Unusual O-alkylation of 2-hydroxy-1,4-naphthoquinone utilizing alkoxymethyl chlorides

Article abstract of DOI:10.1248/cpb.c15-00220

A new type of O-alkylation of 2-hydroxy-1,4-naphthoquinone with alkoxymethyl chlorides is described. The reaction course can be controlled by the choice of base and yields Oalkylated or O-alkoxymethylated products in high yield with high selectivity.

Full text of DOI:10.1248/cpb.c15-00220

Vol. 63, No. 7
Chem. Pharm. Bull. 63, 485–488 (2015)
485
Communication to the Editor
(DMF) at r.t., which is a conventional O-methoxymethylation
method, and 3a was obtained in moderate yield (Table 1, entry
1). Unfortunately, the data obtained under this condition are
not available for the discussion of the mechanism because
of the poor reproducibility of the reaction. Various reaction
conditions were examined to solve this problem, we found
that the amount of water strongly affected the ratio of the
product. Namely, reproducibility was dramatically improved
by moisture control of the reaction system using molecular
sieves 3A.13)
Unusual O-Alkylation of 2-Hydroxy-1,4-
naphthoquinone Utilizing Alkoxymethyl
Chlorides
,†
Tokutaro Ogata,* Tomoyo Yoshida, Manami Tanaka,
Chie Fukuhara, Maki Shimizu, Junko Ishii,
Arisa Nishiuchi, Kiyofumi Inamoto, and
Tetsutaro Kimachi*
The amount of reagent and concentration of solution af-
fected the products. The product ratio of 3a increased in ac-
cordance with the use of a larger amount of base and MOMCl,
although excess use of these reagents caused a decrease in the
3a yield (Table 1, entries 3–5). Under the slight basic condi-
tions, namely, the reaction using excess amount of base over
MOMCl resulted in a great decrease of 3a (Table 1, entry 6).
Remarkably, the selectivity was completely regulated by using
one or three equivalents of the reagents against 1a. These
results strongly suggested that the rate of the formation of 2a
was faster than that of 3a, and 3a was produced via the forma-
tion of 2a. Under higher concentration, good selectivity of 3a
was observed (Table 1, entries 4, 7 and 8). Prolonged reaction
School of Pharmacy and Pharmaceutical Sciences, Mukogawa
Women’s University; 11–68 Koshien Kyu-bancho, Nishinomiya,
Hyogo 663–8179, Japan.
Received March 10, 2015; accepted April 23, 2015
A new type of O-alkylation of 2-hydroxy-1,4-naphthoqui-
none with alkoxymethyl chlorides is described. The reaction
course can be controlled by the choice of base and yields O-
alkylated or O-alkoxymethylated products in high yield with
high selectivity.
Key words naphthoquinone; protecting group; hydride; al-
kylation; heterocycle
1,4-Naphthoquinone is one of the common skeletons found time resulted in a slight decrease of 3a (Table 1, entries 7 vs.
in a various biologically active compounds.1–7) Recently, 9).
our research interests have focused on the total synthesis of
In order to clarify the moisture effect in this O-alkylation,
naturally occurring naphthoquinones, such as rinacanthin A,8) the reaction was performed under wet condition (Table 1,
dehydroiso-β-lapachone9) and lantalucratins10) having biologi- entry 10). As expected, the product ratio of 2a/3a was dra-
cal activities including anti-tumor activity, in order to confirm matically changed, 2a was obtained as a major product. Vari-
the chemical structure and determine the absolute configura- ous types of bases were examined, and the results indicated
tion. In the course of our synthetic study, a key intermediate
(I) was prepared from 1,4-dimethoxynaphthalene, which is
relatively expensive as a commercial source, by the introduc-
tion of a hydroxyl group using directed ortho lithiation-sub-
stitution reaction11) and the following hydroxyl protection by
methoxymethyl group (Chart 1).
In order to utilize intermediate (I) for the syntheses of
naphthoquinones containing various natural products at a
practical level, a more efficient synthetic method had to be
developed and established. This led us to try to develop a con-
cise synthesis of the intermediate (I). Initial entry was started
from ordinary hydroxyl protection of 2-hydroxy-1,4-naphtho-
quinone (1a) using chloromethyl methyl ether (MOMCl) in
basic condition. As a result, an unusual side reaction was ob-
Chart 1. Method for Preparation of Key Intermediate I
served, namely O-methylation proceeded along with the nor-
mal methoxymethylation of the hydroxyl group (Chart 2). This
result prompted us to study the generality and limitation of
this unusual alkylation reaction. Here we describe our findings
related to the changes in the ratio and yield of the product due
to differences in the reaction conditions, and briefly consider
the reaction pathway.
In the initial approach directed toward understanding the
unusual alkylation, the reaction conditions were examined as
summarized in Table 1.12) First, 1a was treated with sodium
hydride (NaH) and MOMCl in N,N-dimethylformamide
† Present address: Faculty of Pharmaceutical Sciences, Hokuriku Univer-
Chart 2. Unusual O-Alkylation of 2-Hydroxy-1,4-naphthoquinone with
MOMCl
sity; Kanagawa-machi, Kanazawa, Ishikawa 920–1181, Japan.
*To whom correspondence should be addressed. e-mail: t-ogata@hokuriku-u.ac.jp; tkimachi@mukogawa-u.ac.jp
© 2015 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
Vol. 63, No. 7 (2015)
Table 1. Scope of the Reaction Conditionsa)
Product
Entry
Base (eq)
MOMCl (eq)
DMF (mol/L)
Time (h)
2a (%)
3a (%)
1b)
2
NaH (2.0)
NaH (2.0)
NaH (1.0)
NaH (2.0)
NaH (3.0)
NaH (3.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
LiH (2.0)
3.0
3.0
1.0
2.0
3.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.2
0.2
0.2
0.2
0.2
0.2
1.0
0.05
1.0
0.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.25
1
34
29
85
14
0
59
61
0
3
1
4
1
83
47
31
73
69
63
10
0
5
1
6
1
0
7
1
5
8
1
13
Trace
76
82
20
75
90
50
64
Trace
9
5
10c)
11
12
13
14
15
16
17d)
0.25
1
KH (2.0)
1
40
0
K2CO3 (2.0)
iPr2NEt (2.0)
KOtBu (2.0)
NaOMe (2.0)
NaOH (2.0)
1
1
0
1
10
0
2
1
0
a) The reaction was carried out using flame-dried round bottom flask and filled with argon gas atmosphere. 1a (2mmol) and activated MS3A (500mg) was used, and stirred
at room temperature. b) The reaction was conducted without using MS3A. c) The reaction was carried out with addition of water (1 drop). d) 1a was almost recovered.
Table 2. Molecular Conversion between 2a and 3a in the Presence of NaH and MOMCla)
Product (Recovered)
Entry
Substrate
Base (eq)
MOMCl (eq)
Time (h)
2a (%)
3a (%)
1
2a
2a
2a
2a
2a
2a
3a
3a
2a
NaH (1.0)
none
1.0
1.0
1
1
39
91
<26b)
quant
69
21
0
2
3
NaH (1.0)
none
none
none
1.0
1
0
4
24
1
0
5c)
6d)
7
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaOCH3 (1.0)
11
36
88
33
4
1.0
1
61
1.0
1
0
8c)
9d)
1.0
1
36
1.0
2
90
a) The reaction was carried out using flame-dried round bottom flask and filled with argon gas atmosphere. 0.5mmol of substrate (2a or 3a), anhydrous DMF (0.5mL) and
activated MS3A (125mg) was used, and stirred at room temperature. b) Unidentified compounds were also obtained. c) One drop of water was added to the reaction solution.
d) 0.6mmol of BHT (dibutylhydroxytoluene) was added.
1
that the base must be of the appropriate basicity and molecular nol in MOMCl confirmed by H-NMR analysis.
size to obtain the methyl ether 3a. In case of using alkoxide
In order to certify that methyl ether 3a was actually pro-
which can also act as nucleophile, 3a was not obtained at duced via 2a, isolated 2a or 3a was treated with the NaH/
all (Table 1, entry 16). Using weaker base or hydride base, MOMCl reagent system (Table 2). As expected, 3a was gen-
including a smaller size of countercation, afforded the me- erated from 2a, and this molecular conversion required both
thoxymethyl ether 2a in good to excellent yield with complete NaH and MOMCl (Table 2, entries 1–4). The reverse reaction
selectivity (Table 1, entries 11, 13, 14). In addition, it became from 3a into 2a did not proceed under anhydrous condition
clear that there were no significant impurities such as metha- (Table 2, entry 7). Interestingly, the transformation of 3a to

Vol. 63, No. 7 (2015)
Chem. Pharm. Bull.
487
Reaction condition: 1a (2mmol), NaH (2eq), BOMCI (2eq), MS3A (500mg), anhydrous DMF (2mL).
Chart 3. Reaction of 1a with Benzyl Chloromethyl Ether
Chart 4. Postulated Reaction Pathway for the Formation of 2a and 3a
2a occurred in the presence of water, and this result indicated obtained by simple SN2 reaction from compound 1a under
that the water in the reaction promoted the degradation of 3a treatment with NaH and MOMCl. The following transforma-
(Table 2, entry 8). On the other hand, the alkoxides are con- tion can be explained by two pathways.16) In route A, deproto-
sidered as one of the degradation fragments of the methoxy- nation at the methylene carbon by a strong base such as NaH
methyl (MOM) group and might promote the O-methylation. occurs to generate 6-membered chelate complex I17) which
However, contrary to our expectation, only a small amount reacts with MOMCl to give intermediate II. The intramolecu-
of methyl ether 3a was obtained using sodium methoxide as a lar Michael addition provides 5-membered spiro-ketal III, and
base (Table 2, entry 9). In addition, the O-methylation was not compound 3a is finally obtained by cleavage of the methyl
inhibited in the presence of dibutylhydroxytoluene (BHT) as a acetate group via formation of labile intermediate IV. On the
free radical scavenger (Table 2, entry 6).
other hand, in route B, 1,3-dioxetane intermediate V18) is gen-
The O-alkylation also occurred using other alkoxyalkyl erated directly by oxa-Michael addition of 2a, and subsequent
halides, such as benzyl chloromethyl ether (Chart 3). The removal of formaldehyde provides 3a. From the experimen-
reaction of 1a using benzyl chloromethyl ether with NaH pro- tal results in Table 2, the transformation of 2a into 3a was
ceeded smoothly; benzyl ether (3b)14) was obtained along with surmised to require both NaH and MOMCl, and this result
benzyloxymethyl ether (2b).15) It was noteworthy that methyl offered support for route A because those reagents are not in-
ether (3a) was not obtained at all in this case. This result indi- volved in the transformation in route B. The radical reduction
rectly indicated that the methyl group of 3a did not originate and/or radical chain reaction pathway perhaps could be elimi-
from the methylene moiety of 2a but from the terminal methyl nated (Table 2, entry 6). The reverse reaction from 3a into 2a
moiety in case of the reaction of 1a with NaH and MOMCl.
is considered to occur by the following processes. A Michael
Based on the experimental findings, the proposed reaction addition between sodium hydroxide, which is generated from
pathway was illustrated in Chart 4. First, compound 2a was NaH and water, and 3a occurs first, and subsequent elimina-

488
Chem. Pharm. Bull.
Vol. 63, No. 7 (2015)
ice bath cooling with addition of sodium hydride 60% dispersion in
mineral oil (160mg, 4mmol) in one portion, methoxymethyl chlo-
ride (320mg, 4mmol) was added dropwise. The reaction mixture
was warmed up to r.t. and stirred for 1h. After complete consump-
tion of the substrate was confirmed by TLC analysis, the reaction
mixture was poured onto ice water. Next, the reaction mixture was
diluted with ethyl acetate and the solution was filtered through a
Celite pad. The filtrate was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layer was suc-
cessively washed with water (×3), brine (×1) and then dried over
Na2SO4. Filtration and concentration under reduced pressure gave a
dark brown crude oil, which was purified by flash column chroma-
tography eluting with hexane and ethyl acetate in 5/1 to 1/1 ratio to
obtain a mixture of 2a and 3a as a yellow solid. The product yield
tion provides 1a. The formation of 2a occurs in a same way as
explained above. However, the detailed reaction pathway from
2a to 3a remains unclear.19)
On the other hand, the reverse transformation (3a to 2a) can
be clearly explained by the alkali hydrolysis pathway. Namely,
1a is reproduced by the alkaline hydrolysis of 3a, and follow-
ing conventional methoxymethylation provide 2a.
In summary, we have developed a novel O-alkylation of
2-hydroxy-1,4-naphthoquinone with alkoxymethyl chlorides.
Precise study of the reaction conditions was carried out, and
which could be realized the separate formation of two type of
product in high yield with high selectivity. Further study on
the mechanism, especially for the transformation of 2a into
3a, substrate scope, limitation and applications are extensively
in progress.
1
was calculated by H-NMR analysis.
13) Anhydrous organic solvents and sodium hydride 60% dispersion in
mineral oil were purchased from Wako Pure Chemical Industries,
Ltd. Products Co. and used for the reactions without further pu-
rification. The results were not changed by using mineral oil free
sodium hydride. MS3A was activated under heating for 1d prior to
use for the reactions.
Conflict of Interest The authors declare no conflict of
interest.
14) Lien J.-C., Huang L.-J., Teng C.-M., Wang J.-P., Kuo S.-C., Chem.
Pharm. Bull., 50, 672–674 (2002).
References and Notes
1) Suttie J. W., Annu. Rev. Nutr., 15, 399–417 (1995).
2) Verma R. P., Anticancer. Agents Med. Chem., 6, 489–499 (2006).
3) Kumagai Y., Shinkai Y., Miura T., Cho A. K., Annu. Rev. Pharma-
col. Toxicol., 52, 221–247 (2012).
15) 2-Benzyloxymethoxy-1,4-naphthoquinone (2b) A yellow solid of
mp 98.2–98.8°C. IR (KBr) cm−1: 1678, 1655, 1613, 1593, 1578, 1499,
1
1331, 1262, 1231, 1196, 1167, 1107, 1082, 1034. H-NMR (CDCl3) δ:
4) Babula P., Adam V., Havel L., Kizek R., Curr. Pharm. Anal., 5,
47–68 (2009).
5) Belorgey D., Lanfranchi D. A., Davioud-Charvet E., Curr. Pharm.
Des., 19, 2512–2528 (2013).
6) Pradhan R., Dandawate P., Vyas A., Padhye S., Biersack B., Scho-
bert R., Ahmad A., Sarkar F. H., Curr. Drug Targets, 13, 1777–1798
(2012).
7) Mizushina Y., Nishiumi S., Nishida M., Yoshida H., Azuma T., Yo-
shida M., Int. J. Oncol., 42, 793–802 (2013).
4.76 (2H, s), 5.42 (2H, s), 6.53 (1H, s), 7.27–7.36 (5H, m), 7.69–7.77
(2H, m), 8.07–8.15 (2H, m). 13C-NMR (CDCl3) δ: 71.4, 92.7, 113.4,
126.1, 126.6, 128.0, 128.2, 128.5, 131.1, 131.9, 133.3, 134.2, 136.2,
157.9, 180.2, 184.9. FAB-MS m/z: 295.0970 (Calcd for C18H15O4:
295.0970).
16) O-Alkylation also occurred with use of a substrate bearing the sub-
stituent group at the 3-position. This result eliminates a mechanism
involving deprotonation by a strong base in the first stage. Detailed
study is in progress.
8) Kimachi T., Torii E., Ishimoto R., Sakue A., Ju-ichi M., Tetrahe-
dron Asymmetry, 20, 1683–1689 (2009).
9) Kimachi T., Torii E., Kobayashi Y., Doe M., Ju-ichi M., Chem.
Pharm. Bull., 59, 753–756 (2011).
10) Ogata T., Sugiyama Y., Ito S., Nakano K., Torii E., Nishiuchi A.,
Kimachi T., Tetrahedron, 69, 10470–10476 (2013).
11) Snieckus V., Chem. Rev., 90, 879–933 (1990).
12) General procedure for the O-alkylation of 2-hydroxy-1,4-naph-
thoquinones. To a flame-dried round bottom flask was added
2-hydroxy-1,4-naphthoquinone (348mg, 2mmol) and activated
MS3A (500mg), and it was then filled with argon gas. Anhydrous
DMF (2.0mL) was added and the mixture was stirred at r.t. for 1h
to absorb the moisture completely. After stirring for 10min under
17) Normally, the deprotonation reactions at the acetal methylene car-
bon do not occur in the presence of NaH. However, in this case, it is
speculated that was made to occur such reaction probably due to the
formation of a stable complex I by chelation between the carbonyl
group and sodium atom as a driving force.
18) Some compounds containing uncharged spiro-1,3-dioxetane skel-
eton are known. For example, check CAS RN: [314289-68-4],
[1195302-89-6].
19) The transformation of 2a into 3a can be also assumed that involving
an addition-elimination mechanism. In this case, nucleophiles such
as alcohol (alkoxide) must be required to proceed for this transfor-
mation. This process probably to be eliminated by the experimental
results (Table 1, entry 16 and Table 2, entry 9).