Nucleophilic addition reaction with dearomatization of naphthalene ring

Article abstract of DOI:10.1248/cpb.c19-01117

Various aromatic lactones have been synthesized and their regioselectivity (1,2-addition vs. 1,4- or 1,6-addition) investigated in reactions with organolithium species, particularly n-BuLi and sec-BuLi. The regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and organolithium species, and types of solvent and cosolvent. In particular, 1,4-addition with dearomatization occurred preferentially using sec-BuLi as the nucleophile in tetrahydrofuran (THF) with hexamethylphosphoramide (HMPA) or N,N′-dimethylpropyleneurea (DMPU) as cosolvent. For sec-BuLi, the reaction was estimated to proceed through a single-electron transfer mechanism.

Full text of DOI:10.1248/cpb.c19-01117

384
Chem. Pharm. Bull. 68, 384–391 (2020)
Vol. 68, No. 4
Regular Article
Highlighted Paper selected by Editor-in-Chief
Nucleophilic Addition Reaction with Dearomatization of Naphthalene Ring
Hirotaka Sasaki, Kotaro Kiyotaki, Ayumi Imayoshi, and Kazunori Tsubaki*
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University; Shimogamo, Sakyo-ku, Kyoto
606–8522, Japan.
Received December 25, 2019; accepted January 29, 2020
Various aromatic lactones have been synthesized and their regioselectivity (1,2-addition vs. 1,4- or
1,6-addition) investigated in reactions with organolithium species, particularly n-BuLi and sec-BuLi. The
regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and
organolithium species, and types of solvent and cosolvent. In particular, 1,4-addition with dearomatiza-
tion occurred preferentially using sec-BuLi as the nucleophile in tetrahydrofuran (THF) with hexameth-
ylphosphoramide (HMPA) or N,Nꢀ-dimethylpropyleneurea (DMPU) as cosolvent. For sec-BuLi, the reaction
was estimated to proceed through a single-electron transfer mechanism.
Key words dearomatization; regioselective; organolithium; 1,4-addition; 1,6-addition
the 1,2-adduct 2 and 1,4-adduct 3 were obtained in 66 and 5%
Introduction
In the last two decades, organic reactions using dearomati- yields, respectively, while in THF/tetramethylethylenediamine
zation have attracted much attention as unique methodologies (TMEDA), the 1,4-adduct 3 was preferred (47% yield) over the
for constructing complex molecules. These reactions are di- 1,2-adduct 2 (22%).
vided into four classes, namely, reduction, oxidation, addition,
From these studies, we speculated that the nucleophilic
and cycloaddition reactions, with many examples of each class 1,4-addition of organometallic reagents to aromatic carboxylic
having been developed.1,2) In particular, nucleophilic addition esters might proceed when the π-face of the aromatic ring and
reactions with dearomatization have been well investigated π-face of the carbonyl group are fixed in a coplanar relation-
(Chart 1). For example, in 1964, Dixon et al. reported that ship. Accordingly, in this study, we report 1,4-addition reac-
t-butyllithium reacted with naphthalene to afford a mixture tions accompanied by dearomatization of non-benzoxanthone
of t-butyldihydronaphthalenes in 17% yield.3–5) Furthermore, skeletons. The substrate ester group was fixed as a lactone by
reactions of organometallic species with naphthyl ketones connection with an aromatic ring.
have been reported by Fuson et al. since the late 1950s.6–8)
Initially, compounds 418) and 519) bearing lactone skeletons
The authors reported the reaction of 1-(1-naphthyl)-2,2,2- were prepared and reactions were conducted using n-BuLi in
triphenyl-ethanone and phenylmagnesium bromide, which pre- THF at −78°C for 1h (Chart 3). Under these reaction condi-
dominantly produced the 1,4-adduct, introducing the phenyl tions, 3equiv of n-BuLi were required for complete conver-
group at the 2-position of the naphthalene ring in 93% yield. sion.
Furthermore, in the 1980s, Meyers et al. reported pioneering
Under these conditions, the reaction of compound 4 bear-
examples of dearomatization reactions using oxazolines as ing a benzene ring afforded ketone 620) and alcohol 7, derived
directing and activating groups for aromatic rings.9–12) Sev- from mono- and bis-additions of n-BuLi to the carbonyl group
eral similar reactions have also been reported. Shindo et al. of 4 in 10 and 81% yields, respectively. No formation of com-
developed a reaction involving collapse of the naphthalene pound 8, generated by the 1,4-addition of n-BuLi with dearo-
ring possessing a bulky 2,6-bis(t-butyl)-4-methoxyphenyl matization, was observed. In contrast, under the same reaction
(BHA) ester.13,14) Miyano and colleagues, and Hattori et al. conditions, compound 5 bearing a naphthalene ring afforded
reported ipso-substitution reactions by combining isopropyl or lactone 11a, derived from the 1,4-addition of n-BuLi, in 41%
BHA esters with an alkoxy group at the ortho-position of the yield, as well as compounds 9a21) (10%) and 10a22) (32%).
naphthalene ring.15,16) In these examples, bulky groups steri- Interestingly, Talinli et al. also reported the reaction between
cally protected the carbonyl group (or carbonyl equivalents), compound 5 and n-BuLi in toluene, which afforded compound
such that nucleophilic addition could not occur at the carbonyl 10a and its dehydrated derivative in 75 and 5% yields, respec-
carbon. Nucleophilic attack instead occurred at the β-position tively,22) representing a quite different product distribution
of the carbonyl group, causing dearomatization of the naphtha- to that observed in the present study. These data suggested
lene ring. In contrast, for the sterically smaller methyl ester, that the solvent played an important role. Therefore, we next
the dearomatization reaction did not proceed, with the reaction screened solvents and alternative organolithium reagents in
inevitable occurring at the carbonyl carbon.
the reaction, as shown in Table 1.
We have recently reported unusual 1,4-addition with dearo-
The result for using THF as solvent (Table 1, entry 1) has
matization reactions of benzoxanthones 1 and n-butyllithium17) already been described above. When toluene was used as
(Chart 2). In these reactions, the selectivity for 1,2- and solvent (entry 2; the same conditions as reported by Talinli),
1,4-addition varied depending on the reaction conditions, such compound 11a was obtained in 10% yield, along with 9a in
as the type of solvent and nucleophile. For example, when 4% yield and 10a in 67% yield. The ratio of 1,2-adduct to
2-methyl-tetrahydrofuran (2-Me-THF) was used as solvent, 1,4-adduct was 7.1:1. The combined yields of compound 9a
*To whom correspondence should be addressed. e-mail: tsubaki@kpu.ac.jp
© 2020 The Pharmaceutical Society of Japan

Vol. 68, No. 4 (2020)
Chem. Pharm. Bull.
385
and 10a were comparable to those reported by Talinli, sug- compounds 9a and 10a were obtained in 10 and 51% yields,
gesting that the formation of 1,4-adduct 11a was overlooked respectively (entry 5). When hexamethylphosphoramide
previously. In our previous reports, using 2-Me-THF as (HMPA) and N,N′-dimethylpropyleneurea (DMPU) were used
solvent led predominantly to 1,2-adducts. However, in this as cosolvents (10 vol% relative to THF), the ratios of 1,2- and
study, the ratio of 1,2- and 1,4-adducts, and yields of those 1,4-adducts were 1:4.3 and 1:2.9, respectively (entries 6 and
compounds, were the same when using 2-Me-THF (entry 4) 7). Compared with entry 1, these cosolvent additives resulted
instead of THF (entry 1). Using diethyl ether as solvent gave in improved 1,4-selectivity. These data also indicated that the
1,4-adduct 11a in a significantly reduced yield of 24%, while solvent greatly affected product selectivity, as initially expect-
ed. Therefore, the degree of n-BuLi aggregation had a major
effect on the product distribution. The selectivity for 1,2- and
1,4-additions changed depending on the type of organolithium
species used (entries 8–10). Only 1,2-adducts were obtained in
high yields when using MeLi and PhLi (entries 8 and 9), with
combined yields of the corresponding ketones (9b23) and 9c24))
and alcohols (10b25) and 10c26)) of 94 and 86%, respectively.
Meanwhile, the ratio of 1,2- and 1,4-additions using n-BuLi
was about 1:1 (entry 1). To our surprise, sec-BuLi showed
the reverse selectivity, favoring 1,4-adduct 11d in 75% yield
compared with the 1,2-adducts in 16% total yield (entry 10).
These results indicated that 1,2-adducts were favored using
less bulky or less basic nucleophiles (entries 8 and 9), while
1,4-adducts were preferred when using bulky nucleophiles.
The bulkiness and basicity of the nucleophile also affected the
product distribution.
Next, with a focus on the ring size and cyclization mode of
the lactones, compounds 1226)–17,27) bearing five- to seven-
membered rings and the presence or absence of a dimethyl
group, were synthesized, and their reactions with n-BuLi and
sec-BuLi as nucleophiles were investigated (Table 2).
For five-membered lactone 12, only 1,2-adduct 18a was ob-
tained in 88% yield using n-BuLi as nucleophile (entry 1). In
contrast, 1,4-adduct 20d was predominantly afforded in 59%
yield over 1,2-adduct 18d in 33% yield when using sec-BuLi
(entry 2). As already described above, the 1,2-adducts (9a +
10a) and 1,4-adduct 11a were obtained in 42% combined yield
and 41% yield, respectively, using n-BuLi, while 1,4-adduct
11d was the main product in 75% yield using sec-BuLi (en-
Chart 1. Several Nucleophilic Reactions with Dearomatization
tries 3 and 4). The preference of sec-BuLi for 1,4-addition was
Chart 2. Our Previous Study of the Nucleophilic Addition of n-BuLi to Benzoxanthone Skeletons
Chart 3. Attempted Reactions of n-BuLi with Aromatic Lactones 4 and 5

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Table 1. Screening of Reaction Solvents and Organolithium Reagents
Conditions
Yields (%) of
Entry
Ratio of 9+10:11
RLi
Equiv
Solvent
9
10
11
1
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
CH3Li
PhLi
3
3
3
3
3
6
6
3
3
3
THF
9a:10
9a:4
10a:32
10a:67
10a:75
10a:40
10a:51
10a:13
10a:16
10b:84
10c:82
10d:8
11a:41
11a:10
11a:—
11a:41
11a:24
11a:73
11a:57
11b:—
11c:—
11d:75
1:1
7.1:1
1:0
2
3a)
Toluene
Toluene
9a:—
9a:2
4
2-Me-THF
Et2O
1:1
5b)
6c)
7c)
8
9a:10
9a:4
2.5:1
1:4.3
1:2.9
1:0
THF:HMPA=9:1
THF:DMPU=9:1
THF
9a:4
9b:10
9c:4
9
THF
1:0
10
sec-BuLi
THF
9d:8
1:4.7
Reaction conditions: Temperature, −78°C; substrate concentration, 44mM. a) Taken from the results of Talinli.22) Conditions: Substrate concentration, 137mM. b) Owing to
the low solubility of compound 5 in diethyl ether, the substrate concentration was 15mM. c) 6equiv of n-BuLi were required for complete conversion.
not observed using substrate 13, which lacked the dimethyl
group, affording 1,4-adduct 21d in a significantly reduced
28% yield (entry 6). These results indicated that the bulki-
ness of both the substrates and organolithium species affected
product selectivity. For compound 14, only 1,2-adducts were
afforded by both n-BuLi and sec-BuLi (entries 7 and 8). Sur-
prisingly, 1,6-adduct 27d was obtained in 56% yield from the
reaction of sec-BuLi with compound 15, representing a dif-
ferent cyclization mode to that of compound 14 (entry 10). In
contrast, using n-BuLi predominantly afforded 1,2-adduct 25a
in 88% yield (entry 9). The preference of sec-BuLi for 1,4-ad-
1,4-addition being preferred over 1,2-addition. In contrast,
coordinative solvent THF increased the selectivity for 1,4-ad-
dition, while adding HMPA or DMPU as cosolvent greatly
increased the proportion of 1,4-adducts. As the lower-order
aggregates derived from coordinative solvents would have a
hard character, 1,2-adducts would be expected to be preferred
over 1,4-adducts. However, in these experiments, the opposite
selectivity occurred. The explanation for this phenomenon has
been proposed in previous studies. Accordingly, when using
a coordinative solvent, a solvent-separated ion pair is formed,
giving the 1,4-adduct.28,29)
In contrast, contact ion pairs kineti-
dition was not observed when using demethylated substrate 16 cally give the 1,2-adduct. The different selectivities observed
(entry 12).
for n-BuLi and sec-BuLi depended not only on steric factors,
Based on DFT calculations, the dihedral angle between the but on their reaction mechanisms. Therefore, the reaction was
π-face of naphthalene and carbonyl group (shown in bold) in assumed to proceed through an ionic mechanism for n-BuLi
seven-membered lactone 17 was about 32°, which was largely and a single-electron transfer mechanism for sec-BuLi.
distorted compared with compounds 5 and 12–16, in which
To verify this speculation regarding the reaction systems,
the dihedral angles were about 4–6°. Therefore, we initially the following experiments were conducted (Table 3). First,
assumed that the 1,4-addition of organolithium species was benzaldehyde was treated with a mixture of n-BuLi (3.0
suppressed and 1,2-addition would be favored in compound 17 equiv) and sec-BuLi (3.0 equiv), and the ratio of the generated
1
owing to the large dihedral angle. Although n-BuLi selectively benzyl alcohols was estimated by H-NMR, with compounds
afforded 1,2-adducts 29a and 30a in 84% combined yield possessing n-Bu and sec-Bu side chains obtained in a ratio
(entry 13), sec-BuLi afforded 1,4-adduct 31d in 59% yield of about 52:48. Therefore, sec-BuLi originally had equal or
(entry 14). These data indicated that the dihedral angle be- slightly lower nucleophilicity and higher basicity compared
tween the π-face of naphthalene and carbonyl group had little with n-BuLi. Considering these characteristics, a mixed solu-
effect on the regioselectivity. Despite compound 17 lacking tion of n-BuLi (3 equiv) and sec-BuLi (3 equiv) was added
the dimethyl group adjacent to the carbonyl group, the 1,4-ad- slowly to a THF solution of compound 15 (1 equiv) at −78°C
dition preference of sec-BuLi (31d; 59% yield) suggested that (entry 1). The same reaction was also conducted in the pres-
the reaction mechanism of sec-BuLi was different to that of ence of 1 or 3 equiv of galvinoxyl30) as a radical trap reagent,
n-BuLi.
To summarize all results above, 1,4-addition reactions with ing integral intensities by H-NMR (entries 2 and 3).
dearomatization of the naphthalene ring depended largely
In the absence of galvinoxyl, compound 27d, resulting from
and the ratio of products was estimated from the correspond-
1
on the nucleophiles, substrates, solvents, and cosolvent ad- the 1,6-addition of sec-BuLi, was obtained as the major prod-
ditives. The selectivity for 1,4-addition was optimal with uct (entry 1). The ratio of products 25a, 25d, and 27d was es-
1H-NMR to be 28:17:55. The sec-Bu adduct was
sterically bulky organolithium reagents and substrates, THF timated by
predominant over the n-Bu adduct, suggesting that sec-BuLi
and n-BuLi reacted through different reaction mechanisms.
As the amount of galvinoxyl was increased, the formation of
as solvent, and coordinating HMPA or DMPU as cosolvents.
Clearly, as the steric hindrance of the substrate increased,
repulsion around the carbonyl group increased, resulting in

Vol. 68, No. 4 (2020)
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387
Table 2. Attempted Reactions of Various Aromatic Lactones with n-BuLi or sec-BuLi
Reaction conditions: substrate (1 equiv), n-BuLi (3 equiv) or sec-BuLi (3 equiv), THF, −78°C, 1h.
sec-Bu adducts markedly decreased and the amount of n-Bu DMPU as cosolvent, and high steric repulsion in the reaction
adducts increased (entries 2 and 3). This indicated that the re- substrates and nucleophiles, conjugate addition accompanied
action of sec-BuLi mainly occurred through a single-electron by dearomatization proceeded readily. Furthermore, conjugate
transfer pathway.
addition of sec-BuLi was strongly suggested to occur through
In conclusion, the regioselectivity of lactones containing a single-electron transfer pathway. These dearomatization
naphthalene rings reacting with n-BuLi and sec-BuLi as nu- reactions are expected to be developed as a new method for
cleophiles was investigated. With THF as solvent, HMPA or the synthesis of complex compounds from relatively simple

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Table 3. Reactions of Compound 15 with n-BuLi and sec-BuLi in the Presence/Absence of Galvinoxyl
NMR ratio (%) of
Entrya)
Equiv of galvinoxyl
25a
25d
27d
n-BuLi : sec-BuLi
1,2- : 1,4-
1
2
3
—
1
28
47
72
17
22
15
55
31
13
28:72
47:53
72:28
45:55
69:31
87:13
3
a) 26a, 27a, and 26d were not observed.
starting materials.
1H, J=1.2, 7.6, 7.6Hz), 6.71 (ddd, 1H, J=1.2, 7.6, 7.6Hz),
6.65 (dd, 1H, J=1.2, 7.6Hz), 5.52 (s, 1H), 1.99–1.90 (m, 2H),
1.68–1.61 (m, 2H), 1.33–1.11 (m, 6H), 1.00–0.89 (m, 2H),
Experimental
General Information All reactions sensitive to air or 0.80–0.75 (m, 6H); 13C{1H} NMR (100MHz, DMSO-d6) δ:
moisture were carried out under argon atmosphere under 156.2, 130.2, 127.8, 127.8, 118.9, 116.6, 78.9, 41.6, 26.1, 23.2,
anhydrous conditions, unless otherwise noted. Solvents and 14.6; high resolution (HR) MS (ESI/FT-ICR-MS) Calcd for
reagents were used without further purification unless oth- C15H24O2Na [M+Na]+ 259.1669, Found 259.1671.
erwise noted. Oil baths were used to heat reaction mixtures.
General Procedure of Reaction of the Organolithium
Analytical TLC was performed using Silica gel 60F254 plates Reagents and Naphthalene 5 A solution of the appropri-
(0.25mm, normal phase), Chlomatorex NH TLC plates and ate lithium reagent (3 equiv) was added to a THF solution
Silica gel 60RP-18F254S plates (0.25mm, reversed phase). of 5 (1.0 equiv) at −78°C. The mixture was stirred for 1h
Normal phase flash column chromatography was performed at −78°C and then treated with NH4Cl aq. The mixture was
using Silica gel 60 (particle size 40–63µm; 230–400 mesh allowed to warm up to r.t. The mixture was extracted with
ASTM) and Chlomatorex NH-DM1020 (SiO2-NH, average ethyl acetate, washed with brine, dried over sodium sulfate,
particle size 100µm). Melting point (mp), determined on a concentrated and purified by chromatography (SiO2, hexane :
micro melting point apparatus, were uncorrected. IR spectra ethyl acetate) to give 1,2-adduct 9 and mixture of 1,2-adduct
1
were recorded using KBr pellets. H and proton-decoupled 10 and 1,4-adduct 11. Then the mixture was again purified
13C (13C{1H}) NMR spectra (400 and 100MHz, respectively) by chromatography (SiO2–NH, hexane : ethyl acetate) to give
were recorded using chloroform-d (CDCl3) and dimethylsulf- corresponding 1,2-adducts 10 and 1,4-adducts 11.
oxide-d6 (DMSO-d6) as a solvent. Chemical shift values are
Compound 9a: Known.21) Yield 5mg (10%) from 50mg
expressed in δ (ppm) relative to the solvent resonance (CDCl3, (0.22mmol) of 5.
1
δ 7.26ppm for H-NMR and δ 77.0ppm for 13C-NMR; DMSO-
Compound 10a: Known.22) Yield 20mg (32%) from 50mg
d6, δ 2.54ppm for H-NMR and δ 40.45ppm for 13C-NMR) (0.22mmol) of 5.
1
or tetramethylsilane (TMS, δ 0.00ppm). Data are reported as
Compound 11a: Yield 26mg (41%) from 50mg (0.22mmol)
follows: chemical shift, multiplicity (s=singlet, d=doublet, of 5; colorless oil; IR (neat) 1726, 1661, 1458, 1417, 1404cm−1;
t=triplet, br=broad, m=multiplet), coupling constants (J; 1H-NMR (400MHz, DMSO-d6) δ: 7.30–7.18 (m, 4H), 3.88
Hz), and integration. Mass spectra were obtained by Fou- (brs, 1H), 3.80 (dd, 1H, J=2.8, 2J=22.0Hz), 3.48 (d, 1H,
rier transformation ion cyclotron resonance mass spectrometry 2J=22.0Hz), 1.73 (s, 3H), 1.67–1.61 (m, 5H), 1.25–0.94
(FT-ICR-MS) using a spectrometer with electrospray ioniza- (m, 4H), 0.78 (t, 3H, J=7.2Hz); 13C{1H} NMR (100MHz,
tion (ESI).
DMSO-d6) δ: 164.7, 160.6, 138.4, 131.8, 128.5, 128.4, 127.1,
Synthesis of Compounds 6 and 7 A hexane solution of n- 126.7, 106.4, 104.1, 37.7, 37.4, 32.3, 28.1, 26.8, 23.8, 22.6,
butyllithium (536µL, 0.84mmol, 3 equiv) was added to a THF 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C18H23O3 [M+H]+
solution (5mL) of the 4 (50mg, 0.28mmol, 1 equiv) at –78°C. 287.1642, Found 287.1638.
The mixture was stirred for 1h at –78°C and then quenched
with NH4Cl aq. The mixture was allowed to warm up to (0.22mmol) of 5.
Compound 9b: Known.23) Yield 4mg (10%) from 50mg
room temperature (r.t.). The mixture was extracted with ethyl
Compound 10b: Known.25) Yield 37mg (84%) from 50mg
acetate, washed with brine, dried over sodium sulfate, concen- (0.22mmol) of 5.
trated and purified by chromatography (SiO2, hexane : ethyl
Compound 9c: Known.24) Yield 2mg (4%) from 50mg
acetate=100:3–10:1) to give compound 6 (5mg, 0.03mmol, (0.22mmol) of 5.
10%) and compound 7 (54mg, 0.23mmol, 81%).
Compound 10c: Known.26) Yield 59mg (82%) from 50mg
(0.22mmol) of 5.
Compound 6: Known.20)
Compound 7: White solid; mp 88–89°C; IR (KBr) 3333,
Compound 9d: Yield 4mg (8%) from 50mg (0.22mmol)
1
2955, 1589, 1468, 1412cm−1; H-NMR (400MHz, DMSO-d6) of 5; yellow oil; IR (neat) 3059, 2967, 1645, 1634, 1514,
δ: 9.94 (brs, 1H), 7.12 (dd, 1H, J=1.2, 7.6Hz), 7.00 (ddd, 1454 cm−1; H-NMR (400MHz, DMSO-d6) δ: 8.53 (s, 1H),
1

Vol. 68, No. 4 (2020)
Chem. Pharm. Bull.
389
7.99 (d, 1H, J=8.4Hz), 7.75 (d, 1H, J=8.4Hz), 7.54 (dd, 1H, fluoroacetic acid (0.02 equiv) and trifluoroacetic anhydride
J=7.2, 7.2Hz), 7.36 (dd, 1H, J=7.2, 7.2Hz), 7.29 (s, 1H), (0.01 equiv) was added to an acetone (3 equiv) solution of
3.75 (tq, 1H, J=6.4, 6.4Hz), 1.78–1.73 (m, 1H), 1.51–1.46 appropriate naphthoic acid (1 equiv) under ice bath cooling.
(m, 1H), 1.17–1.11 (m, 3H), 0.93–0.87 (m, 3H); 13C{1H} NMR The mixture was stirred for 24h at r.t. The organic layer was
(100MHz, DMSO-d6) δ: 210.6, 155.8, 137.3, 132.9, 130.0, concentrated and purified by chromatography (SiO2, hexane :
129.6, 127.4, 126.3, 124.3, 124.3, 111.5, 43.3, 26.9, 17.1, 11.9; ethyl acetate) to give a corresponding lactone.
HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M+Na]+
Compound 14: Yield 286mg (47%) from 500mg
(2.66mmol) of 1-hydroxy-2-naphthoic acid; white solid; mp
251.1043, Found 251.1049.
Compound 10d (Diastereomeric mixture): Yield 5mg 83–84°C; IR (KBr) 1734, 1719, 1634, 1582, 1508, 1393cm−1;
(8%) from 50mg (0.22mmol) of 5; colorless oil; IR (neat) 1H-NMR (400MHz, DMSO-d6) δ: 8.18 (d, 1H, J=7.6Hz),
1
3420, 2967, 1638, 1516, 1508, 1456cm−1; H-NMR (400MHz, 8.03 (d, 1H, J=8.0Hz), 7.82–7.76 (m, 2H), 7.70–7.67 (m,
DMSO-d6) δ: 11.53 (brs, 1H), 7.78 (d, 1H, J=8.0Hz), 7.63 2H), 1.81 (s, 6H); 13C{1H} NMR (100MHz, DMSO-d6) δ:
(d, 1H, J=8.4Hz), 7.59 (s, 1H), 7.36 (dd, 1H, J=6.8, 6.8Hz), 160.9, 154.1, 137.7, 130.8, 128.8, 127.8, 123.6, 123.5, 122.9,
7.24 (dd, 1H, J=6.8, 6.8Hz), 7.05 (s, 1H), 6.42 (brs, 1H), 122.7, 107.7, 107.6, 25.7; HRMS (ESI/FT-ICR-MS) Calcd for
2.33–2.12 (m, 1H), 1.94–1.84 (m, 1H), 1.53–1.40 (m, 1H), C14H12O3Na [M+Na]+ 251.0679, Found 251.0672.
1.10–0.78 (m, 15H); 13C{1H} NMR (100MHz, DMSO-d6) δ:
Compound 15: Yield 305mg (50%) from 500mg
159.0, 157.8, 133.8, 128.4, 127.5, 126.2, 125.5, 122.9, 110.3, (2.66mmol) of 2-hydroxy-1-naphthoic acid; white solid; mp
88.0, 87.4, 43.0, 42.6, 24.7, 22.8, 22.6, 14.3, 13.0, 12.7, 12.4 89–90°C; IR (KBr) 1717, 1622, 1518, 1375cm−1; 1H-NMR
(many peaks overlapped); HRMS (ESI/FT-ICR-MS) Calcd for (400MHz, DMSO-d6) δ: 9.06 (d, 1H, J=8.8Hz), 8.29 (d,
C19H26O2Na [M+Na]+ 309.1825, Found 309.1832.
1H, J=9.2Hz), 8.01 (d, 1H, J=8.0Hz), 7.72 (ddd, 1H,
Compound 11d (Diastereomeric mixture): Yield 47mg J=1.2, 8.4, 8.4Hz), 7.55 (dd, 1H, J=7.6, 7.6Hz), 7.29 (d, 1H,
(75%) from 50mg (0.22Mmol) of 5; colorless oil; IR (neat) J=9.2Hz), 1.76 (s, 6H); 13C{1H} NMR (100MHz, DMSO-d6)
1
2961, 1724, 1651, 1458, 1417, 1404cm−1; H-NMR (400MHz, δ: 160.3, 157.8, 139.0, 131.5, 130.1, 130.0, 129.7, 125.8, 125.2,
DMSO-d6) δ: 7.29–7.23 (m, 4H), 3.92–3.89 (m, 1H), 3.79–3.73 118.0, 106.1, 105.2, 25.4; HRMS (ESI/FT-ICR-MS) Calcd for
(m, 1H), 3.51–3.44 (m, 1H), 1.77–1.68 (m, 7H), 1.47–1.36 (m, C14H12O3Na [M+Na]+ 251.0673, Found 251.0679.
1H), 1.11–1.04 (m, 0.5H), 0.90–0.85 (m, 3.5H), 0.71–0.65 (m,
General Procedure of Reaction of n- or sec-Butyllithium
3H); 13C{1H} NMR (100MHz, DMSO-d6) δ: 165.6, 165.2, and Naphthalenes (Table 2) A hexane solution of n- or
160.9, 160.7, 138.1, 136.5, 132.9, 132.5, 129.1, 128.8, 128.4, sec-butyllithium (3 equiv) was added to a THF solution (100
128.3, 127.0, 126.7, 126.6, 106.3, 106.1, 103.7, 102.5, 44.5, 43.1, v/w) of the appropriate naphthalene (1.0 equiv) at −78°C. The
42.8, 42.5, 33.1, 27.4, 27.2, 26.6, 23.4, 23.1, 16.0, 15.6, 12.6, mixture was stirred for 1h at −78°C and then quenched with
12.5 (3C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for NH4Cl aq. The mixture was allowed to warm up to r.t. The
C18H23O3 [M+H]+ 287.1642, Found 287.1642.
mixture was extracted with ethyl acetate, washed with brine,
Synthesis of Compounds 13 and 16 K3PO4 (2.7 equiv) dried over sodium sulfate, concentrated and purified by chro-
was added to a DMF solution (20v/w) of appropriate naph- matography (SiO2 or SiO2–NH, hexane : ethyl acetate) to give
thoic acid (1 equiv) and CH2I2 (6 equiv). The mixture was corresponding 1,2-adducts and 1,4-adducts.
stirred for 1h at 140°C in an oil bath, then the mixture was
Compound 18a: Yield 56mg (88%) from 50mg (0.24mmol)
allowed to cool down to r.t. The mixture was extracted with of 12; colorless oil; IR (neat) 3447, 2967, 1751, 1734, 1717,
1
ethyl acetate, washed with brine, dried over sodium sulfate, 1506, 1464cm−1; H-NMR (400MHz, DMSO-d6) δ: 7.99–7.97
concentrated and purified by chromatography (SiO2, hexane : (m, 1H), 7.94–7.91 (m, 1H), 7.82 (s, 1H), 7.76 (s, 1H) 7.52–7.46
ethyl acetate) to give a corresponding lactone.
(m, 2H), 6.18 (s, 1H), 2.00 (tt, 2H, J=7.2, 7.2Hz), 1.60 (s,
Compound 13: Yield 213mg (40%) from 500mg 3H), 1.50 (s, 3H), 1.37–1.21 (m, 3H), 1.05–0.98 (m, 1H), 0.80
(2.66mmol) of 3-hydroxy-2-naphthoic acid; yellow solid; mp (t, 3H, J=7.2Hz); 13C{1H} NMR (100MHz, DMSO-d6) δ:
109–110°C; IR (KBr) 1748, 1641, 1506, 1346cm−1; H-NMR 147.3, 141.7, 134.1, 133.5, 128.8, 128.3, 126.4, 126.0. 121.1,
1
(400MHz, CDCl3) δ: 8.65 (s, 1H), 7.94 (d, 1H, J=8.0Hz), 119.2, 107.1, 83.2, 31.5, 29.8, 27.0, 22.9, 14.5; HRMS (ESI/FT-
7.80 (d, 1H, J=8.0Hz), 7.61 (ddd, 1H, J=1.2, 6.8, 6.8Hz), ICR-MS) Calcd for C18H22O2Na [M+Na]+ 293.1512, Found
7.48 (ddd, 1H, J=1.2, 6.8, 6.8Hz), 7.44 (s, 1H), 5.73 (s, 2H); 293.1513.
13C{1H} NMR (100MHz, CDCl3) δ: 161.8, 153.4, 137.4, 133.1,
Compound 18d (Diastereomeric mixture): Yield 21mg
129.9, 129.7, 129.5, 127.1, 125.8, 115.2, 112.4, 91.5; HRMS (33%) from 50mg (0.24mmol) of 12; colorless oil; IR (neat)
1
(ESI/FT-ICR-MS) Calcd for C12H9O3 [M+H]+ 201.0546, 3460, 2968, 2930, 2876, 1506, 1456cm−1; H-NMR (400MHz,
Found 201.0545.
DMSO-d6) δ: 7.99–7.90 (m, 2H), 7.81–7.80 (m, 1H), 7.75 (s,
Compound 16: Yield 319mg (60%) from 500mg 1H), 7.51–7.45 (m, 2H), 6.05 (s, 1H), 2.02–1.90 (m, 1H), 1.59
(2.66mmol) of 2-hydroxy-1-naphthoic acid; yellow solid; (s, 3H), 1.50–1.49 (m, 3H), 1.35–1.28 (m, 0.5H), 1.14–1.06 (m,
mp 88–89°C; IR (KBr) 1719, 1686, 1520, 1439, 1292cm−1; 2.5H), 0.92–0.89 (m, 2H), 0.85–0.76 (m, 3H); 13C{1H} NMR
1H-NMR (400MHz, DMSO-d6) δ: 8.96 (d, 1H, J=7.6Hz), (100MHz, DMSO-d6) δ: 147.5, 147.3, 141.7, 141.5, 134.1, 134.1,
8.29 (d, 1H, J=9.2Hz), 8.03 (d, 1H, J=8.0Hz), 7.75 (ddd, 133.5, 133.5, 128.8, 128.2, 126.4, 125.9, 121.3, 119.2, 108.9,
1H, J=1.2, 7.2, 7.2Hz), 7.58 (ddd, 1H, J=1.2, 6.8, 6.8Hz), 83.1, 83.1, 44.4, 43.9, 31.8, 29.4, 29.4, 25.0, 23.2, 15.1, 13.5,
7.39 (d, 1H, J=8.8Hz), 5.88 (s, 2H); 13C{1H} NMR (100MHz, 13.0, 12.9 (8C overlapped); HRMS (ESI/FT-ICR-MS) Calcd
DMSO-d6) δ: 161.2, 160.5, 138.6, 131.8, 130.3, 130.0, 129.6, for C18H22O2Na [M+Na]+ 293.1512, Found 293.1517.
126.0, 125.5, 117.3, 107.1, 91.0; HRMS (ESI/FT-ICR-MS)
Compound 20d (Diastereomeric mixture): Yield 38mg
Calcd for C12H9O3 [M+H]+ 201.0546, Found 201.0544.
(59%) from 50mg (0.24mmol) of 12; colorless oil; IR (neat)
Synthesis of Compounds 14 and 15 A mixture of tri- 3460, 2968, 2930, 2876, 1506, 1456cm−1; H-NMR (400MHz,
1

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Vol. 68, No. 4 (2020)
DMSO-d6) δ: 7.30–7.29 (m, 4H), 3.78–3.62 (m, 3H), 1.78 14H); 13C{1H} NMR (100MHz, DMSO-d6) δ: 154.4, 154.1,
(s, 1H), 1.50 (s, 3H), 1.44–1.37 (m, 4H), 1.10–0.99 (m, 153.8, 133.4, 133.3, 129.4, 128.7, 127.3, 126.3, 126.0, 125.8,
1H), 0.92–0.85 (m, 3H), 0.64–0.61 (m, 3H); 13C{1H} NMR 125.5, 125.0, 122.5, 118.5, 118.3, 118.2, 117.3, 117.2, 42.8, 42.6,
(100MHz, DMSO-d6) δ: 171.4, 171.1, 169.7, 168.8, 137.9, 135.9, 42.2, 41.9, 24.7, 24.6, 22.8, 22.7, 14.3, 14.3, 12.7, 12.6, 12.5
134.1, 133.6, 129.9, 129.5, 129.2, 129.0, 127.0, 126.8, 126.7, (many peaks overlapped); HRMS (ESI/FT-ICR-MS) Calcd for
125.8, 124.8, 85.5, 44.2, 42.2, 41.5, 41.3, 28.3, 27.2, 26.6, 26.0, C19H26O2Na [M+Na]+ 309.1825, Found 309.1828.
25.8, 24.6, 24.5, 15.7, 15.5, 12.8, 12.7 (3C overlapped); HRMS
Compound 25a: Yield 44mg (88%) from 50mg
(ESI/FT-ICR-MS) Calcd for C18H22O2Na [M+Na]+ 293.1512, (0.22mmol) of 15; colorless oil; IR (neat) 3366, 2958, 1624,
1
Found 293.1513.
1574, 1466cm−1; H-NMR (400MHz, DMSO-d6) δ: 10.33 (brs,
Compound 21d (Diastereomeric mixture): Yield 18mg 1H), 7.86–7.82 (m, 2H), 7.58 (d, 1H, J=8.8Hz), 7.44 (ddd,
(28%) from 50mg (0.25mmol) of 13; yellow oil; IR (neat) 1H, J=1.2, 8.0, 8.0Hz), 7.32 (ddd, 1H, J=1.2, 8.0, 8.0Hz),
1
2961, 2930, 1732, 1643, 1414, 1400cm−1; H-NMR (400MHz, 7.21 (d, 1H, J=8.4Hz), 2.93 (t, 2H, J=7.2Hz), 1.63 (tt, 2H,
DMSO-d6) δ: 7.31–7.19 (m, 4H), 5.85–5.79 (m, 1H), 5.68–5.65 J=7.2, 7.2Hz,), 1.59–1.30 (m, 2H), 0.88 (t, 3H, J=7.2Hz);
(m, 1H), 3.95–3.79 (m, 2H), 3.61–3.54 (m, 1H), 1.71–1.62 (m, 13C{1H} NMR (100MHz, DMSO-d6) δ: 207.5, 152.9, 131.6,
1H), 1.50–1.26 (m, 1H), 1.09–0.81 (m, 4H), 0.71–0.63 (m, 3H); 131.2, 128.7, 128.2, 127.7, 123.6, 123.5, 122.0, 118.7, 44.4, 26.3,
13C{1H} NMR (100MHz, DMSO-d6) δ: 168.6, 168.2, 161.5, 22.4, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na
161.4, 137.7, 136.2, 132.1, 131.6, 128.5, 128.2, 127.8, 127.7, [M+Na]+ 251.1043, Found 251.1054.
126.5, 126.2, 126.2, 126.1, 105.2, 103.8, 90.1, 89.9, 43.6, 42.4,
Compound 25d: Yield 9mg (18%) from 50mg (0.22mmol)
42.3, 42.1, 31.9, 31.8, 26.4, 25.1, 15.5, 14.1, 11.9, 11.8; HRMS of 15; colorless oil; IR (neat) 3198, 2965, 1684, 1624, 1578,
1
(ESI/FT-ICR-MS) Calcd for C16H19O3 [M+H]+ 259.1329, 1508, 1458cm−1; H-NMR (400MHz, CDCl3) δ: 11.97 (s, 1H),
Found 259.1329.
7.92 (d, 1H, J=8.4Hz), 7.87 (d, 1H, J=8.8Hz), 7.79 (dd, 1H,
Compound 22a: Yield 14mg (28%) from 50mg (0.22mmol) J=1.2, 8.0Hz), 7.54 (ddd, 1H, J=1.2, 8.0, 8.0Hz), 7.39 (ddd,
of 14; yellow solid; mp 77–78°C ; IR (KBr) 1626, 1570, 1H, J=0.8, 7.2, 7.2Hz), 7.14 (d, 1H, J=8.8Hz), 3.66–3.58
1
1472, 1408 cm−1; H-NMR (400MHz, DMSO-d6) δ: 8.34 (d, (m, 1H), 1.89–1.78 (m, 1H), 1.61–1.50 (m, 1H), 1.33 (d, 2H,
1H, J=9.6Hz), 7.93–7.89 (m, 2H), 7.72 (ddd, 1H, J=1.2, J=6.4Hz), 0.84 (t, 3H, J=7.6Hz); 13C{1H} NMR (100MHz,
6.8, 6.8Hz), 7.60 (ddd, 1H, J=1.2, 6.8, 6.8Hz), 7.42 (d, 1H, CDCl3) δ: 213.2, 160.9, 136.3, 131.6, 129.3, 128.7, 127.8, 124.4,
J=8.0Hz), 3.16 (t, 2H, J=8.0Hz), 1.69 (tt, 2H, J=8.0, 123.8, 119.5, 116.3, 46.5, 28.3, 17.3, 11.7; HRMS (ESI/FT-
8.0Hz), 1.45–1.37 (m, 2H), 0.94 (t, 3H, J=8.0Hz); 13C{1H} ICR-MS) Calcd for C15H16O2Na [M+Na]+ 251.1043, Found
NMR (100MHz, DMSO-d6) δ: 208.0, 161.6, 137.4, 130.7, 251.1051.
128.1, 126.7, 125.7, 124.9, 124.1, 118.9, 113.3, 38.3, 26.7,
22.3, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na (56%) from 50mg (0.22mmol) of 15; colorless oil; IR (neat)
[M+Na]+ 251.1043, Found 251.1052. 2963, 1732, 1622, 1489, 1404cm−1; 1H-NMR (400MHz,
Compound 27d (Diastereomeric mixture): Yield 35mg
Compound 23a: Yield 44mg (70%) from 50mg DMSO-d6) δ: 7.98–7.96 (m, 1H), 7.24–7.20 (m, 1H), 7.17–7.14
(0.22mmol) of 14; colorless oil; IR (neat) 3435, 3227, 1577, (m, 2H), 2.91–2.73 (m, 2H), 2.51–2.41 (m, 1H), 1.72–1.69 (m,
1
1466, 1387cm−1; H-NMR (400MHz, DMSO-d6) δ: 11.4 (s, 6H), 1.57–1.53 (m, 1H), 1.49–1.24 (m, 1H), 1.18–1.02 (m, 1H),
1H), 8.12–8.09 (m, 1H), 7.77–7.73 (m, 1H), 7.46–7.40 (m, 0.86–0.73 (m, 6H); 13C{1H} NMR (100MHz, DMSO-d6) δ:
2H), 7.28 (d, 1H, J=8.8Hz), 7.12 (d, 1H, J=8.8Hz), 6.49 (s, 168.7, 158.8, 136.0, 135.5, 129.7, 129.3, 128.9, 127.0, 126.9,
1H), 1.99–1.90 (m, 2H), 1.81–1.72 (m, 2H), 1.48–1.35 (m, 2H), 126.3, 126.2, 125.8, 106.5, 106.5, 101.7, 101.6, 42.0, 41.4, 38.3,
1.27–1.14 (m, 4H), 1.05–0.93 (m, 2H), 0.78 (t, 6H, J=7.2Hz); 37.8, 30.0, 29.0, 27.0, 26.1, 26.0, 24.5, 24.4, 17.2, 15.8, 12.1,
13C{1H} NMR (100MHz, DMSO-d6) δ: 152.8, 133.5, 127.5, 11.7 (5C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for
126.3, 125.5, 125.2, 122.4, 120.7, 118.3, 81.7, 43.1, 25.9, 23.0, C18H22O3Na [M+Na]+ 309.1461, Found 309.1470.
14.5 (1C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for
Compound 28d (Diastereomeric mixture): Yield 18mg
C19H27O2 [M+H]+ 287.2006, Found 287.2018.
(28%) from 50mg (0.25mmol) of 16; colorless oil; IR (neat)
Compound 22d: Yield 15mg (30%) from 50mg (0.22mmol) 2963, 1736, 1620, 1489, 1450, 1400cm−1; H-NMR (400MHz,
1
of 14; colorless oil; IR (neat) 3061, 2967, 1622, 1599, 1574, DMSO-d6) δ: 7.76–7.73 (m, 1H), 7.21–7.17 (m, 3H), 5.77–5.75
1
1470, 1416, 1389 cm−1; H-NMR (400MHz, DMSO-d6) δ: 8.35 (m, 1H), 5.65–5.62 (m, 1H), 2.93–2.72 (m, 2H), 2.53–2.45 (m,
(d, 1H, J=7.6Hz), 7.96–7.92 (m, 2H), 7.73 (ddd, 1H, J=1.2, 1H), 1.54–1.50 (m, 1H), 1.40–1.36 (m, 0.5H), 1.29–1.23 (m,
6.8, 6.8Hz), 7.61 (ddd, 1H, J=1.2, 6.8, 6.8Hz), 7.44 (d, 1H, 0.5H), 1.13–0.96 (m, 1H), 0.85–0.68 (m, 6H); 13C{1H} NMR
J=9.2Hz), 3.71–3.66 (m, 1H), 1.83–1.74 (m, 1H), 1.56–1.45 (100MHz, DMSO-d6) δ: 171.6, 171.6, 160.0, 136.3, 135.7,
(m, 1H), 1.19 (d, 3H, J=6.4Hz), 0.90 (t, 3H, J=7.2Hz); 129.7, 129.3, 128.9, 127.0, 126.9, 126.7, 126.5, 126.3, 104.6,
13C{1H} NMR (100MHz, DMSO-d6) δ: 211.5, 162.5, 137.5, 104.5, 90.6, 41.9, 41.2, 38.7, 38.1, 29.4, 28.2, 26.9, 25.6, 17.0,
130.9, 128.1, 126.8, 125.4, 125.1, 124.2, 118.9, 112.6, 41.5, 27.0, 15.6, 12.1, 11.8 (4C overlapped); HRMS (ESI/FT-ICR-MS)
17.3, 12.0; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na Calcd for C16H19O3 [M+H]+ 259.1329, Found 259.1330.
[M+Na]+ 251.1043, Found 251.1051.
Compound 29a: Yield 10mg (16%) from 50mg (0.23mmol)
Compound 23d (Diastereomeric mixture): Yield 40mg of 17; colorless oil; IR (neat) 3451, 2954, 2930, 1678, 1626,
(63%) from 50mg (0.22mmol) of 14; colorless oil; IR 1595, 1447cm−1; H-NMR (400MHz, DMSO-d6) δ: 8.02 (s,
1
(neat) 3566, 3227, 2967, 2936, 2876, 1636, 1575, 1464cm−1; 1H), 7.94 (d, 1H, J=8.0Hz), 7.84 (d, 1H, J=8.0Hz), 7.54
1H-NMR (400MHz, DMSO-d6) δ: 11.98 (brs, 1H), 8.11 (d, (ddd, 1H, J=1.2, 8.0, 8.0Hz), 7.47 (s, 1H), 7.39 (ddd, 1H,
1H, J=8.0Hz), 7.77–7.73 (m, 1H), 7.46–7.38 (m, 2H), 7.23 (d, J=1.2, 8.0, 8.0Hz), 4.91 (t, 1H, J=4.8Hz, OH), 4.22–4.19 (m,
1H, J=8.4Hz), 7.12–7.08 (m, 1H), 6.29 (brs, 1H), 2.15–1.99 2H), 3.84–3.80 (m, 2H), 3.03 (t, 2H, J=7.2Hz), 1.62–1.54 (m,
(m, 2H), 1.87–1.80 (m, 1H), 1.50–1.18 (m, 1H), 1.00–0.77 (m, 2H), 1.36–1.28 (m, 2H), 0.88 (t, 3H, J=7.6Hz); 13C{1H} NMR

Vol. 68, No. 4 (2020)
Chem. Pharm. Bull.
391
(100MHz, DMSO-d6) δ: 203.8, 154.6, 136.0, 131.5, 130.1,
Supplementary Materials The online version of this ar-
129.3, 128.6, 128.0, 127.0, 124.8, 107.9, 70.7, 60.0, 43.3, 26.7, ticle contains supplementary materials.
22.4, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C17H20O3Na
[M+Na]+ 295.1305, Found 295.1299.
References and Notes
1) Ortiz F. L., Iglesias M. J., Fernández I., Sánchez C. M. A., Gómez
Compound 30a: Yield 52mg (68%) from 50mg (0.23mmol)
of 17; colorless oil; IR (neat) 3439, 1633, 1599, 1454cm−1;
1H-NMR (400MHz, DMSO-d6) δ: 7.97 (s, 1H), 7.79–7.73 (m,
2H), 7.38 (ddd, 1H, J=1.2, 8.0, 8.0Hz), 7.30 (ddd, 1H, J=1.2,
8.0, 8.0Hz), 7.23 (s, 1H), 4.84 (t, 1H, J=4.8Hz, OH), 4.58
(s, 1H), 4.11–4.08 (m, 2H), 3.82–3.78 (m, 2H), 2.30 (dt, 2H,
J=4.8, 13.2Hz), 1.67 (dt, 2H, J=4.8, 13.2Hz,), 1.29–1.11 (m,
6H), 0.77–0.67 (m, 8H); 13C{1H} NMR (100MHz, DMSO-d6)
δ: 155.0, 136.5, 133.7, 128.5, 128.0, 127.5, 126.4, 126.0, 123.8,
106.5, 78.4, 70.1, 60.2, 40.7, 26.5, 23.2, 14.6; HRMS (ESI/FT-
ICR-MS) Calcd for C21H30O3Na [M+Na]+ 353.2087, Found
353.2096.
Compound 31d (Diastereomeric mixture): Yield 30mg
(59%) from 40mg (0.19mmol) of 17; colorless oil; IR (neat)
2961, 2926, 1684, 1616, 1584, 1456, 1404cm−1; 1H-NMR
(400MHz, DMSO-d6) δ: 7.25–7.10 (m, 4H), 4.57–4.50 (m,
2H), 4.47–4.36 (m, 2H), 4.03–4.01 (m, 1H), 3.81 (d, 1H,
2J=20.4Hz), 3.43–3.38 (m, 1H), 1.68–1.57 (m, 1H), 1.47–1.24
(m, 1H), 1.16–1.02 (m, 0.5H), 0.90–0.75 (m, 4.5H), 0.60 (d,
2H, J=6.8Hz); 13C{1H} NMR (100MHz, DMSO-d6) δ: 169.1,
G. R., Chem. Rev., 107, 1580–1691 (2007).
2) Wertjes W. C., Southgate E. H., Sarlah D., Chem. Soc. Rev., 47,
7996–8017 (2018).
3) Dixon J. A., Fishman D. H., Dudinyak R. S., Tetrahedron Lett., 5,
613–616 (1964).
4) Dixon J. A., Fishman D. H., J. Am. Chem. Soc., 85, 1356–1357
(1963).
5) Eppley R. L., Dixon J. A., J. Am. Chem. Soc., 90, 1606–1612 (1968).
6) Fuson R. C., Berlin K. D., J. Am. Chem. Soc., 81, 2130–2132 (1959).
7) Fuson R. C., Mon M. T., J. Org. Chem., 26, 756–758 (1961).
8) Fuson R. C., Larson J. R., J. Am. Chem. Soc., 81, 2149–2150 (1959).
9) Meyers A. I., Lutomski K. A., Laucher D., Tetrahedron, 44, 3107–
3118 (1988).
10) Gant T. G., Meyers A. I., Tetrahedron, 50, 2297–2360 (1994).
11) Reuman M., Meyers A. I., Tetrahedron, 41, 837–860 (1985).
12) Meyers A. I., J. Heterocycl. Chem., 35, 991–1002 (1998).
13) Shindo M., Koga K., Asano Y., Tomioka K., Tetrahedron, 55,
4955–4968 (1999).
14) Tomioka K., Shindo M., Koga K., Tetrahedron Lett., 31, 1739–1740
(1990).
15) Hotta H., Suzuki T., Miyano S., Chem. Lett., 19, 143–144 (1990).
168.7, 161.5, 161.2, 139.1, 137.8, 134.2, 134.0, 128.6, 128.4, 16) Hattori T., Hotta H., Suzuki T., Miyano S., Bull. Chem. Soc. Jpn.,
66, 613–622 (1993).
127.5, 126.5, 126.4, 126.3, 126.2, 103.8, 103.3, 71.8, 71.7,
17) Our previous research is being submitted under the manuscript title
66.1, 66.0, 50.0, 49.2, 36.6, 36.5, 27.5, 26.4, 16.8, 16.0, 12.5,
“Nucleophilic Addition Reactions of Benzoxanthone Derivatives
with Collapse of Aromaticity.”
18) Yoshino T., Sato I., Hirama M., Org. Lett., 14, 4290–4292 (2012).
19) Compound 5 was synthesized by using the same procedure as com-
12.0 (3C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for
C17H20O3Na [M+Na]+ 295.1305, Found 295.1312.
Reaction of n- or sec-Butyllithium and 15 in the Pres-
ence or Absence of Galvinoxyl (Table 3) A mixture of
n-butyllithium (3 equiv) and sec-butyllithium (3 equiv) was
pound 4.
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added to a THF solution (100 v/w) of 15 (1.0 equiv) and gal-
vinoxyl (0 or 1 or 3 equiv) at −78°C. The mixture was stirred
for 1h at −78°C and then quenched with water. The mixture
was allowed to warm up to r.t. The mixture was extracted
with ethyl acetate, dried over sodium sulfate, and concentrated
to give a residue. The ratio of products was estimated from
2825–2836 (2005).
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1
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Acknowledgments The authors are grateful to Ms. Kyoh-
ko Ohmine (ICR, Kyoto University) for the NMR measure-
ments and Ms. Akiko Fujihashi (ICR, Kyoto University) for
the high resolution mass spectrometry. This study was carried
out using the Fourier transform ion cyclotron resonance mass
spectrometer and NMR in the Joint Usage/Research Center at
the Institute for Chemical Research, Kyoto University. This
study was supported in part by KAKENHI (18K19150) and
Grant-in-Aid from the Tokyo Biochemical Research Founda-
tion. The authors thank Simon Partridge, Ph.D., for editing a
draft of this manuscript.
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Conflict of Interest The authors declare no conflict of
interest.