A novel synthetic approach to benzo[h]chromones via sequential intramolecular alkynoyl transfer followed by 6-endo ring closure

Article abstract of DOI:10.1016/S0040-4039(00)00037-X

An intramolecular acyl transfer reaction took place on treatment of 1- methoxymethoxy-3-(2-alkynoyloxy)methyl-2-iodonaphthalenes with n-BuLi at - 78°C to give 1-methoxymethoxy-2-alkynoyl-3-hydroxymethylnaphthalenes in high yields. After protection of the hydroxymethyl group as benzoates, formation of a γ-pyrone ring was easily achieved by deprotection of the MOM group followed by spontaneous 6-endo-digonal ring closure under mild acidic conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00037-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1819–1823
A novel synthetic approach to benzo[h]chromones via sequential
intramolecular alkynoyl transfer followed by 6-endo ring closure
Katsuji Sakamoto,a Erina Honda,a Noboru Ono b and Hidemitsu Uno a,∗
aAdvanced Instrumentation Center for Chemical Analysis, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
bDepartment of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
Received 22 November 1999; accepted 24 December 1999
Abstract
An intramolecular acyl transfer reaction took place on treatment of 1-methoxymethoxy-3-(2-
alkynoyloxy)methyl-2-iodonaphthalenes with n-BuLi at −78°C to give 1-methoxymethoxy-2-alkynoyl-3-
hydroxymethylnaphthalenes in high yields. After protection of the hydroxymethyl group as benzoates, formation
of a γ-pyrone ring was easily achieved by deprotection of the MOM group followed by spontaneous 6-endo-digonal
ring closure under mild acidic conditions. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: intramolecular acyl transfer; 6-endo ring closure; benzo[h]chromones; espicufolin; naphtho[2,3-h]chromone
quinones.
There has been considerable interest in pyran-fused quinones due to their important bioactivity, and
many methods for construction of the pyranoquinones have been reported.1 Although the traditional
synthesis of chromones and chromenes represented by the Kostaneki–Robinson and Simonis reactions2
is still useful, a strategy involving an intramolecular Michael addition of a phenoxide anion to an α,β-
unsaturated ketone moiety seems to be the method of choice especially in the synthesis of highly
substituted pyranoquinones. The success of this approach depends largely upon preparation of the α-
alkenoyl or alkynoylphenols and control of the cyclization mode: 5-exo versus 6-endo. There is no
problem in the control of cyclization of o-alkenoylphenols; a 6-endo-trigonal cyclization predominates
over a 5-exo-trigonal ring closure.3 However, a subsequent oxidation of the resulting dihydropyrans
is, somehow, problematic.4 Contrary to the case of o-alkenoylphenols, both 6-endo-digonal and 5-exo-
digonal processes were reported to occur in the base-catalyzed cyclization of o-alkynoylphenols.5 The
precise study of Saito’s group revealed that the 5-exo-digonal closure was fairly favored under the kinetic
conditions, while the 6-endo-digonal products were preferably obtained via an equilibrium between
the anionic intermediates in the absence of a proton donor.6 We have devised a novel approach to the
pyranoquinones based on an intramolecular alkynoyl transfer followed by the 6-endo-digonal closure
∗
Corresponding author. Tel: +81-89-927-9663; fax: +81-89-927-9670; e-mail: uno@dpc.ehime-u.ac.jp (H. Uno)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00037-X
tetl 16317

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under acidic conditions, and succeeded in preparing (S)-espicufolin (ent-1),7 which is an enantiomer of
espicufolin 1 bearing a neuronal cell-protecting activity (Scheme 1). In this paper, we describe the utility
and limitations of our approach.
Scheme 1.
The starting 3-(acyloxymethyl)naphthalenes 2 and 37 were obtained in good overall yields (>50%)
from the known 7-chloro-3-hydroxymethyl-5,8-dimethoxynaphthol.8 An acyl-transfer reaction (Eq. (1))
was examined by generation of an anion at the 2-position of the naphthalenes under various conditions
depicted in Table 1 . First, a bromine–lithium exchange reaction of 2a was carried out by using n-BuLi
at −78°C to give an almost equal amount of the aimed product 4a as a mixture of its hemiacetal form
(ca. 7:1 in CDCl3 at ambient temperature) and a simply deacylated alcohol 5a. In order to avoid the
undesired nucleophilic attack, t-BuLi was employed instead of n-BuLi. The transacylation compound 4a
was obtained in good yield as well as a small amount of 6 (run 2). Under similar conditions, however, the
acyl-transfer reaction of 2b was partially hampered by the nucleophilic attack to give a mixture of 4b and
6, probably due to the sterically less hindered nature of the alkynoyl ester moiety. The side reaction could
not be suppressed by reduction of the reaction temperature to −100°C (run 4). This problem was finally
solved by changing the starting bromide 2b to iodide 3b, and the desired 4b was obtained in good yield
(run 5). The other alkynoyloxy derivatives 3c–f were also converted to 4c–f in good yields as shown in
Table 1.
(1)
Next, the pyran ring formation was examined, and the MOM group of 4b was intended to be
removed under acidic conditions (3.0 M HCl:THF:i-PrOH=1:2:7; reflux) (Scheme 2). However, an
oxepin derivative 8 derived via favorable 7-endo-digonal ring closure9 was obtained in 62% yield instead
of a simply MOM-deprotected compound. Thus, prior to the acidic deprotection, the primary hydroxyl
group of 4 was protected as a benzoate by treatment with BzCl in pyridine to give 7 in good to excellent
yields. Removal of the MOM group of 7b under the acidic conditions (3.0 M HCl:THF:i-PrOH=1:2:7;
reflux) was carried out and the progress was monitored by TLC. A thin yellow spot near 7b appeared
at the very first stage and a polar spot increased as time passed. After leaving overnight, all of 7b had
disappeared. Two spots were identified and separated by chromatography. The polar spot was proved to
be benzo[h]chromone 9b derived from the deprotection of the MOM group followed by a simultaneous
ring closure forming a pyran ring. From the NMR and MS analyses, the other material was assigned as
a mixture of several compounds, some of which were dimeric compounds bearing at least a phenolic
hydroxyl group. In order to prevent the dimerization, the reaction was carried out under an argon

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Table 1
Acyl transfer reaction of 2 and 3
atmosphere (Table 2). In the cases of aliphatic alkynoyl derivatives 7b–d, the benzo[h]chromones 9b–d
were obtained in good yields (runs 1–3), while the reaction of the phenylpropynoyl derivative 7e under
similar conditions gave an almost equal amount of benzo[h]chromone 9e and a new orange material (run
4). From the NMR, MS, and analytical data, the orange compound was determined to be an isomer of 9e.
The IR spectra (1693 cm−1) suggested that this compound had a benzylidenefuranone skeleton, which
was unambiguously determined by the X-ray analysis (Fig. 1).10 A similar result was obtained in the
reaction of 7f (run 6).
Scheme 2.
We were surprised by the formation of the naphtho[1,2-b]furanones 10, because we thought that the
key intermediate of this cyclization was a protonated alkynone such as 12 (Scheme 3). The intermediate
should be attacked only at the β-position either by an intramolecular hydroxyl group or by water followed
by 6-exo-trigonal ring closure11 to give 9. Taking into account that the oxidative dimerization was
observed in the presence of oxygen (vide ante) and that the furanone formation was observed only in the
reactions of the aromatic derivatives 7e–f, it was presumed that a radical intermediate might participate to

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Table 2
Pyrone ring formation
Fig. 1. ORTEP drawing of 10e
give the undesired furanones 10e–f.12 Even in the presence of tocopherol as a radical scavenger, however,
the ratio was not changed. The mechanism for formation of the furanones 10e–f is not clear at this
moment.
Scheme 3. Reaction pathways
In order to suppress the undesired furanone formation, a two-step method was examined.11 Thus, the
alkynones 7e–f were first converted to enaminones by treatment with diethylamine and then refluxed
under similar acidic conditions without isolation of the intermediate enaminones. In this procedure, the
desired benzo[h]chromones 9e–f were obtained in good yields (Table 2, runs 5 and 7).
In conclusion, we have demonstrated an efficient synthesis of benzo[h]chromone derivatives based on

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intramolecular alkynoyl transfer followed by the 6-endo ring closure. This methodology could provide a
new synthetic entry to naphtho[2,3-h]chromone quinones including espicufolin and indomycinones.
References
1. Thomson, R. H. Naturally Occurring Quinones, III; Chapman and Hall: London, 1987.
2. Brogden, P. J.; Gabbutt, C. D.; Hepworth, J. D. Comprehensive Heterocyclic Chemistry; Boulton, A. J.; McKillop, A., Eds.;
Pergamon: Oxford, 1984; Vol. 3, Part 2B, 2.22.
3. Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846.
4. Mahal, H. S.; Rai, H. S.; Venkataraman, K. J. Chem. Soc. 1935, 866.
5. Garcia, H.; Iborra, S.; Primo, J.; Miranda, M. A. J. Org. Chem. 1986, 51, 4432.
6. Nakatani, K.; Okamoto, A.; Yamanuki, M.; Saito, I. J. Org. Chem. 1994, 59, 4360; Nakatani, K.; Okamoto, A.; Matsuno, T.;
Saito, I. J. Am. Chem. Soc. 1998, 120, 11 219.
7. Uno, H.; Sakamoto, K.; Honda, E.; Ono, N. Chem. Commun. 1999, 1005.
8. Bloomer, J. L.; Stagliano, K. W.; Gazzillo, J. A. J. Org. Chem. 1993, 58, 7906.
9. Bottini, A. T.; Corson, F. P.; Böttner, E. F. J. Org. Chem. 1965, 30, 2988.
10. Compound 10e: C29H21ClO6; P-1 (#2); of the collected 3875 reflections, 3668 were unique (Rint=0.0369). The final cycle
of full-matrix least-squares refinement yields R=0.047, RW=0.059 and goodness-of-fit=1.92 for 3325 observed reflections
[I>1.00s(I)] and 409 variable parameters. Atomic coordinates for this structure were deposited with the Cambridge
Crystallographic Data Centre (CCDC-138106). The coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
11. Torii, S.; Okumoto, H.; Hu, L. H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin, V. N. Tetrahedron
1993, 49, 6773.
12. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734; Kandil, S. A.; Dessy, R. E. J. Am. Chem. Soc. 1966, 88, 3027.