attempts
to optimize the yields of compounds 10a-g by varying reaction
time and the stoichiometry of reagents resulted in the conclusion
that 2 equiv of iodobenzene diacetate was optimum for all the
alcohols whereas reaction times varied from 40 to 70 min (Table
1). To reduce reaction time and improve on the yields of
compounds 10a-g, the reaction of compound 7 with 2 equiv
of iodobenzene diacetate in the appropriate alcohol was repeated
using microwave irradiation at 40 °C. Optimum reaction times
for these reactions were found to be 4-9 min (Table 1). The
corresponding products 10a-g were isolated in 62-79% yields.
In Table 1, a comparison of reaction times and yields of the
conventional heating method and the microwave irradiation
method is given. The microwave method is superior because it
reduces the conventional reaction time from a maximum 70 to
8 min and the conventional minimum time of 30 to 4 min. There
is a moderate increase in the yield of products by the microwave
method ranging from 6 to 18%.
(4) (a) Supsana, P.; Tsoungas, P. G.; Varvounis, G. Tetrahedron Lett.
2000, 41, 1845. (b) Supsana, P.; Tsoungas, P. G.; Aubry, A.; Skoulika, S.;
Varvounis, G. Tetrahedron 2001, 57, 3445.
(5) (a) Holland, H. L. AdV. Appl. Microbiol. 1997, 44, 125. (b) Di
Gennaro, G. E.; Albini, G.; Pelizzoni, F.; Sello, G.; Pestetti, G. Res.
Microbiol. 1997, 148, 355
.
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Org. Lett., Vol. 11, No. 14, 2009

Scheme 2
.
Proposed Mechanism for the Formation of 10 and 11
Scheme 3. Proposed Mechanism for the Formation of 13 from 7
propanol using 100 W irradiation at 40 °C for 6 min followed
by 150 W irradiation at 120 °C for 4 min. To our surprise, the
product we isolated was identified as 8-isopropoxynaphthalene-
1,7-diol 13 (Scheme 3). A mechanism for this result is tentatively
proposed. The first two steps of the reaction correspond to those
of Scheme 2 and lead to compound 11d. The i-propanol containing
water probably hydrolyses the nitrile 11d to the ketoacid9 which
could be decarboxylated to 12. Intermediate 12 may then tautom-
erise/aromatize to 13. Partial evidence for this mechanism was
obtained by a further experiment where 11d was converted to 13
using 150 W microwave irradiation at 120 °C for 4 min.
In conclusion, we have designed a new, convenient and
high yielding synthetic approach to 1,1-disubstituted-8-
hydroxynaphthalen-2(1H)-ones from 2-hydroxy-1-naphthal-
dehyde oxime in the presence of alcohols. The reaction
occurs in two-steps, a one-pot oxidative ring closure to
naphtho[1,8-de][1,2]oxazin-4-ol and then alkoxylation to 3a-
alkoxynaphtho[1,8-de][1,2]oxazin-4(3aH)-ones, followed by
thermal ring-opening. Each reaction step was performed
comparatively under thermal and microwave conditions. The
advantage of microwave irradiation is shorter reaction time
and higher yields (with one exception) of products. Further-
more, we obtained a novel one-pot conversion of 2-hydroxy-
1-naphthaldehyde oxime to 8-isopropoxynaphthalene-1,7-diol
in i-propanol by a two-stage microwave irradiation.
impeded and the latter hydrolyses back to 8 upon aqueous
workup. Furthermore, we found out that oxidation of compound
8 with 1 equiv of iodobenzene diacetate in methanol gives the
expected 3a-methoxynaphthooxazin-4(3aH)-one 10a in 75%
yield. We therefore unequivocally established that compound
8 is an intermediate in this reaction. The formation of compound
8 from oxime 7 has been previously described using lead(IV)
tetraacetate.4 Herein we propose a similar mechanistic pathway
whereby the organoiodo intermediate 7d collapses to the
reactive o-naphthoquinone nitrosomethide intermediate 7e that
undergoes intramolecular peri-cyclization to intermediate naph-
thooxazinone 7f. The latter then tautomerises/aromatizes to
naphthooxazine 8. In the next step, we propose that organoiodo
intermediate 9 triggers nucleophilic attack by the alcohol onto
strongly electrophilic C-3a atom that leads to 10. There is
substantial evidence for this type of reaction in the literature
such as, for example, the iodobenzene diacetate oxidative
alkoxylation of 2,3-disubstituted indoles to 3-alkoxyindolenines,
of 4-alkyl- and 4-alkoxyphenols to the corresponding 4-alkyl-
4-methoxy- and 4-alkoxy-4-methoxy-cyclohexadienones,7 as
well as the oxidative cyclization of 2′-alkenyl-substituted
p-phenyl phenols to spiro-annulated 2,5-cyclohexadienones.8
The ring-opening step of this reaction sequence employs DMF
as the solvent at a temperature of 120 °C that causes the
cleavage of the O-N bond of compound 10 with concomitant
prototropic isomerization to naphthalenone 11. A similar type
of ring-opening was substantiated in our previous work.4
We also examined the possibility of converting, in a one-pot
reaction, compound 7 to alkoxynaphthalenone-carbonitriles 11
with 2 equiv of iodobenzene diacetate in alcoholic solutions
using microwave irradiation. The reaction took place in i-
Acknowledgment. Financial support from the Socrates/
Erasmus Exchange Programme between the University of
Ioannina and Katholieke Universiteit Leuven (grant to C.D.)
is gratefully acknowledged.
Supporting Information Available: Detailed synthetic
procedures, product characterization, 1H NMR, 13C NMR and
MS spectra of synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9008574
(9) A referee has kindly suggested that alternatively, hydrolysis of the
cyano group of 11d to the ketoacid may occur via the hydrated form of the
keto group acting intramolecularly as a nucleophile.
(10) CCDC-725437 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44-1223-336033; or
deposit@ccdc.cam.uk).
(6) Awand, D. V. C.; Vincent, A. Can. J. Chem. 1980, 58, 1589.
(7) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.
(8) Callinan, A.; Chen, Y.; Morrow, G. W.; Swenton, J. S. Tetrahedron
Lett. 1990, 31, 4551.
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