Selective C-alkylation of substituted naphthols under non-aqueous conditions

Article abstract of DOI:10.1016/j.tet.2021.132278

A simple and selective C-alkylation of 1- and 2-naphthols with benzylic and allylic halides was developed. In an organic solvent, like cyclopentyl methyl ether, or toluene in the presence of the ether or alcohol additives, a selective ortho-addition leadi

Full text of DOI:10.1016/j.tet.2021.132278

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective C-alkylation of substituted naphthols under non-aqueous
conditions
*
ꢀ
Anni Kooli, Tatsiana Shalima, Eleana Lopusanskaja, Anne Paju, Margus Lopp
Department of Chemistry and Biotechnology, Faculty of Science, Tallinn University of Technology, Akadeemia Tee 15, 12618, Tallinn, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and selective C-alkylation of 1- and 2-naphthols with benzylic and allylic halides was devel-
oped. In an organic solvent, like cyclopentyl methyl ether, or toluene in the presence of the ether or
alcohol additives, a selective ortho-addition leading to substituted naphthalenones up to 90 % was
achieved.
Received 19 April 2021
Received in revised form
31 May 2021
Accepted 3 June 2021
Available online xxx
© 2021 Published by Elsevier Ltd.
Keywords:
1-naphthol
Dearomatization
C-alkylation
Naphthalenones
1. Introduction
dearomatization of both, 1- and 2-naphthols with yields up to 99 %
[22]. However, the possibilities of the direct selective C-alkylation
Phenols and phenolates belong to a group of electron-rich aro-
matic compounds which bear nucleophilic sites at C- and O-atoms,
giving rise to both, C- and O-alkylating products with electrophilic
reagents [1,2]. In the case of substituted phenolates C-alkylation
leads to dearomatization, resulting in cyclic keto dienones [3,4]. We
recently developed a regioselective method for the C-alkylation of
substituted phenols in anhydrous conditions [5]. Naphthols behave
similarly to phenols. The O-alkylation with electrophiles is a typical
SN2 reaction (Williamson reaction [6,7]), affording in excellent
yield naphthol ethers, particularly in the presence of phase-transfer
catalysts [8,9]. C-alkylation results in substitution in the naphthol
ring. Usually a mixture of O-alkylation and isomeric C-alkylation
products is obtained [8,10e12]. Common alkylating agents are alkyl
halides, alcohols and alkenes [13e15]. With substituted naphthols
C-alkylation leads to dearomatization, affording chiral substituted
naphthalenones [16,17], which are useful starting compounds for
the synthesis of various natural products and bioactive compounds
[18e20]. Usually, transition metal-catalysed reactions are applied
[21]. One example of a successful non-catalytic alkylation with an
oxy-allyl cation precursor from 2-chlorocyclopentanone, was
recently described by Yang et al., demonstrating a successful
of naphthols, especially of 1-naphthols, with common alkyl halides,
remains undeveloped [23e25]. To the best of our knowledge, there
have been no systematic studies in this field.
In the present study, we tried to apply the anhydrous alkylation
conditions developed for phenols to naphthols in order to achieve a
method for selective C-alkylation of naphthols with halides. The
model naphthols 1a, 1b, 1c and 1d were alkylated with allylic and
benzylic halides 2, without a use of the transition metal catalyst.
These results may serve as a good basis for further developing an
asymmetric version of alkylation for obtaining enantiomeric
substituted naphthalenones.
2. Results and discussion
The common alkylation of naphthols is performed in water so-
lution. In order to obtain comparable reference data, we first
studied the reaction of 2-methyl-1-naphthol 1a with benzyl bro-
mide 2a using a water solution. LiOH, lithium l-lactate and DBU
were used as the bases to generate naphtholate anion. The obtained
results are presented in Table 1.
With naphthol 1a in LiOH water solution, C-alkylation with the
formation of a mixture of o- and p-alkylated products 4a and 5a
occurred, with only traces of naphthol ether 3a. The regioselectivity
of alkylation was poor and depended on the concentration of LiOH:
in a 0.5 M LiOH solution, a mixture with an o/p ratio of ~0.47/1 was
* Corresponding author.
E-mail address: margus.lopp@taltech.ee (M. Lopp).
https://doi.org/10.1016/j.tet.2021.132278
0040-4020/© 2021 Published by Elsevier Ltd.
ꢀ
Please cite this article as: A. Kooli, T. Shalima, E. Lopusanskaja et al., Selective C-alkylation of substituted naphthols under non-aqueous
conditions, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132278

ꢀ
A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Alkylation of 2-methyl- and 2,4-dimethyl-1-naphthols with benzyl bromide in watera.
Entry
Naphthol
Base
Isolated yield %
1
3
4
5
6
1b
2c
3b
4d
5d
6e
1a
1a
1b
1a
1b
1a
0.5 M LiOH
2 M LiOH
0.5 M LiOH
Li-l-lactate
Li-l-lactate
DBU
3
e
2
2
e
e
e
48
23
39
60
18
51
5
49
22
17
27
13
4
6
9
e
e
27
e
5
e
e
27
a
Reaction conditions: base, 1a or 1b (0.5 mmol), 2a (0.6 mmol, 1.2 equiv), room temperature, 20 h.
H2O (0.5 mL), 1 M LiOH (0.5 mL).
2 M LiOH (0.5 mL).
b
c
d
e
H2O (1 mL), HFIP (300
mL), lithium l-lactate (1 equiv).
H2O (1 mL), DBU (1.1 equiv).
obtained; in 2 M LiOH solution, the yield of C-alkylated products
was higher, and the o/p selectivity also increased to 1.8/1. The C/O
selectivity remained high (Table 1, entries 1 and 2). The use of
lithium l-lactate as a base reduced the yield of alkylation of the
naphthol 1a with only 18 % of 4a formed, together with a sub-
stantial amount of isomeric 5a, with a ratio of 4a/5a 0.7/1 in favour
of the p-product 5a. A considerable amount of the substrate 1a
remained unreacted (27 %; Table 1, entry 4).
2,4-Dimethyl-1-naphthol 1b was more reactive and regiose-
lective, mainly yielding the ortho-product 4b in 60 % yield and the
ratio of 4b/5be3.5/1. Similarly, with lithium l-lactate the yield of 4b
was 51 %, with 13 % of the para-product 5b formed (a ratio of 4b/
5be4/1; Table 1, entries 3 and 5). It was also observed that
formation of the dialkylation product 6a in up to 10 % yield was
observed only in the case of 2-methyl-1-naphthol 1a (Table 1, en-
tries 1, 2 and 4).
Using the organic base DBU led predominately to O-alkylation
with the formation of 3a in 48 % yield and leaving of 27 % of the
substrate unreacted under the used reaction conditions (Table 1,
entry 6).
We have previously observed increase in alkylation yield and
selectivity in phenol alkylations in anhydrous condition [5], so the
n-BuLi generated Li-enolate of 2-methyl-1-naphthol 1a was
allowed to react in ether solvents with benzyl bromide 2a. The
obtained results are presented in Table 2.
The reaction in tetrahydrofuran (THF) proceeded smoothly,
Table 2
Alkylation of substituted 1-naphthols with benzyl bromide in ether solventsa.
Entry
Naphthol
Solvent
4b yield %
1c
2
1a
1a
1b
1c
1d
1a
THF
16
65
85
62
73
50
CPME
CPME
CPME
CPME
CPME
3d
4
5e
6f
a
Reaction conditions: 1a-1d (0.5 mmol) in hexane, n-BuLi in hexane (2 equiv), solvent exchange, 2a (1.2 equiv), 80 ꢀC for 20 h.
b
c
d
e
f
Isolated yield.
Temperature 70 ꢀC for 20 h, 3a 51 %.
5b 4 % and 6b 4 %. 1d 22 %.
1d in Et2O.
n-BuLi in hexane was added to 1a in CPME.
2

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A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
Table 3
Alkylation of substituted 1-naphthols in toluene with ether and alcohol additivesa.
Entry
Temperature, oC
Naphthol
BnBr; equiv.
Additive; equiv.
Isolated yield %
3
4
1
80
80
90
80
80
90
80
65
65
80
80
80
80
80
80
1a
1a
1a
1b
1c
1c
1d
1a
1b
1a
1a
1a
1a
1b
1a
1.2
1.2
2
1.2
1.2
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
e
e
3
5
e
2
CPME; 2
CPME; 2
CPME; 2
CPME; 2
CPME; 2
CPME; 2
MTBE; 4
MTBE; 4
Anisole; 2
i-PrOH; 1
t-BuOH; 2
l-menthol; 2
l-menthol; 2
e
73
54
68
37
90
45
76
56
40
57
44
70
76
54
3b
4
e
e
e
e
e
e
e
e
e
5
5
6b
7
8
9
10
11
12
13
14
15c
e
6
cPhMe (1 mL).
dPhMe (0.4 mL).
a
Reaction conditions: 1a-1d (0.5 mmol) in PhMe (0.6 mL), n-BuLi in PhMe (2 equiv), additive and 2a were added, the mixture was stirred for 20 h.
1a or 1c (0.5 mmol) in PhMe (0.3 mL), n-BuLi in PhMe (1.2 equiv).
t-BuOLi (2 equiv) was used instead n-BuLi, t-BuOH from the transmetallation of naphthol.
b
c
although mainly an O-alkylation reaction occurred, resulting in
addition to carbon C1, resulting in 4c only in a 37 % yield. The
naphthol 1d gave a slightly higher yield of dearomatized product
4d (Table 3, entry 7), than the less substituted naphthol 1c. Using
more concentrated solution, i.e. adding less n-BuLi and more BnBr,
the yield of 4c raised to 90 % (Table 3, entries 5 and 6). Under these
conditions, 1-naphthol 1a afforded a 54 % yield of 4a (Table 3, entry
3). Therefore, it is seen that the reaction is quite sensitive to the
substrate structure.
In order to elucidate the scope of possible additives to toluene,
different ethers and alcohols were tested. We found that other
ethers are also suitable as additives. Thus, methyl tert-butyl ether
(MTBE) with 1a afforded a selective C2-alkylated product 4a in 76 %
yield. With 1b, the C2-alkylated product 4b was obtained in 56 %
yield (Table 3, entries 8 and 9). A slightly bigger amount of MTBE (4
equivalents) and a lower temperature (65 ꢀC) to avoid the loss of
during the reaction because of its low boiling point, was needed
with MTBE. The methyl phenyl ether (anisole) additive gave a
relatively low yield (40 %) of the addition. (Table 3, entry 10).
Alcohols which are weaker acids then phenols, were also tested
as additives to toluene. The 1-naphthol 1a with alcoholic additives
i-PrOH and t-BuOH afforded a selective ortho-addition, forming 4a
with moderate yield (57 % and 44 %, respectively; Table 3, entries 11
and 12). l-menthol, which is a more sterically hindered secondary
alcohol afforded the highest yield with both substrates 1a and 1b
(Table 3, entries 13 and 14). In some cases, the formation of a small
amount of O-alkylation product 3 was also observed (Table 3, en-
tries 2, 3, 13 and 15).
ether 3a in 51 % yield, together with only 16 % of the ring addition
product 4a (Table 2, entry 1). Knowing from the literature [26] and
from our previous study [5] that cyclopentyl methyl ether (CPME) is
a good alternative to THF, we turned to that solvent. Indeed, in
CPME a selective C-alkylation reaction proceeded, affording the
ortho-addition product 4a in 65 % yield (Table 2, entry 2). As ex-
pected, 2,4-dimethyl-1-naphthol 1b was again more reactive,
resulting predominantly in the ortho-product 4b in 85 % yield,
together with only a trace amount of the para-addition product 5b
and the dialkylated product 6b (4 % each; Table 2, entry 3).
1-Methyl-2-naphthol 1c and 1,3-dimethyl-2-naphthol 1d also
reacted easily with 2a, affording mainly the 1-Bn-substituted
products 4c and 4d in 62 % and 73 % yield, respectively (Table 2,
entries 4 and 5).
To simplify the procedure, Li-naphtholate generation n-BuLi in
hexane solution was replaced by a toluene solution, affording a
better solubility of naphthols in the reaction medium. The alkyl-
ation results with different additives in toluene are presented in
Table 3.
When performing the reaction of 2-Me-1-naphthol 1a with
benzyl bromide 2a in toluene as a solvent without additives, only
an inseparable mixture of different aromatic products was formed,
with only 10 % of the substrate 1a recovered (Table 3, entry 1).
The alkylation reaction proceeded well when additives were
applied to the reaction medium. So, when 2 equivalents of CPME
was added to toluene and the reaction was carried out at 80 ꢀC a
selective ortho-addition of benzyl bromide to 1a occurred, affording
naphthalenone 4a in 73 % isolated yield (Table 3, entry 2). 2,4-Di-
Me-1-naphthol 1b also reacted well with CPME additive, resulting
only in the ortho-C-alkylated product 4b, in 68 % yield (Table 3,
entry 4). Quite surprisingly, the 2-naphthol 1c afforded with 2a
These results forced us to check Li alcoholates as the bases for
generating naphtholates. With 2 equivalents of t-BuOLi naphthol
1a together with 2a afforded the alkylated product 4a in 54 % yield,
which was similar to that obtained with n-BuLi (Table 3, entry 12
and entry 15). This means that alcoholates may be an alternative
3

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A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
Scheme 1. C-alkylation of substituted naphthols with active halides in toluene with CPME additive. Isolated yields are shown.
when selecting a suitable base for the alkylation of naphthols.
To broaden the choice of possible halides different allylic and
benzylic halides were used. The obtained results are presented in
Scheme 1.
naphthols 1b and 1c, alkylation with 2a and 2c afforded lower
yields than that for 1a (Scheme 1, 78 % for 4bc and 46 % for 4 cc).
Additionally, the different substituted benzyl bromides 4-Me-
benzyl bromide (2d), 4-Br-benzyl bromide (2f) and 4-NO2-benzyl
bromide (2e) were applied for alkylation of naphthols. The
substituted benzyl bromides 2d and 2f afforded a yield comparable
with that of 2a, while p-nitrobenzyl bromide 2e gave lower yield of
the alkylation (Scheme 1, 4ad, 4af and 4ae). Even a bulky benzyl
derivative 9-(chloromethyl)anthracene 2g with 1a gave a moderate
yield of the alkylation (Scheme 1, 4 ag). To our disappointment,
other common electrophiles, such as iodomethane and methyl
tosylate, did not give any C-alkylation product. With methyl tosy-
late only O-alkylation with the formation of OeMe naphthol in 52 %
yield was obtained.
We found that prenyl bromide 2c, together with 2 equivalents of
n-BuLi in the presence of CPME at room temperature yielded a C-
alkylation of only 4 %. We assumed that the active electrophiles
might react with the excess of n-BuLi, consuming the reagent and
so reducing the yield of alkylation. Indeed, when a reduced amount
of n-BuLi (1.2 equivalents) was used, the best alkylation yield was
obtained (84 %; Scheme 1, 4ac). At the same time, with benzyl
bromide 2a a reduced amount of n-BuLi (1.2 equivalents) caused a
slight decrease in yield of 4a, from 73 % to 67 % (Table 3, entry 2;
Scheme 1, 4a).
These results are in good accordance with the Lovchik et al.
report, demonstrating that prenyl chloride alkylates 1a when using
an a-isosparteine additive in 54 % yield with ee 34 % [25]. With
4

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A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
3. Conclusion
d
8.19e8.13 (m, 1H), 7.95e7.88 (m, 1H), 7.53e7.45 (m, 2H), 7.09 (s,
1H), 4.92 (s, 1H), 2.60 (d, J ¼ 0.9 Hz, 3H), 2.39 (s, 3H). Analytical data
The separation of isomeric naphthols is a complicated task,
especially in a preparative scale. The alkylation of 1- and 2-
naphthols in anhydrous condition offers a selective way to get
only one of the possible isomers. Moderate to good yields with high
selectivity make the method competitive for the synthesis of
substituted naphthalenones. Especially suitable is the approach for
1-naphthols, giving a lower yield for direct ortho alkylation in
water. The obtained results provide a good basis for further
developing an asymmetric alkylation of naphthols.
are in agreement with the literature data [28].
4.2. General method A
To the corresponding naphthol (1a-1c) (0.5 mmol) solution in
toluene (0.6 mL) at 0 ꢀC n-BuLi 2.7 M in toluene (0.22 mL, 0.6 mmol)
was added dropwise. The reaction mixture was stirred for 15 min
and then at room temperature until precipitation occurred or
20 min. As an additive CPME (116 mL, 1 mmol) was added dropwise
and stirred for 5 min. Alkylating agent 2a-2g (1.2 equiv) was added
dropwise/portion wise and the reaction mixture was stirred at
80 ꢀC for 20 h. The reaction mixture was diluted with water and
extracted with EtOAc (3x7 mL), dried over MgSO4 and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (PE/EtOAc).
4. Experimental section
All reactions were carried out under argon atmosphere with
oven-dried glassware. All reagents were used as received unless
noted otherwise. CPME, Et2O and toluene for reaction were dried
with 4 Å molecular sieves. 1a, 1b, 1c, 1d [27] were vacuum dried for
15 min before reaction.
4.2.1. 2-benzyl-2-methyl-1-naphthalenone (4a)
PE refers to petroleum ether b.p 40e60 ꢀC, EtOAc refers to ethyl
acetate, CPME refers to cyclopentyl methyl ether, BnBr refers to
benzyl bromide, and MTBE refers to methyl tert-butyl ether. 1H and
13C NMR spectra were recorded on a Bruker Avance III instrument
at 400 MHz for 1H and 100 MHz for 13C. HRMS were recorded by
using an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/
MS spectrometer by using ESI ionization. IR spectra were recorded
on a Bruker Tensor 27 FT-IR spectrophotometer. Precoated silica gel
plates (Merck 60 F254) were used for TLC. Column chromatography
was performed on a Biotage Isolera Prime preparative purification
Compound 4a was prepared using method A. To a 1a in reaction
as an alkylating agent benzyl bromide 2a (71.5 mL, 0.6 mmol) was
used. Column chromatography PE/EtOAc 1e20 %. Gave 2-benzyl-2-
methyl-1-naphthalenone 4a as a yellow oil (91 mg, 73 %). PE/
EtOAc ¼ 10:1, Rf ¼ 0.53. IR (neat): 3028.85, 1672.52, 1644.10,
1598.26, 1451.11, 1285.90, 982.64, 792.66 cme11H NMR (400 MHz,
CDCl3)
d
8.08e7.98 (m, 1H), 7.55e7.44 (m, 1H), 7.31 (td, J ¼ 7.6,
1.2 Hz, 1H), 7.20e7.04 (m, 6H), 6.51 (d, J ¼ 9.8 Hz, 1H), 6.09 (d,
J ¼ 9.8 Hz,1H), 3.25 (d, J ¼ 13.2 Hz,1H), 2.83 (d, J ¼ 13.2 Hz, 1H),1.32
(s, 3H). 13C NMR (101 MHz, CDCl3)
d 203.15, 139.32, 138.35, 137.16,
system with silica gel Kieselgel 63e200
mm.
134.39, 130.23, 129.24, 127.91, 127.86, 127.34, 127.10, 126.54, 123.92,
50.32, 45.97, 24.97. HRMS (ESI) m/z calculated for C18H16ONa
[MþNa]þ 271.1093, found 271.1087.
4.1. 2,4-dimethylnaphthalen-1-ol (1b)
4.1.1. 4-Hydroxy-3-methyl-1-naphthaldehyde
4.2.2. 2-allyl-2-methylnaphthalen-1(2H)-one (4 ab)
At ꢁ20 ꢀC to 1a (2 g, 12.7 mmol) in CH2Cl2 (130 mL) 1 M TiCl4 in
toluene (38 mL, 38 mmol) was added dropwise. To mixture
dichloro(methoxy)methane (1.8 mL, 19 mmol) was added drop-
wise. Mixture was stirred for 30 min. Reaction mixture was allowed
to warm up to room temperature and was stirred other 30 min.
Mixture was cooled down to 0 ꢀC and ice-cold water (100 mL) was
added. After 10 min of vigorous stirring 1 M HCl (200 mL) was
added. Mixture was stirred until all salts were dissolved. Reaction
was extracted with CH2Cl2 and extracts were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by column chromatography (CH2Cl2/EtOAc, 2e20 %).
To give 4-hydroxy-3-methyl-1-naphthaldehyde (1.65 g, 70 %) as a
yellow oil. PE/EtOAc ¼ 10:1, Rf ¼ 0.43.1H NMR (400 MHz, MeOD)
Compound 4 ab was prepared using method A. To 1a in reaction
as an alkylating agent allyl bromide 2b (52 mL, 0.6 mmol) was used.
Reaction mixture was stirred at 40 ꢀC for 20 h. Column chroma-
tography PE/EtOAc 1e20 %. To give 2-allyl-2-methylnaphthalen-
1(2H)-one 4 ab as a yellow oil (14 mg, 14 %). PE/EtOAc ¼ 10:1,
Rf ¼ 0.49. IR (neat): 2976.62, 1674.39, 1643.25, 1598.40, 1483.15,
1319.85, 985.48, 729.16, 693.65 cme11H NMR (400 MHz, CDCl3)
d
8.08e8.02 (m, 1H), 7.55 (td, J ¼ 7.5, 1.4 Hz, 1H), 7.34 (td, J ¼ 7.6,
1.2 Hz, 1H), 7.26e7.19 (m, 1H), 6.59 (d, J ¼ 9.7 Hz, 1H), 6.10 (d,
J ¼ 9.8 Hz, 1H), 5.66e5.49 (m, 1H), 5.06e4.88 (m, 2H), 2.73e2.63
(m, 1H), 2.34e2.25 (m, 1H), 1.27 (s, 3H). 13C NMR (101 MHz, CDCl3)
d
203.09, 139.61, 138.47, 134.45, 133.47, 129.32, 127.94, 127.41,
127.08, 124.00, 118.14, 49.28, 44.62, 24.77. HRMS (ESI) m/z calcu-
d
10.04 (s, 1H), 9.24e9.13 (m, 1H), 8.35e8.23 (m, 1H), 7.80 (s, 1H),
lated for C14H14ONa [MþNa]þ 221.0937, found 221.0936.
7.63e7.44 (m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, MeOD)
d
194.14,
158.49, 144.26, 132.43, 129.33, 126.88, 126.45, 125.58, 124.89,
123.34, 118.08, 16.16.
4.2.3. 2-methyl-2-(3-methylbut-2-en-1-yl)naphthalen-1(2H)-one
(4ac)
Compound 4ac was prepared using method A. To a 1a in reac-
4.1.2. 2,4-dimethylnaphthalen-1-ol (1b)
tion as an alkylating agent prenyl bromide 2c (69.5 mL, 0.6 mmol)
To 4-hydroxy-3-methyl-1-naphthaldehyde (1.65 g, 8.9 mmol) in
p-xylene (40 mL) 3.5 M Red-Al in toluene (3.9 mL, 13.3 mmol) was
added dropwise. Reaction mixture was refluxed for 1 h. After 1 h
reaction mixture was allowed cool down to room temperature and
Et2O (15 mL) was added. Reaction mixture was cooled to 0 ꢀC and
10 % KOH (20 mL) was added. Two little pieces of dry ice (CO2) were
added carefully to neutralise mixture. Reaction was extracted with
Et2O (4x50 mL), extracts were washed with brine and dried over
Na2SO4 and concentrated in vacuo. The crude product was purified
by column chromatography (PE/EtOAc, 1e15 %). To give 2,4-
dimethylnaphthalen-1-ol 1b as a white pinkish solid (1.18 g,
77 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.30.1H NMR (400 MHz, CDCl3)
was used. Reaction mixture was stirred at room temperature for
20 h. Column chromatography PE/EtOAc 1e20 %. To give 2–methyl-
2-(3-methylbut-2-en-1-yl)naphthalen-1(2H)-one 4ac as a yellow
oil (95 mg, 84 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.56. IR (neat): 3028.95,
1775.82, 1598.41, 1482.51, 1449.03, 981.49, 792.47, 692.00 cme11H
NMR (400 MHz, CDCl3)
d
8.05e8.01 (m, 1H), 7.54 (td, J ¼ 7.5, 1.4 Hz,
1H), 7.33 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.24e7.19 (m, 1H), 6.60e6.54 (m,
1H), 6.10 (d, J ¼ 9.8 Hz, 1H), 4.99e4.91 (m, 1H), 2.65e2.56 (m, 1H),
2.28e2.19 (m, 1H), 1.61e1.52 (m, 6H), 1.26 (s, 3H). 13C NMR
(101 MHz, CDCl3)
d 203.60, 140.12, 138.55, 134.72, 134.27, 129.39,
127.75, 127.28, 126.94, 123.77, 119.06, 49.73, 38.82, 25.90, 24.38,
18.11. HRMS (ESI) m/z calculated for C16H18ONa [MþNa]þ 249.1250,
5

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A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
found 249.1243.
24.99. HRMS (ESI) m/z calculated for C26H20ONa [MþNa]þ 371.1406,
found 371.1407.
4.2.4. 2-methyl-2-(4-methylbenzyl)naphthalen-1(2H)-one (4ad)
Compound 4ad was prepared using method A. To a 1a in reac-
tion as an alkylating agent 4-methylbenzyl bromide 2d (111 mg,
0.6 mmol) was used. Column chromatography PE/EtOAc 1e15 %. To
give 2-methyl-2-(4-methylbenzyl)naphthalen-1(2H)-one 4ad as an
orange oil (100 mg, 76 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.55. IR (neat):
3029.15, 1672.83, 1597.74, 1482.89, 1448.80, 981.83, 791.53,
4.2.8. 2-benzyl-2,4-dimethylnaphthalen-1(2H)-one (4b)
To 1b (86 mg, 0.5 mmol) solution in hexane (3 mL) at 0 ꢀC n-BuLi
2.5 M in hexane (0.4 mL, 1 mmol) was added dropwise. Reaction
mixture was allowed rise to room temperature and all solvents
were removed with argon. CPME (1 mL) was added dropwise and
stirred for 10 min 2a (71.5 mL, 0.6 mmol) was added dropwise and
691.20 cme11H NMR (400 MHz, CDCl3)
d
8.10e8.05 (m, 1H), 7.50
reaction mixture was stirred at 80 ꢀC for 20 h. Reaction was diluted
with water and extracted with EtOAc (3x7 mL), dried over MgSO4
and concentrated in vacuo. The crude product was purified by
column chromatography PE/EtOAc (1e18 %). To give 2- benzyl-2,4-
dimethylnaphthalen-1(2H)-one 4b as a light yellow oil (111 mg,
85 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.70. IR (neat): 3028.87, 1672.48,
1597.39, 1483.79, 1451.23, 1220.73, 983.78, 764.52 cme11H NMR
(td, J ¼ 7.5, 1.4 Hz, 1H), 7.32 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.18e7.13 (m, 1H),
7.05e6.95 (m, 4H), 6.53 (d, J ¼ 9.8 Hz, 1H), 6.11 (d, J ¼ 9.8 Hz, 1H),
3.23 (d, J ¼ 13.2 Hz, 1H), 2.82 (d, J ¼ 13.2 Hz, 1H), 2.25 (s, 3H), 1.33 (s,
3H). 13C NMR (101 MHz, CDCl3)
d 203.13, 139.46, 138.31, 135.93,
134.29, 134.01, 130.05, 129.14, 128.59, 127.76, 127.29, 127.03, 123.73,
50.28, 45.39, 24.82, 21.07. HRMS (ESI) m/z calculated for C19H18ONa
[MþNa]þ 285.1250, found 285.1246.
(400 MHz, CDCl3)
d
8.12e8.07 (m, 1H), 7.55 (td, J ¼ 7.6, 1.5 Hz, 1H),
7.37e7.27 (m, 2H), 7.20e7.05 (m, 5H), 5.94e5.88 (m, 1H), 3.21 (d,
J ¼ 13.1 Hz, 1H), 2.83 (d, J ¼ 13.1 Hz, 1H), 2.13 (d, J ¼ 1.4 Hz, 3H), 1.33
4.2.5. 2-methyl-2-(4-nitrobenzyl)naphthalen-1(2H)-one (4ae)
Compound 4ae was prepared using method A. To a 1a in reac-
tion as an alkylating agent 4-nitrobenzyl bromide 2e (130 mg,
0.6 mmol) was used. Column chromatography PE/EtOAc 1e20 %. To
give 2-methyl-2-(4-nitrobenzyl)naphthalen-1(2H)-one 4ae as an
orange oil (17 mg, 12 % yield). PE/EtOAc ¼ 10:1, Rf ¼ 0.14. IR (neat):
2925.50, 1673.28, 1597.95, 1518.65, 1345.13, 794.76, 772.70 cme11H
(s, 3H). 13C NMR (101 MHz, CDCl3)
d 203.45, 139.20, 137.11, 136.03,
134.20, 130.20, 129.21, 127.97, 127.71, 127.44, 127.16, 126.37, 124.13,
49.84, 46.26, 24.76, 19.29. HRMS (ESI) m/z calculated for C19H18ONa
[MþNa]þ 285.1250, found 285.1252.
4.2.9. 2,4-dimethyl-2-(3-methylbut-2-en-1-yl)naphthalen-1(2H)-
one (4bc)
NMR (400 MHz, CDCl3) d 8.02e7.99 (m, 1H), 7.98e7.94 (m, 2H), 7.50
(td, J ¼ 7.5,1.4 Hz,1H), 7.31 (td, J ¼ 7.6,1.2 Hz,1H), 7.24e7.18 (m, 2H),
Compound 4bc was prepared using method A. To a 1b in reac-
tion as an alkylating agent prenyl bromide 2c (69.5 mL, 0.6 mmol)
7.15e7.10 (m, 1H), 6.53 (d, J ¼ 9.6 Hz, 1H), 6.10 (d, J ¼ 9.8 Hz, 1H),
3.45 (d, J ¼ 13.1 Hz, 1H), 2.87 (d, J ¼ 13.1 Hz, 1H), 1.37 (s, 3H). 13
C
was used. Reaction mixture was stirred at room temperature for
20 h. Column chromatography PE/EtOAc 1e20 %. To give 2,4-
dimethyl-2-(3-methylbut-2-en-1-yl)naphthalen-1(2H)-one 4bc as
a pale yellow oil (94 mg, 78 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.70. IR (neat):
2925.29, 1673.89, 1597.51, 1448.72, 1377.60, 1219.94, 982.07, 763.67,
NMR (101 MHz, CDCl3)
d 202.27, 146.77, 145.13, 138.11, 137.99,
134.79, 130.76, 129.05, 128.24, 127.55, 127.07, 124.88, 123.11, 50.52,
45.61, 25.81. HRMS (ESI) m/z calculated for C18H15NO3Na [MþNa]þ
316.0944, found 316.0941.
698.39 cme11H NMR (400 MHz, CDCl3)
d 8.11e8.01 (m, 1H), 7.60
4.2.6. 2-(4-bromobenzyl)-2-methylnaphthalen-1(2H)-one (4af)
Compound 4af was prepared using method A. To a 1a in reaction
as an alkylating agent 4-bromobenzyl bromide 2f (150 mg,
0.6 mmol) was used. Column chromatography PE/EtOAc 1e15 %. To
give 2-(4-bromobenzyl)-2-methylnaphthalen-1(2H)-one 4af as an
orange oil (111 mg, 68 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.45. IR (neat):
2923.62,1673.37, 1597.47, 1487.57, 1448.63, 1072.18, 1011.69, 792.83,
(td, J ¼ 7.6, 1.5 Hz, 1H), 7.41e7.33 (m, 2H), 5.94e5.84 (m, 1H),
5.01e4.86 (m, 1H), 2.62e2.50 (m, 1H), 2.27e2.17 (m, 1H), 2.16 (d,
J ¼ 1.4 Hz, 3H), 1.59e1.53 (m, 6H), 1.24 (s, 3H). 13C NMR (101 MHz,
CDCl3)
d 204.08, 139.50, 136.96, 134.61, 134.19, 129.41, 127.75,
127.44,127.15, 124.18, 119.25, 49.43, 38.97, 25.92, 24.36, 19.46, 18.08.
HRMS (ESI) m/z calculated for C17H20ONa [MþNa]þ 263.1406, found
263.1402.
691.83 cme11H NMR (400 MHz, CDCl3)
d 8.04e7.98 (m, 1H), 7.48
(td, J ¼ 7.5, 1.4 Hz, 1H), 7.29 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.27e7.21 (m,
2H), 7.14e7.09 (m, 1H), 6.96e6.91 (m, 2H), 6.50 (d, J ¼ 9.8 Hz, 1H),
6.06 (d, J ¼ 9.8 Hz, 1H), 3.23 (d, J ¼ 13.2 Hz, 1H), 2.74 (d, J ¼ 13.2 Hz,
4.2.10. 2,4-dimethyl-2-(4-methylbenzyl)naphthalen-1(2H)-one
(4bd)
Compound 4bd was prepared using method A. To a 1b in re-
action as an alkylating agent 4-methylbenzyl bromide 2d (111 mg,
0.6 mmol) was used. Column chromatography PE/EtOAc 1e15 %. To
give 2,4-dimethyl-2-(4-methylbenzyl)naphthalen-1(2H)-one 4bd
as a pale yellow oil (95 mg, 69 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.66. IR
(neat): 2922.91, 1672.22, 1596.99, 1514.40, 1447.75, 1220.64, 983.30,
1H), 1.30 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 202.70, 138.76, 138.14,
136.18, 134.50, 131.74, 130.94, 129.05, 127.95, 127.40, 127.00, 124.27,
120.49, 50.24, 45.19, 25.23. HRMS (ESI) m/z calculated for
C
18H15BrONa [MþNa]þ 349.0198, found 349.0194.
4.2.7. 2-(anthracen-9-ylmethyl)-2-methylnaphthalen-1(2H)-one
(4 ag)
793.31, 701.53 cme11H NMR (400 MHz, CDCl3)
d
8.10 (dd, J ¼ 7.8,
1.4 Hz, 1H), 7.56 (td, J ¼ 7.6, 1.5 Hz, 1H), 7.39e7.27 (m, 2H), 6.99 (s,
4H), 5.94e5.84 (m, 1H), 3.15 (d, J ¼ 13.1 Hz, 1H), 2.80 (d, J ¼ 13.1 Hz,
1H), 2.25 (s, 3H), 2.13 (d, J ¼ 1.5 Hz, 3H), 1.31 (s, 3H). 13C NMR
Compound 4 ag was prepared using method A. To a 1a in re-
action as an alkylating agent 9-(Chloromethyl)anthracene 2g
(136.2 mg, 0.6 mmol) was used. Column chromatography PE/EtOAc
1e20 %. To give 2-(anthracen-9-ylmethyl)-2-methylnaphthalen-
1(2H)-one 4 ag as a yellow oil (45 mg, 26 %). PE/EtOAc ¼ 10:1,
Rf ¼ 0.33. IR (neat): 3051.83, 1670.00, 1596.91, 1446.50, 983.50,
(101 MHz, CDCl3)
d 203.55, 139.24, 136.25, 135.80, 134.17, 134.00,
130.12, 129.15, 128.46, 127.78, 127.42, 127.19, 124.14, 49.86, 45.68,
24.61, 21.06, 19.30. HRMS (ESI) m/z calculated for C20H20ONa
[MþNa]þ 299.1406, found 299.1405.
796.96, 734.80, 689.04 cme11H NMR (400 MHz, CDCl3)
d 8.39e8.30
(m, 3H), 8.13e8.08 (m, 1H), 8.00e7.95 (m, 2H), 7.57e7.38 (m, 6H),
7.34 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.15e7.09 (m, 1H), 6.30 (d, J ¼ 9.8 Hz,
1H), 5.82 (d, J ¼ 9.9 Hz, 1H), 4.29 (d, J ¼ 14.6 Hz, 1H), 4.00 (d,
4.2.11. 1-benzyl-1-methylnaphthalen-2(1H)-one (4c)
To 1c (79 mg, 0.5 mmol) solution in CPME (116 m
L) at 0 ꢀC n-BuLi
2.7 M in toluene (0.17 mL, 0.45 mmol) was added dropwise. Then
toluene was added (0.3 mL). The reaction mixture was stirred for
15 min and then at room temperature for 20 min 2a (171
J ¼ 14.6 Hz, 1H), 1.31 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 203.92,
139.98, 138.24, 134.52, 131.63, 131.56, 129.52, 129.11, 129.02, 127.83,
127.33, 127.21, 127.19, 126.01, 125.36, 124.88, 122.69, 50.98, 34.98,
mL,
1 mmol) was added dropwise and reaction mixture was stirred at
6

ꢀ
A. Kooli, T. Shalima, E. Lopusanskaja et al.
Tetrahedron xxx (xxxx) xxx
90 ꢀC for 20 h. Reaction was diluted with water and extracted with
EtOAc (3x7 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by column chromatography PE/EtOAc
(1e20 %). To give 1-benzyl-1-methylnaphthalen-2(1H)-one 4c as a
yellow oil (111 mg, 90 %). PE/EtOAc ¼ 10:1, Rf ¼ 0.35. IR (neat):
3028.60, 1656.05, 1452.90, 835.56, 759.04, 700.87 cme11H NMR
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132278.
References
(400 MHz, CDCl3) d 7.48e7.38 (m, 2H), 7.29e7.22 (m, 1H), 7.20e7.10
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d 204.00, 145.41, 145.03, 136.60, 130.06,
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ꢀ
€
was used. Reaction mixture was stirred at room temperature for
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d
7.44e7.36 (m, 3H), 7.33e7.24 (m, 2H), 6.14 (d, J ¼ 9.9 Hz, 1H),
4.70e4.60 (m, 1H), 2.82e2.74 (m, 1H), 2.50e2.41 (m, 1H), 1.50e1.48
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d
204.42, 146.21, 144.97, 134.63, 129.90, 129.83, 129.40, 126.87,
126.68, 125.36, 118.76, 51.99, 41.77, 25.86, 25.80, 17.86. HRMS (ESI)
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1640.45,1493.26, 1451.54, 1373.16, 1273.43, 1029.31, 765.90,
698.80.1H NMR (400 MHz, CDCl3)
7.44e7.39 (m, 1H), 7.34 (td,
¼
10:1, Rf
¼
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J ¼ 7.6, 1.4 Hz, 1H), 7.21 (td, J ¼ 7.4, 1.3 Hz, 1H), 7.09e7.03 (m, 1H),
7.02e6.99 (m, 1H), 6.98e6.92 (m, 2H), 6.92e6.87 (m, 1H),
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The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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Excellence in Molecular Cell Engineering grant no. 2014-
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8