Phosphazene Base tBu-P4 Catalyzed Methoxy–Alkoxy Exchange Reaction on (Hetero)Arenes

Article abstract of DOI:10.1002/chem.201900498

The organic superbase tBu-P4 catalyzes methoxy-alkoxy exchange reactions on (hetero)arenes with alcohols. The catalytic reaction proceeded efficiently with electron-deficient methoxy(hetero)arenes as well as with a variety of alcohols, including 3-amino-1-propanol, β-citronellol, menthol, and cholesterol. An intramolecular version of this reaction furnished six- and seven-membered ring compounds.

Full text of DOI:10.1002/chem.201900498

A Journal of
Accepted Article
Title: Phosphazene base t-Bu-P4-catalyzed methoxy−alkoxy exchange
reaction on (hetero)arenes Masanori Shigeno,*[a] Kazutoshi
Hayashi,[a] Kanako Nozawa-Kumada,[a] and Yoshinori Kondo*[a]
Authors: Masanori Shigeno, Kazutoshi Hayashi, Kanako Nozawa-
Kumada, and Yoshinori Kondo
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To be cited as: Chem. Eur. J. 10.1002/chem.201900498
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10.1002/chem.201900498
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COMMUNICATION
Phosphazene base t-Bu-P4-catalyzed methoxyalkoxy exchange
reaction on (hetero)arenes
Masanori Shigeno,*[a] Kazutoshi Hayashi,[a] Kanako Nozawa-Kumada,[a] and Yoshinori Kondo*[a]
Abstract: We herein describe that the organic superbase t-Bu-P4
catalyzes methoxyalkoxy exchange reactions on (hetero)arenes with
alcohols. The catalytic reaction proceeds efficiently with electron-
deficient methoxy(hetero)arenes, as well as a variety of alcohols,
including 3-amino-1-propanol, -citronellol, menthol, and cholesterol.
An intramolecular version of this reaction furnishes six- and seven-
membered ring compounds.
Methoxyarenes are important structures in organic synthesis
because of their widespread availability and application in various
reactions including orthometallation1 and electrophilic aromatic
substitution.2 Hence, development of the direct transformation of
C(aryl)OMe bonds is considered to be of great importance.
However, because of the inertness of C(aryl)OMe bonds, these
reactions have limited scope as compared with those of
C(aryl)(pseudo)halogen bonds, such as transition-metal
catalysis3 and nucleophilic aromatic substitution (SNAr).4 For
example, transition-metal complexes catalyze the transformation
of the methoxy group on (hetero)arenes with carbon, hydride,
amine, boron, and silane nucleophiles to form CC,5a-5d CH,5e-5g
CN,5h CB,5i and CSi bonds.5j As a result of the strict guidelines
for trace amounts of transition metals in medicines and electronic
Figure 1. Transition-metal-free methoxy substitutions on arenes
functional materials, the development of a non-transition-metal
system for methoxy-group conversion is imperative. Biswas and
coworkers showed that TfOH catalyzes methoxy substitutions on
electron-rich (hetero)arenes with nucleophiles by generating an
effective activation of nucleophiles.14-16 For example, t-Bu-P4
catalyzes the SNAr reaction of fluoroarenes with alcohols in the
presence of Et3SiH.14d We herein wish to report that t-Bu-P4
electrophilic
oxocarbenium
intermediate
from
a
methoxy(hetero)arene, which results in CO, CS, CN, and CC
bond formations (Figure 1, a).6 Nicewicz and coworkers
demonstrated that acridinium photocatalysis promotes CN bond
forming reactions of methoxy(hetero)arenes with amines through
allows
a catalytic methoxyalkoxy exchange reaction on
(hetero)arenes in the presence of alcohols as nucleophiles
(Figure 1, d). The obtained alkyl (hetero)aryl ether is a privileged
motif in natural products, pharmaceutical compounds, and
functional materials, and this has motivated organic chemists to
develop the methodologies for its synthesis.17,18 The present
catalytic reaction is complementary to the well-studied
methodologies using aryl (pseudo)halides as electrophiles, such
as the Pd-catalyzed Buchwald/Hartwig18c,19 and Cu-catalyzed
Ullmann aryl ether formations18h,19,20 or SNAr reactions.4,21 Our
system is advantageous over the conventional reactions because
it does not generate stoichiometric amounts of inorganic waste
materials. The reaction proceeds efficiently in the case of
methoxyarenes bearing electron-withdrawing cyano, keto, and
a
single-electron oxidation process (Figure 1, b).7 As
a
complementary method, basic conditions with a stoichiometric
amount of Brønsted base and pronucleophiles or pre-prepared
anionic nucleophiles were found to be effective for methoxy
substitution on arenes, forming CC,8 CN,9,10 and CO bonds
(Figure 1, c).11 There is, however, essentially no report of
Brønsted base-catalyzed methoxy substitutions with a wide
substrate scope.12
We have previously reported that the organic superbase t-Bu-
P413 can catalyze deprotonative transformations of heteroarenes,
alcohols, and amines with electrophiles (carbonyls, heteroarene
N-oxides, alkynes, epoxides, and fluoroarenes) through the
aldehyde
groups,
as
well
as
electron-deficient
methoxyheteroarenes. The reaction allows the chemoselective
introduction of a diverse array of alcohols bearing amine, ether,
olefin, and sugar moieties.
[a]
Dr. M. Shigeno, K. Hayashi, Dr. K. Nozawa-Kumada, Prof. Dr. Y.
Kondo
Department of Biophysical Chemistry
Graduate School of Pharmaceutical Science, Tohoku University
6-3 Aoba, Sendai 980-8578 (Japan)
Initially, the methoxy substitution reaction of 4-cyanoanisole
(1a) with neopentyl alcohol (2a) was carried out in the presence
of 20 mol % of t-Bu-P4 in THF (Table 1). The reaction of 1a with
2 equivalents of 2a at 90 ºC afforded the desired product 3aa in
50% yield (entry 2). The reversibility of the reaction was confirmed
by the treatment of 3aa with 2 equivalents of MeOH under the
E-mail: mshigeno@m.tohoku.ac.jp (MS), ykondo@m.tohoku.ac.jp
(YK)
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of the reaction conditionsa
Entry
Deviation from standard conditions
None
3aa (%)b
96
1
2
90 ºC, in the absence of 5Å MS
90 ºC, 4Å MS instead of 5Å MS
90 ºC
50
3
63
4
80
5
rt
(13)c
52
6
10 mol % of t-Bu-P4
6 h of reaction time
In the absence of t-Bu-P4
1,4-dioxane as solvent
toluene as solvent
7
55
8
(0)c
91
9
10
50
aStandard conditions: 1a (0.20 mmol), 2a (0.40 mmol), t-Bu-P4 (0.04 mmol),
c
5Å MS (70 mg), THF (0.7 mL), 50 ºC, 18 h. bIsolated yields. The yields in
parentheses were determined by 1H-NMR spectroscopy with 1,1,2-
trichloroethane as an internal standard.
same conditions to obtain 1a (Scheme S1). The reaction of 1a
was then performed with molecular sieves in order to trap the
generated MeOH and shift the equilibrium to the product side; this
provided 3aa in an increased yield of 80% with 5Å MS (entries 3
and 4). When the reaction temperature was lowered to 50 ºC, 3aa
was obtained in 96% yield (entries 1 and 5). Decreasing the
catalytic amount of t-Bu-P4 to 10 mol % or shortening the reaction
time to 6 h reduced the product yields (entries 6 and 7). In the
absence of t-Bu-P4, 3aa was not formed (entry 8). Use of 1,4-
dioxane as a solvent also afforded 3aa in a high yield of 91%,
while that of toluene furnished a medium yield of 50% (entries 9
and 10). Other organic or inorganic Brønsted bases were
ineffective for the reaction, thus confirming the critical role of t-Bu-
P4 as the catalyst (Table S1). Deprotonation of alcohol by t-Bu-
P4 generates an alkoxide and a large soft cation ([t-Bu-P4]+H,
~500 Å3); the naked alkoxide is extraordinarily reactive for the
present reaction.22
With the optimized conditions in hand, we evaluated the scope
of the methoxy(hetero)arenes that could be used in the reaction
with 2a (Figure 2). The reaction of 4-benzoylanisole (1b)
proceeded to furnish 3ba in 92% yield. Anisoles 1c and 1d,
possessing formyl and pivaloyl groups, provided the
corresponding products 3ca and 3da in 84% and 67% yields,
respectively. Interestingly, 4-acetylanisole (1e) also provided the
corresponding product in 56% yield, although it has an acidic
C(sp3)–H bond at the -position of the carbonyl group.23,24 The
reaction of 4-nitroanisole (1f) proceeded at room temperature to
give 3fa in 74% yield. Halogen atoms (Cl and Br) were tolerated
in the formation of 3ga and 3ha, respectively. The reaction of 2-
cyanoanisole (1i) resulted into 3ia in a low yield of 24%, whereas
that of 3-cyanoanisole (1j) afforded a trace amount of product. In
Figure 2. Scope of methoxy(hetero)arenesa, b aReactions were conducted on a
0.2 mmol scale. bIsolated yields. cReaction was conducted at 40 ºC. dReaction
was conducted in 1,4-dioxane at 120 ºC. eReaction was conducted at 90 ºC.
fReaction was conducted for 12 h. gReaction was conducted at room
temperature. hYield was determined by 1H-NMR spectroscopic analysis.
iReaction was conducted at 80 ºC.
the cases of 2-formylanisole (1k) and 3-formylanisole (1l) as
substrates, the former provided the product 3ka in 68% yield;
however, the latter did not form 3la. In the reaction of 2,4-
dimethoxybenzonitrile (1m), the methoxy substitution occurs
mainly at the para-position of the cyano group to form a mixture
of 3ma-1 and 3ma-2 in 45% yield (3ma-1:3ma-2 = 91:9) along
with the formation of 3ma-3 in 4% yield. Thus, the reactivity of the
methoxyarenes is dependent on the position of an electron-
withdrawing group and increases in the order of meta- < ortho- <
para-position. This is probably because the stability of the
cyclohexadienyl anion intermediate, formed by the nucleophilic
attack of the alkoxide onto the methoxyarene, increases in that
order.4c,25
Next, electron-deficient methoxyheteroarenes were employed
in the reaction (Figure 2). 2-Methoxy-quinoline (1n) and 6-bromo-
2-methoxy-quinoline (1o) afforded the corresponding products
3na and 3oa in 90% and 74% yields, respectively.26 2-
Methoxypyrazine (1p) and 4-methoxypyridine (1q) provided the
respective products in 87% and 42% yields.27
In the next phase of this study, the scope of the methoxy
substitution was examined by using various alcohols (Figure 3).
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Figure 3. Scope of alcoholsa, b aReactions were conducted on a 0.2 mmol scale.
4a and 4b were carried out with 20 mol % of t-Bu-P4 to construct
six- and seven-membered ring products in high yields of 82% and
86%, respectively.29 In the catalytic intramolecular cyclization,
electron-withdrawing groups were not required on the arenes.
A
proposed mechanism for the t-Bu-P4-catalyzed
methoxyalkoxy exchange reaction is shown in Figure 5. Initially,
t-Bu-P4 triggers the deprotonation of alcohol 2. The high
nucleophilicity of the generated alkoxide
A
facilitates
methoxyalkoxy exchange on (hetero)arenes 1 via an SNAr
process to form product 3. Then, B reacts with 2 to regenerate A,
with the concomitant formation of MeOH.
bIsolated yields. cReaction was conducted at 90 ºC. dProduct was isolated after
acetylation of the amino group. e2h (3 equiv.) was used. fReaction was
conducted with t-Bu-P4 (30 mol %). g2i (3 equiv.) was used. hReaction was
conducted for 48 h.
Figure 5. Proposed mechanism
In summary, we have developed
a t-Bu-P4-catalyzed
The reactions with the secondary alcohols isopropyl alcohol (2b)
and cyclohexanol (2c) proceeded to form 3ab and 3ac in high
yields of 81% and 98%, respectively. Benzyl alcohols 2d2f
underwent the methoxy substitution and afforded the
corresponding products in 61%, 64%, and 70% yields,
respectively.28 In the case of 3-amino-1-propanol (2g), the
reaction occurred chemoselectively at the hydroxy moiety to form
ether 3ag, which was isolated in 83% yield after acetylation of the
amino group. In a related reaction, pyrrole (2h) and 3-
methylpyrrole (2i) were employed as the nitrogen nucleophiles to
provide 3ah and 3ai in 78% and 59% yields, respectively. ()--
Citronellol (2j), bearing an olefin moiety, also gave the
corresponding product 3aj in a good yield of 79%. Additionally,
1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (2k) and ()-
menthol (2l) could be used for the methoxy substitution in this
protocol. Lastly, cholesterol (2m) was used for this reaction,
affording the desired product 3am in 46% yield.
methoxyalkoxy exchange reaction on (hetero)arenes with cyano,
formyl, (non)enolizable ketonic carbonyl, and halo groups to form
alkoxy (hetero)arenes. Various alcohols bearing amine, ether,
olefin, and sugar moieties participated in the reaction to furnish
the desired products. The application of this protocol to an
intramolecular reaction was also demonstrated by using non-
activated substrates without an electron-withdrawing group to
form six- and seven-membered ring skeletons.
Acknowledgements
This work was financially supported by JSPS KAKENHI Grant
Number 16H00997 in Precisely Designed Catalysts with
Customized Scaffolding (YK), JSPS KAKENHI Grant Number
17K15419 (MS), Grand for Basic Science Research Projects from
The Sumitomo Foundation (MS), Yamaguchi Educational and
Scholarship Foundation (MS), and also the Platform Project for
Supporting Drug Discovery and Life Science Research funded by
Japan Agency for Medical Research and Development (AMED)
(MS, KNK, and YK).
An intramolecular variant of the present catalytic methoxy
substitution was also demonstrated (Figure 4). The reactions of
Keywords: Phosphazenes • Methoxyarenes • Aromatic
substitution • Alcohols • Organocatalysis
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[14] For the deprotonative transformations, see: (a) Y. Araki, K. Kobayashi,
M. Yonemoto, Y. Kondo, Org. Biomol. Chem. 2011, 9, 78. (b) Y. Hirono,
K. Kobayashi, M. Yonemoto, Y. Kondo, Chem. Commun. 2010, 46, 7623.
(c) H. Naka, D. Koseki, Y. Kondo, Adv. Synth. Catal. 2008, 350, 1901.
[26] It was previously reported that several methoxy heteroarenes such as
26b
benzothiazole-,26a,
quinazoline-,26b cinnoline-,26b and phthalazine-
derivatives,26b reacted with alcohols by using stoichiometric amounts of
NaOH, KOH, or Na-alkoxides, which was, however, inapplicable to the
reaction of quinoline-derivative.26b (a) H. H. Fox, M. T. Bogert, J. Am.
Chem. Soc. 1941, 63, 2996. (b) K. Adachi, Yakugaku Zasshi 1955, 75,
1426.
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[27] In the reaction of an electron-deficient heteroarene of 1p with 2a, organic
Brønsted bases of proton sponge (1,8-bis-(dimethylamino)naphthalene),
DBU (1,8-diazabicyclo[5.4.0]-7-undecene), TBD (1,5,7-triazabicyclo-
[29] It was previously reported that a stoichiometric amount of Bønsted bases
promotes intramolecular methoxy-alkoxy exchange reactions to form
five- and six-membered ring products, see: (a) N. Ogawa, Y. Yamaoka,
K. Yamada, K. Takasu, Org. Lett., 2017, 19, 3327. (b) L. Zhi, J. D.
Ringgenberg, J. P. Edwards, C. M. Tegley, S. J. West, B. Pio, M.
Motamedi, T. K. Jones, K. B. Marschke, D. E. Mais, W. T. Schrader, Bio.
Med. Chem. Lett., 2003, 13, 2075.
[4.4.0]dec-5-ene),
and
t-Bu-P2
(1-(tert-butylimino)-1,1,3,3,3-
pentakis(dimethylamino)-1λ5, 3λ5-diphosphazene) were employed as a
catalyst instead of t-Bu-P4, however, no desired product 3pa was
obtained (results not shown).
[28] In the reactions affording 3ad, 3ae, and 3af, dibenzyl ether, bis(p-
methylbenzyl) ether, and bis(p-methoxylbenzyl) ether were also formed
in the NMR yields of 2%, 5%, and 3%, respectively.
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10.1002/chem.201900498
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Entry for the Table of Contents
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Masanori Shigeno,* Kazutoshi Hayashi,
Kanako Nozawa-Kumada, and Yoshinori
Kondo*
Page No. – Page No.
Phosphazene base t-Bu-P4-catalyzed
methoxyalkoxy exchange reaction
on (hetero)arenes
The organic superbase t-Bu-P4 catalyzes methoxyalkoxy exchange reactions on
(hetero)arenes with alcohols. The catalytic reaction proceeds efficiently with
electron-deficient methoxy(hetero)arenes, as well as a variety of alcohols, including
3-amino-1-propanol, -citronellol, menthol, and cholesterol. An intramolecular
version of this reaction furnishes six- and seven-membered ring compounds.
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