Synthesis of 1,2,3,4-tetrasubstituted naphthalenes through a cascade reaction triggered by silyl acetal activation

Article abstract of DOI:10.1039/c6cc03510h

1,2,3,4-Tetrasubstituted naphthalenes bearing four different substituents were synthesized in a regioselective manner through a fluoride-induced cascade reaction of lactol silyl ethers, which could be easily prepared from 4-alkynylisocoumarins and ketene silyl acetal.

Full text of DOI:10.1039/c6cc03510h

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DOI: 10.1039/C6CC03510H
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Synthesis of 1,2,3,4-tetrasubstituted naphthalenes through
cascade reaction triggered by silyl acetal activation
Hikaru Yanai,*,a Nobuyuki Ishii,a and Takashi Matsumoto*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
1,2,3,4-Tetrasubstituted naphthalenes bearing four different
substituents were synthesized in a regioselective manner by
fluoride-induced cascade reaction of lactol silyl ethers, which
could be easily prepared from 4-alkynylisocoumarins and ketene
silyl acetal.
Polysubstituted naphthalenes are found in nature as second
metabolites. Their interesting biological activities1 make such
structural motif an attractive target of organic synthesis.2 However,
combination of classical electrophilic aromatic substitution (SEAr)
reactions is less effective because steric congestion by the
substituent(s) encumbers the bond formation. Precise control of
the regiochemistry is still more difficult. As the alternatives, several
benzannulation approaches have been reported. For example, (4+2)
cycloaddition chemistry,3 anionic annulation reactions,4 ring-closing
methathesis–aromatization,5 and transition metal-catalyzed
benzannulation reactions6 provide the effective routes to 1,2,3- or
1,2,4-trisubstituted naphthalenes. The Hauser annulation of ,-
unsaturated carbonyls with phthalide derivatives was also used to
construct the polycyclic systems including natural products.7
However, an effective access to 1,2,3,4-tetrasubstituted
naphthalenes bearing four different substituents, which are found
in some lignans8 and polyketides,9 are still challenging.10
Scheme 1 Zwitterion-induced addition reaction of KSA to 1H-isochromen-1-one (Tf =
CF3SO2, TBS = t-BuMe2Si)
Upon treatment of alkynylated lactol silyl ether A with suitable
fluoride sources, desilylative ring-opening reaction (formation of B)
followed by proton transfer would occur to yield enolate
intermediates C and/or D. Here, intramolecular aldol reaction of C
could take place to give 4-alkynylnaphthalene E. On the other hand,
Recently, we reported that acidic zwitterion 111 nicely promoted
the addition reaction of ketene silyl acetals (KSAs) to 1H-
isochromen-1-one derivatives to give the lactol silyl ethers in
excellent yields as exemplified by the reaction of lactone 2 with a
KSA derived from ethyl acetate (Scheme 1).12 This finding prompted
us to conceive an idea of a novel cascade reaction using alkynylated
lactol silyl ether A for a regioselective synthesis of the 1,2,3,4-
tetrasubstituted naphthalenes (Fig 1).
a.School of Pharmacy, Tokyo University of Pharmacy and Life Sciences. 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: yanai@toyaku.ac.jp (HY)
and tmatsumo@toyaku.ac.jp (TM)
† Electronic Supplementary Information (ESI) available: Details of experiments,
NMR data for all compounds. For ESI see
Fig 1 1,2,3,4-Tetrasubstituted naphthalene formation through cascade reactions of A
DOI: 10.1039/x0xx00000x
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intermediate could yield 4-acylnaphthalene
Journal Name
Table 1 Survey of effective reaction conditions
D
F
through
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DOI: 10.1039/C6CC03510H
intramolecular Michael reaction or 6-electrocyclization. The
formation of E might be disfavored because the formation of
intermediates C from B would be reversible, despite of irreversible
formation of allenyl ketone D. We anticipated selective formation
of F via D.13 Herein we report successful implementation of this idea.
The starting lactones were easily available. Typical synthesis is
shown in Scheme 2. Under the Larock’s conditions,14 methyl o-
(phenylethynyl)benzoate 5, which was obtained by the Sonogashira
reaction of methyl o-iodobenzoate
4 with ethynylbenzene,
smoothly cyclized by treating with ICl to give 6-membered
iodolactone 6 in 92% yield. The following Sonogashira reaction of 6
with hex-1-yne or with ethynylbenzene yielded 4-alkynyl-1H-
isochromen-1-ones 7a and 7b in 88% and 95% yields, respectively.15
According to similar procedure, several lactones were prepared in
good to excellent overall yields (see, ESI). The obtained lactone 7a
was subjected to the addition reaction of KSA in the presence of a
catalytic amount of zwitterion 1, and the desired adduct 8a was
isolated in 95% yield. Likewise, 8b was obtained in 90% yield from
7b.
Scheme 3 Plausible mechanism
Scheme 2 Synthesis of starting lactol silyl ethers
shown in Scheme 3, divinyl ether 10 would be formed by kinetically
favored O-cyclization of D, while it also was transformed to D via -
elimination reaction in a reversible manner in the presence of MS4A.
In a case of phenylethynyl substrate 8b, MS4A was not necessary;
the reaction of 8b with 3.0 equiv of TBAF at 70 °C gave 4-
benzoylnaphthalene 9b in 91% yield without formation of the
corresponding divinyl ether 10b (entry 5). The use of MS4A gave an
essentially same result (entry 6). The structures of naphthalenes 9a
and 9b were determined by X-ray crystallographic analyses (Fig 2).
To reveal substrate scope of this two-step naphthalene
synthesis, we examined the application of several lactones (Table 2).
The zwitterion-induced addition reaction of KSA to 1H-isochromen-
With these lactol silyl ethers in hands, we conducted model
reactions with tetrabutylammonium fluoride (TBAF) as
a
conventional fluoride source.16,17 The reaction of 8a with 1.0 equiv
of TBAF at room temperature gave desired 4-benzoylnaphthalene
9a in 53% yield along with a small amount of divinyl ether 10a
(entry 1). At the same time, 1H-isochromen-1-one 7a was also
isolated in 24% yield. The formation of 7a suggested fluoride-
induced retro-aldol type reaction and the following protonation of
the resulting enolate by some proton sources existing in the
reaction mixture. Higher reaction temperature and additional
loading of TBAF were not effective to improve the yield of 9a
(entries 2 and 3). Finally, we found that the yield was dramatically
increased by using molecular sieves (MS) 4A as an additive. The use
of 1.0 g of MS4A powder per 1.0 mL of the TBAF solution resulted in
quantitative formation of 9a (entry 4). MS4A would work as a
dehydrating agent for the reaction system and cause enhancement
of both nucleophilicity and basicity of fluoride ion. In TLC analysis of
this reaction, we observed a spot of 10a within short reaction time
with accompanying formation of 9a. After enough reaction time (3
h), completed consumption of 10a led to clean formation of 9a. As
Fig 2 ORTEP drawings of 9a (a) and 9b (b)
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Table 2 Two-step synthesis of 1,2,3,4-tetrasubstituted naphthalenes
conditions (1 mol% of 1, 1.2 equiv of KSA). NVoietwabAlryti,cleaOcnidliniec
zwitterion 1 did not affect acid-sensitiveDfOuIn: c1t0i.o10n3a9li/tCie6sCCs0u3c5h10aHs
thienyl, acetyloxy, and MOM groups. The ring rearrangement
reaction of these adducts also worked nicely. In the reaction of 8c
bearing phenyl group on the alkyne moiety, MS4A was not
necessary and the desired naphthalene 9c was obtained in 92%
yield by using 1.0 equiv of TBAF. On the other hand, lactol silyl ether
8d bearing a butyl pendant on the alkyne moiety required MS4A to
meet excellent yield of naphthalene 9d (96% yield). Likewise, in the
presence of MS4A, arylated alkynes 8e-8i yielded the corresponding
3-(arylmethyl)naphthalenes 9e-9i without formation of undesired
regioisomers. Naphthylmethyl and thienylmethyl naphthalenes 9j
and 9k were also obtained in excellent yields. The reaction of silyl
ethers 8m and 8n bearing some protecting groups such as acetyl
and MOM groups was also proceeded to give the corresponding
naphthalenes 9m and 9n in 70% and 93% yields, respectively. In the
reaction of lactol silyl ether 8o (3.0 equiv of TBAF), the trimethylsilyl
group on alkynyl moiety did not survive, affording 3-
methylnaphthalol 9o in 91% yield. The use of 1.0 equiv of TBAF also
resulted in selective formation of 9o (62% yield).
The naphthalene synthesis from lactone 7p is worth of
comment (Scheme 4). In this case, zwitterion-induced reaction
using 2.2 equiv of KSA gave bis-silylated product 8p, which was
formed by the TBS protection of the hydroxyl group and the
simultaneous Mukaiyama aldol type reaction. The treatment of 8p
with 3.0 equiv of TBAF and MS4A successfully produced primary
alcohol 9p in 97% yield.
Scheme 4 Naphthalene synthesis from primary alcohol 7p
In order to demonstrate synthetic utilities of the present
methodology, we finally examined synthesis of higher polycyclic
systems (Scheme 5). By using TfOH as a superacidic media, we
realized the direct intramolecular Friedel–Crafts acylation of 9b
having an ethyl ester functionality as the acyl donor part;18 when a
solution of 9b in TfOH was stirred for 2 h at room temperature,
additional ring formation proceeded to give tetracenone 11 in 86%
yield. Moreover, the reaction of lactol silyl ether 8q, which was
obtained from lactone 7q, with TBAF gave tetrahydrotetraphene 12
in 67% yield. This reaction would proceed via fluoride-induced ring-
opening reaction, intramolecular Michael reaction, 6-
electrocyclization of intermediate G, and the following dehydrative
aromatization.
1-one derivatives 7c-7o was smoothly proceeded to give the
corresponding adducts 8c-8o in excellent yields under optimized
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Journal Name
5
6
W. A. L. van Otterlo and C. B. de Koning, Chem. Rev., 2009,
View Article Online
109, 3743.
Selected examples, see: T. TakahashiD, ORI.: 1H0i.r10a3, 9Y/.C6NCisCh0i3h5a1r0aH,
and M. Kotora, J. Am. Chem. Soc., 1996, 118, 5154; R. C.
Larock and Q. Tian, J. Org. Chem., 1998, 63, 2002; Y. Kita, K.
Iio, K. i. Kawaguchi, N. Fukuda, Y. Takeda, H. Ueno, R.
Okunaka, K. Higuchi, T. Tsujino, H. Fujioka, and S. Akai,
Chem.–Eur. J., 2000,
6, 3897. N. Iwasawa, M. Shido, K.
Maeyama, and H. Kusama, J. Am. Chem. Soc., 2000, 122
,
10226; N. Umeda, H. Tsurugi, T. Satoh, and M. Miura, Angew.
Chem. Int. Ed., 2008, 47, 4019; A. Matsumoto, L. Ilies, and E.
Nakamura, J. Am. Chem. Soc., 2011, 133, 6557.
7
8
9
F. M. Hauser and R. P. Rhee, J. Org. Chem., 1978, 43, 178.; A.
S. Mitchell and R. A. Russell, Tetrahedron, 1995, 51, 5207; D.
Mal and P. Pahar, Chem. Rev., 2007, 107, 1892.
K. Munakata, S. Marumo, and K. Ohta, Tetrahedron Lett.,
1965, 6, 4167; K. Ohta and K. Munakata, Tetrahedron Lett.,
1970, 11, 923.
M. Gill and W. Steglich, Pigments of Fungi (Macromycetes),
In Progress in the Chemistry of Organic Natural Products,
Springer, 1987, Vol. 51, pp. 1–317; J.-M. Gao, J.-C. Qin, G.
Pescitelli, S. Di Pietro, Y.-T. Ma, and A.-L. Zhang, Org. Biomol.
Chem., 2010, 8, 3543.
10 Recent examples, see: H. Xu, S. Li, H. Liu, H. Fu, and Y. Jiang,
Chem. Commun., 2010, 46, 7617; Y. Chen, L. Wang, N. Sun, X.
Xie, X. Zhou, H. Chen, Y. Li, and Y. Liu, Chem.–Eur. J., 2014, 20
12015; F.; Yoshimura, T. Abe, and K. Tanino, Org. Lett., 2016,
18, 1630.
,
Scheme 5 Construction of higher polycyclic systems
In summary, we successfully developed a synthetic methodology for
1,2,3,4-tetrasubstituted naphthalenes bearing four different
substitutens from 4-alkynyl-1H-isochromen-1-ones, which were
easily synthesized in good to excellent overall yields. The present
methodology included the Mukaiyama aldol type reaction induced
by acidic zwitterion 1 and the ring rearrangement reaction of thus
obtained adducts with TBAF. This ring rearrangement reaction took
11 H. Yanai, T. Yoshino, M. Fujita, H. Fukaya, A. Kotani, F. Kusu,
and T. Taguchi, Angew. Chem. Int. Ed., 2013, 52, 1560; H.
Yanai, Chem. Pharm. Bull., 2015, 63, 649.
12 H. Yanai, N. Ishii, T. Matsumoto, and T. Taguchi, Asian J. Org.
Chem., 2013,
2, 989; H. Yanai and T. Taguchi, Chem.
Commun., 2012, 48, 8967.
13 X. Yu, H. Ren, Y. Xiao, and J. Zhang, Chem.–Eur. J., 2008, 14
,
8481; Q. Yao, Y. Liao, L. Lin, X. Lin, J. Ji, X. Liu, and X. Feng,
Angew. Chem. Int. Ed., 2016, 55, 1859.
place in
a wide range of lactol silyl ethers and undesired
14 T. Yao and R. C. Larock, J. Org. Chem., 2003, 68, 5936.
regioisomers were not formed. In addition, further ring formation
directed to higher polycyclic systems was achieved.
This work was partially supported by a Grant-in-Aid for Scientific
15 The Suzuki–Miyaura reaction of
6 afforded 4-phenyllactone
in only moderate yield (also see, ref. 14). However, fluoride-
induced naphthalene synthesis including intramolecular
aldol condensation step was successfully achieved (see, ESI).
16 Metal fluorides such as KF and CsF were ineffective under
these conditions.
Research
on
Innovative
Areas
“Advanced
Molecular
Transformations by Organocatalysts” from the MEXT, a Grand-in-
Aid for Scientific Research (C) from JSPS, the Hoansha Foundation,
and the Naito Foundation. We also thank Ms. Saki Takayanagi for
her technical assistance.
17 In the reaction of lactone 7b with 2.0 equiv of BrZnCH2CO2Et
in benzene at 85 °C, poor conversion of 7b was observed.
See: F. M. Hauser and R. Rhee, J. Am. Chem. Soc., 1977, 99
4533.
,
18 J. P. Hwang, G. K. S. Prakash, and G. A. Olah, Tetrahedron,
2000, 56, 7199.
Notes and references
1
2
3
S. Mori, S. Takechi, S. Shimizu, S. Kida, H. Iwakura, and M.
Hajima, Tetrahedron Lett., 1999, 40, 1165.
C. B. de Koning, A. L. Rousseau, and W. A. L. van Otterlo,
Tetrahedron, 2003, 59, 7.
S. Danishefsky and T. Kitahara, J. Am. Chem. Soc., 1974, 96
,
7807; J. Banville and P. Brassard, J. Chem. Soc., Perkin Trans.
1, 1976, 1852; M. Kitamura, K. Ohmori, T. Kawase, and K.
Suzuki, Angew. Chem., Int. Ed. Engl., 1999, 38, 1229; L. F.
Tietze, K. M. Gericke, and R. R. Singidi, Angew. Chem. Int. Ed.,
2006, 45, 6990.
4
M. Paiier and O. Vostrowsky, Monatsh. Chem., 1971, 102,
951; M. Yamaguchi, K. Hasebe, H. Higashi, M. Uchida, A. Irie,
and T. Minami, J. Org. Chem., 1990, 55, 1611; C. B. de Koning,
J. P. Michael, and A. L. Rousseau, J. Chem. Soc., Perkin Trans.
1, 2000, 787; M. Shindo, Y. Sato, and K. Shishido, J. Org.
Chem., 2001, 66, 7818; D. Mal, A. K. Jana, P. Mitra, and K.
Ghosh, J. Org. Chem., 2011, 76, 3392.
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