Catalytic C(sp2)-C(sp3) bond formation of methoxyarenes by the organic superbase t-Bu-P4

Article abstract of DOI:10.1021/acs.orglett.0c03507

The organic superbase catalyst t-Bu-P4 achieves nucleophilic aromatic substitution of methoxyarenes with alkanenitrile pronucleophiles. A variety of functional groups [cyano, nitro, (non)enolizable ketone, chloride, and amide moieties] are allowed on methoxyarenes. Moreover, an array of alkanenitriles with/without an aryl moiety at the nitrile α-position can be employed. The system also features no requirement of a stoichiometric base, MeOH (not salt waste) formation as a byproduct, and the production of congested quaternary carbon centers.

Full text of DOI:10.1021/acs.orglett.0c03507

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Letter
Catalytic C(sp2)−C(sp3) Bond Formation of Methoxyarenes by the
Organic Superbase t‑Bu-P4
Masanori Shigeno,* Kazutoshi Hayashi, Kanako Nozawa-Kumada, and Yoshinori Kondo*
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ABSTRACT: The organic superbase catalyst t-Bu-P4 achieves
nucleophilic aromatic substitution of methoxyarenes with alka-
nenitrile pronucleophiles. A variety of functional groups [cyano,
nitro, (non)enolizable ketone, chloride, and amide moieties] are
allowed on methoxyarenes. Moreover, an array of alkanenitriles
with/without an aryl moiety at the nitrile α-position can be
employed. The system also features no requirement of a
stoichiometric base, MeOH (not salt waste) formation as a
byproduct, and the production of congested quaternary carbon
centers.
he nucleophilic aromatic substitution (SNAr) reaction of
(pseudo)haloarenes with pronucleophiles, proceeding
reactions using In(OTf)3,12 triflic acid,13 and acridium
photoredox catalyst14,15 are available (Figure 1a). Additionally,
C(sp2)−OMe to C(sp2)−C(sp3) bond transformations have
also been demonstrated by nickel16 and chromium10a,b
catalysis with preprepared organometallic nucleophiles (Figure
1b, upper).17 However, to date, no SNAr approach toward
C(sp2)−C(sp3) bond formation, which would be comple-
mentary to transition-metal catalysis, has been reported.
Our group has recently demonstrated that the organic
superbase t-Bu-P418 catalyzes the SNAr reactions of methox-
yarenes with pronucleophiles, specifically, reactions with
alcohols and amines that form C(sp2)−O and C(sp2)−N
bonds, respectively.19,20 We herein report t-Bu-P4 as a potent
catalyst for the C(sp2)−C(sp3) bond formations of methox-
yarenes and alkanenitriles with the creation of quaternary
carbon centers (Figure 1b, lower).21−23 The t-Bu-P4 base
catalysis does not require the use of an additional
stoichiometric base and forms MeOH as a byproduct, in
contrast with the conventional SNAr reactions of (pseudo)-
haloarenes.24 Good functional group compatibility on
methoxyarenes is shown by examples of cyano, nitro,
(non)enolizable ketone, chloride, and amide moieties. An
array of alkanenitriles with/without an aryl moiety at the α-
carbon of the nitrile group are applicable.25
T
regioselectively at the ipso-carbon of the arenes, is one of the
most important chemical reactions in organic chemistry
(Figure 1A).1 Indeed, the reaction is frequently used in
medicinal chemistry.2 Catalytic systems with a transition metal
and an organocatalyst were established for achieving efficient
reactions:1,3,4 the former uses an electron-deficient ruthenium
complex to enhance the electrophilicity of arenes by η6-
coordination;3 the latter employs N-heterocyclic carbene,4a,b
acridinium and xanthylium salts,4c phosphazene base,4d and
amide base4e for the activation of arenes or pronucleophiles.
The protocol, however, generally requires the use of an
additional stoichiometric chemical reagent (base, silane
additive, or sometimes an excess amine pronucleophile) to
trap the generated acid or prepare a nucleophilic anionic
species from the pronucleophile. Moreover, a stoichiometric
salt waste is produced as a byproduct. Thus, the development
of a reaction without these drawbacks is highly desirable.
However, such studies are not advanced. For example, Lambert
et al. recently demonstrated that the electrophotocatalytic
reactions of fluoroarenes occur with azoles and alcohols in the
absence of base;5 Schley et al. reported that the ruthenium−
1,5-bis(diphenylphosphino)pentane complex catalyzes the
amination of fluorobenzene, wherein morpholine was used as
a limiting reagent and no other reagent was needed.6
Initially, we screened the reaction conditions using 4-
benzoylanisole 1a and 2-phenylpropionitrile 2a as model
The direct catalytic molecular transformation of low reactive
C(sp2)−OMe bonds in arenes has been recently well-studied
owing to their wide and easy availability and high stability in
multistep synthesis.7 This protocol is expected to reinforce
and/or revise conventional studies of transformations using
(pseudo)haloarenes.1,8 Regarding the C−C bond formations, a
variety of C(sp2)−C(sp) and C(sp2)−C(sp2) bond-forming
methodologies by transition-metal catalysis7,9−11 and SNAr
Received: October 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03507
© XXXX American Chemical Society
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A

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of MS to trap the generated MeOH was not as significant as in
our previously reported alkoxylation19a and amination19b
reactions (Table 1, entries 1 and 7). This was attributed to
the relatively acidic nature of 2a, as shown by the small pKa
value (23.0, DMSO).26a This allows smooth deprotonation to
form an anionic species, compared with those of alcohol and
amine nucleophiles [EtOH (29.8, DMSO)26b and N-
methylaniline (29.5, DMSO),26c respectively] and the side
product MeOH (29.0, DMSO).26b,27 A high yield was still
observed when the catalytic amount of t-Bu-P4 was reduced to
10 mol %, while a lower loading (5 mol %) decreased the
efficiency of the reaction (entries 8 and 9, respectively).28,29
Lowering the reaction temperature to room temperature
resulted in a decrease in the product yield (entry 10). Scale-
up of the reaction to a 1.0 mmol scale produced 3aa in 90%
yield (entry 11). Brønsted bases other than t-Bu-P4 were
insufficient to provide the product (Table S1), highlighting the
important role of t-Bu-P4 in the reaction.30
Using the established protocol, we next examined the scope
of the alkanenitriles (Figure 2). Electron-donating and
Figure 1. SNAr reactions of (pseudo)haloarenes with pronucleophiles
(A) and catalytic reactions of methoxyarenes with carbon
nucleophiles (B).
substrates with t-Bu-P4 (pKBH = 28.0 in THF;18a pKBH = 30.3
in DMSO18b). A survey of solvents revealed THF, THP, and
cyclohexane as good solvents, which afforded the target
product 3aa in high yields (90−92%; Table 1, entries 1−4).
Subsequent investigation of the effects of molecular sieves
(MS) showed that the product yield was the highest with 5 Å
MS (Table 1, entries 1 and 5−7). In this reaction, the addition
Table 1. Optimization of the Reaction Conditions of 1a and
a
2a
b
Figure 2. Scope of alkanenitriles.a,b aReactions were conducted on a
entry
deviation from standard conditions
3aa (%)
c
1
2
3
4
5
6
7
8
none
92
74
90
92
82
77
85
93
84
73
90
0.2 mmol scale. bIsolated yields. t-Bu-P4 (10 mol %) was used.
e
dReaction was conducted in cyclohexane. t-Bu-P4 (30 mol %) was
1,4-dioxane as solvent
THP as solvent
f
g
used. Reaction was conducted in THP at 120 °C. Reaction was
h
conducted at 80 °C. 2 (2 equiv) was used.
cyclohexane as solvent
3 Å MS instead of 5 Å MS
4 Å MS instead of 5 Å MS
in the absence of 5 Å MS
10 mol % t-Bu-P4
5 mol % t-Bu-P4
-withdrawing groups (methyl, methoxy, chloro, and amide
substituents) were acceptable on the aromatic moiety of 2-
arylpropionitriles, providing the target products 3ab−3ae,
respectively. The reaction of α-methyl-1,3-benzodioxole-5-
acetonitrile 2f efficiently proceeded to form the corresponding
product in 81% yield. 2-Phenylbutyronitrile 2g and 2,4-
diphenylbutanenitrile 2h also participated in the reactions to
furnish products 3ag and 3ah in respective yields of 89 and
83%. On the other hand, the reaction did not proceed with the
more sterically hindered substrate 2i. To understand the
9
10
11
room temperature
scale-up of the reaction
c
a
Standard conditions: 1a (0.20 mmol), 2a (0.40 mmol), t-Bu-P4
(0.04 mmol), 5 Å MS (100 mg), THF (0.7 mL), 60 °C, and 18 h.
Isolated yields. 1a (1.0 mmol), 2a (2.0 mmol), t-Bu-P4 (0.20
mmol), 5 Å MS (500 mg), THF (3.5 mL), 60 °C, and 18 h.
b
c
B
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reaction, 2i was treated with CD3OD in the presence of t-Bu-
P4, affording deuterium-labeled 2i-d at the α-position of the
cyano moiety (Scheme S1). The results showed that the
deprotonation of 2i occurs by t-Bu-P4, while subsequent
methoxy substitution of 1a by the generated carbanion does
not take place. Both 1-indancarbonitrile 2j and 1-tetralincar-
bonitrile 2k smoothly afforded the corresponding products.
Substrates 2l−2n, containing heteroaryl moieties (2-thienyl, 3-
N-Me-indolyl, and 3-pyridyl), were successfully converted to
the target products in high yields of 83, 93, and 84%,
respectively.
moieties in 1e−1g were well compatible under these
conditions.
The use of an indanone derivative resulted in the formation
of 3ha in 89% yield. However, the reaction did not proceed
when 2-benzoylanisole 1i was employed. When substrates 1j
and 1k were tested, their chloride atoms remained intact under
the tested conditions to afford 3ja and 3ka in 80 and 77%
yields, respectively. Amide functionality was also tolerable on
the pyridine ring, yielding the target product 3la in 61% yield.
2-Methoxynaphthalene 1m did not afford the desired product,
revealing that an electron-withdrawing group is essential for
promoting the current SNAr reaction.
Alkanenitriles without an aryl group at the nitrile α position
were next tested (Figure 2). Interestingly, these served as
suitable substrates, even though they are much less acidic than
2a (23.0, DMSO),26a as represented by the large pKa value of
propionitrile (32.5, DMSO).26d In the case of isobutyronitrile
2o, the desired product 3ao was obtained in 72% yield.31
Notably, in the absence of MS, 3ao was formed in a much
lower yield of 18%, and 1a was recovered in 62% yield. This
revealed that trapping of the generated MeOH is essential for
the low acidic alkanenitrile pronucleophile. Cyclopentyl nitrile
2p delivered product 3ap in 56% yield. Reactions of 2q and 2r,
with saturated heterocyclic rings, were also realized and yielded
the corresponding products in 71 and 70% yields, respectively.
We next evaluated the scope of the methoxyarenes, whereby
4-cyanoanisole 1b and 4-nitroanisole 1c afforded the
corresponding products in 84 and 75% yields, respectively
(Figure 3). Subsequently, we examined substrates 1d−1g,
equipped with a ketonic carbonyl functionality. In addition to
the nonenolizable pivaloyl group in 1d, the enolizable ketonic
The proposed mechanism is illustrated in Figure 4. Initially,
deprotonation of the nitrile α-C−H bond occurs by t-Bu-P4 to
Figure 4. Proposed mechanism.
form carbanion A. Subsequently, the methoxy substitution of 1
with A proceeds to afford alkylated product 3 with
concomitant generation of B. Intermediate A is sufficiently
reactive toward the substitution, since its anionic part is almost
naked and nucleophilic owing to the large soft cation [t-Bu-
P4]+H (∼500 Å3).32 MeOH is then liberated from B to afford
t-Bu-P4, achieving the catalytic cycle (path a). Alternatively,
regeneration of A caused by deprotonation of 2 with the
methoxide ion in B is also conceivable (path b).33,34
In summary, t-Bu-P4 catalysis proceeds for a variety of
methoxyarenes equipped with electrophilic functionalities
[cyano, nitro, (non)enolizable ketone, and amide moieties]
and a diverse range of alkanenitrile pronucleophiles (with/
without an aryl group at the nitrile α-position), which cover a
wide range of pKa values. Formation of quaternary carbon
centers is also involved. As distinct features from the
conventional SNAr reactions of (pseudo)haloarenes,1,23 this
system employs t-Bu-P4 as a base catalyst, does not need an
additional external base, and solely produces MeOH (not salt
waste) as a byproduct.
Figure 3. Scope of methoxyarenesa,b aReactions were conducted on a
b
c
0.2 mmol scale. Isolated yields. Reaction was conducted with 2a (2
ASSOCIATED CONTENT
* Supporting Information
equiv) at room temperature. dReaction was conducted at 80 °C.
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sı
f
eReaction was conducted for 12 h. Reaction was conducted in
g
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03507.
cyclohexane at 40 °C for 3 h. Reaction was conducted with t-Bu-P4
(30 mol %) at 90 °C.
C
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(b) Walton, J. W.; Williams, J. M. J. Catalytic SNAr of Unactivated
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Effects of organic or inorganic bases in the reaction of 1a
and 2a (Table S1), reaction of 2i with CD3OD in the
presence of t-Bu-P4 (Scheme S1), reactions of
haloarenes 4a−c and 2o (Scheme S2), reversibility of
the reaction of 1a and 2a (Scheme S3), preparations of
2d, 2e, 2f, and 2n, experimental procedures and spectra
data for obtained products, and 1H and 13C NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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Masanori Shigeno − Department of Biophysical Chemistry,
Graduate School of Pharmaceutical Sciences, Tohoku
University, Sendai 980-8578, Japan; orcid.org/0000-
0002-9640-8283; Email: masanori.shigeno.e5@
tohoku.ac.jp
Yoshinori Kondo − Department of Biophysical Chemistry,
Graduate School of Pharmaceutical Sciences, Tohoku
University, Sendai 980-8578, Japan;
Email: yoshinori.kondo.a7@tohoku.ac.jp
Authors
Kazutoshi Hayashi − Department of Biophysical Chemistry,
Graduate School of Pharmaceutical Sciences, Tohoku
University, Sendai 980-8578, Japan
Kanako Nozawa-Kumada − Department of Biophysical
Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan; orcid.org/
0000-0001-8054-5323
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03507
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. 19H03346 (Y.K.), JSPS KAKENHI Grant No. 19K06967
(M.S.), the Environment Research and Technology Develop-
ment Fund (JPMEERF20202R02) of the Environmental
Restoration and Conservation Agency of Japan (M.S.), The
Uehara Memorial Foundation (M.S.), The Tokyo Biochemical
Research Foundation (M.S.), The Research Foundation for
Pharmaceutical Sciences (M.S.), Daicel Corp. (M.S.), and also
the Platform Project for Supporting Drug Discovery and Life
Science Research funded by Japan Agency for Medical
Research and Development (AMED) (M.S., K.N.K., and
Y.K.). K.H. thanks JSPS for a Fellowship for Young Japanese
Scientists (No. 20J20712).
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Figure 2.
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Bu-P4 afforded 3aa in 51 and 42% yields, respectively, which are
(21) Transition-metal catalysis of methoxyarenes also demonstrates
the construction of quaternary carbon centers using 1-adamantyl-
F
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lower than that obtained with THF (84%, Table 1, entry 9). Thus,
THF was selected as the standard solvent in this study.
(29) For most of the substrates in this study, the use of 20 mol % t-
Bu-P4 was more effective than with 10 mol %. In Figures 2 and 3, the
results obtained using 20 mol % catalyst are shown except for 3ab,
3ac, 3ag, 3aj, and 3am (10 mol %) and 3ae and 3la (30 mol %).
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(31) For comparison, reactions using haloarenes (i.e., 4-fluoro-, 4-
chloro-, and 4-bromobenzophenones) instead of 1a were tested,
resulting in low yields of product formation (Scheme S2).
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deprotonate alkanenitrile 2, like t-Bu-P4, based on the pKa values of
MeOH (29.0, DMSO),26b 2a (23.0, DMSO),26a and propionitrile
(32.5, DMSO)26d and the pKBH of t-Bu-P4 (30.3 in DMSO).18b
(34) The reversibility of this SNAr reaction was examined using 3aa
and MeOH (Scheme S3): 1a was formed in a low yield of 2%,
showing that the reaction is reversible but with the equilibrium mainly
shifted to the product side.
G
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