Catalytic Direct-type 1,4-Addition Reactions of Alkylazaarenes

Article abstract of DOI:10.1002/anie.201611374

1,4-addition reactions of alkylazaarenes catalyzed by strong Br?nsted bases have been developed for the first time. The desired reactions with α,β-unsaturated amides proceeded under mild reaction conditions to give the 1,4-adducts in high yields. Both ortho- and para-substituted azaarenes afforded the desired adducts in high yields. Regioselective reactions of di- or trimethylpyridine were found to be possible depending on the acidity of the α-hydrogen atoms. Furthermore, a candidate of allosteric protein kinase modulators was synthesized in two steps. An asymmetric variant of this reaction was also found to be feasible.

Full text of DOI:10.1002/anie.201611374

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201611374
German Edition: DOI: 10.1002/ange.201611374
Heteroarenes
Catalytic Direct-type 1,4-Addition Reactions of Alkylazaarenes
Hirotsugu Suzuki, Ryo Igarashi, Yasuhiro Yamashita, and Shu¯ Kobayashi*
Abstract: 1,4-addition reactions of alkylazaarenes catalyzed
by strong Brønsted bases have been developed for the first time.
The desired reactions with a,b-unsaturated amides proceeded
under mild reaction conditions to give the 1,4-adducts in high
yields. Both ortho- and para-substituted azaarenes afforded the
desired adducts in high yields. Regioselective reactions of di- or
trimethylpyridine were found to be possible depending on the
acidity of the a-hydrogen atoms. Furthermore, a candidate of
allosteric protein kinase modulators was synthesized in two
steps. An asymmetric variant of this reaction was also found to
be feasible.
conducted under high-temperature reaction conditions.
À
Moreover, regioselectivity is limited in most cases: the a-C
H bond of an alkyl substituent at the ortho position relative to
the nitrogen atom of the azaarene (e.g., 2-methylpyridine) is
activated. Therefore, a new and general reaction system
which works under much milder reaction conditions (below
room temperature) is highly desired.
À
We focused on C C bond-forming reactions of alkyla-
zaarenes by using a strong Brønsted base catalyst under mild
reaction conditions. It is known that smooth deprotonation of
a-hydrogen atoms of alkylazaarenes occurs even at À788C by
using strong Brønsted bases such as nBuLi.[10] Although C C
À
À
C
atalytic carbon–carbon (C C) bond formation is one of
bond-forming reactions of alkylazaarenes, using a stoichio-
metric amount of strong Brønsted base, have been inves-
tigated,[11] to our knowledge, Brønsted base catalyzed reac-
tions have not been reported to date. The main issue relates to
the difficulty of completing the turnover of strong Brønsted
base catalysts because of the weak acidity of the a-hydrogen
atoms of alkylazaarenes. We have recently developed an
efficient method of catalytic deprotonation for such weakly
acidic substrates by using strong Brønsted base catalysts
through the generation of strongly basic reaction intermedia-
tes.[4c,d,f,12] Herein, we expand this methodology and describe
the first example of Brønsted base catalyzed 1,4-addition
reactions of a range of alkylazaarenes under mild reaction
conditions.
the most promising and desired methods for efficient
construction of complex carbon frameworks.[1] In particular,
Brønsted base catalyzed reactions are ideal from the view-
point of atom economy because the reactions proceed under
simple proton-transfer conditions.[2] To date, many kinds of
Brønsted base catalyzed reactions have been developed,
however, available pronucleophiles are limited to compounds
with relatively acidic hydrogen atoms,[3] such as nitromethane
and malonate. The use of carbon pronucleophiles bearing
weakly acidic hydrogen atoms (pKa in DMSO > 35) in the
Brønsted base catalyzed reactions has been considered to be
challenging.[4]
Azaarenes, which are heteroaromatics that contain nitro-
gen atoms in the ring, are common motifs in alkaloid
structures. They often show interesting biological activity
and typically act through coordination of the nitrogen atoms
to the active sites of biomolecules, such as enzymes.[5] For
modification of azaarenes, not only direct introduction of
substituents on the aromatic parts[6] but also new bond
formation at the a-positions of already introduced alkyl
substituents on the aromatic rings are useful methods.[7]
However, hydrogen atoms at the a-positions are weakly
acidic and less reactive. Recently, several transition-metal-
The reaction of 4-methylpyridine (2a) with N,N-dime-
thylcinnamamide (1a) was first conducted in THF at 08C in
the presence of a catalytic amount of KHMDS (Table 1). 4-
Methylpyridine has not often been employed successfully as
À
a substrate in catalytic C C bond-forming reactions of alkyl
À
azaarenes through C H activation by using transition-metal
catalysts. Contrary to our expectation, deprotonation of the
a-hydrogen atom of 2a was sluggish, and a small amount of
the desired product 3aa was formed together with some side
products (entry 1). We then added the crown ether 18-crown-
6 to improve the efficiency of the deprotonation. It was found
that KHMDS with 18-crown-6 catalyzed the reaction effec-
tively to afford the desired product 3aa in high yield without
any side reaction (entry 2). The effect of the solvent was then
examined, and the use of THF was found to give the best
result (entries 2–5). Only KHMDS gave the desired product
3aa, and other bases, including NaHMDS and LiHMDS, did
not catalyze the reaction (entries 2 versus 6 and 7). Finally, it
was found that the 1,4-addition reaction proceeded well with
5 mol% KHMDS and 18-crown-6 by using a slight excess of
2a (1.2 equiv; entry 8).
À
catalyzed bond formations through C H bond activation at
the a-positions of alkylazaarenes have been investigated.[8,9]
À
One major strategy is oxidative activation of C H bonds by
using late-transition-metal catalysts,[8] and another approach
À
is activation of C H bonds by using either a Brønsted or
Lewis acid through formation of enamine or enamide
species.[9] However, cleavage of inert C H bonds generally
À
requires high energy, and these reactions are typically
[*] Dr. H. Suzuki, R. Igarashi, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo (Japan)
The generality of the reaction with respect to the a,b-
unsaturated amide 1 was then investigated under the opti-
mized reaction conditions. The position of the methyl group
on the terminal aromatic ring did not affect the reactivity, and
the desired product 3 was afforded in good to high yields
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611374.
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Table 1: Catalytic direct-type 1,4-addition reaction of 4-methylpyridine
(2a).[a]
gave the product 3 in similar or slightly higher yield than those
with electron-deficient groups (F, Cl, Br; entries 4–7). The use
of an a,b-unsaturated amide bearing an electron-rich hetero-
aromatic 2-furyl ring decreased the reactivity. However,
a good yield was obtained by using an increased amount of
the catalyst (entry 8). Larger aromatics, 1- and 2-naphthyl, did
not hinder the reaction, and the desired products were formed
in high yields (entries 9 and 10). Gratifyingly, a,b-unsaturated
amides with sterically hindered aliphatic tert-butyl and 2-
allylpropan-2-yl groups also reacted with 2a to afford the
product in high yield under the optimized reaction conditions
(entries 11 and 12). The a,b-unsaturated amide bearing
another N-alkyl group was also applicable (entry 13).
In our hypothesis, the acidity of the reactive hydrogen
atoms on pronucleophiles is key for efficient reactions. The
1,4-addition reaction would proceed smoothly when the pKa
value of the hydrogen atoms (in DMSO) was around 35.[4f]
Therefore, we next focused on reactions using other alkyla-
zaarenes bearing weakly acidic a-hydrogen atoms as good
pronucleophiles (Table 3). 2-Methylpyridine (2b) reacted less
readily than 4-methylpyridine (2a) to afford the product 3ab,
however, a high yield was obtained when a higher catalyst
loading (20 mol%) was used. A related compound, 2,6-
dimethylpyridine (2c), reacted with 1a to afford 3ac under
similar reaction conditions. We then focused on regioselective
Entry
MHMDS
Crown ether
Solvent
Yield [%]
1[b]
2
3
4
5
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
LiHMDS
KHMDS
–
THF
THF
CPME
TBME
toluene
THF
8[c]
96
20
40
17
n.r.
n.r.
96
18-crown-6
18-crown-6
18-crown-6
18-crown-6
15-crown-5
12-crown-4
18-crown-6
6
7
THF
THF
8[d]
[a] The reaction of 1a (0.40 mmol) with 2a (0.80 mmol) was performed
in a solvent (0.2m) at 08C for 3 h in the presence of a base catalyst
prepared from MHMDS (5 mol%) and the crown ether (5.5 mol%)
under an Ar atmosphere unless otherwise noted. n.r.=no reaction,
HMDS=hexamethyldisilazide, THF=tetrahydrofuran, CPME=cyclo-
pentyl methyl ether, TBME=tert-butyl methyl ether. [b] 4-Methylpyridine
(4.0 equiv) was used. [c] Yield based on 1H NMR spectroscopic analysis.
[d] 4-Methylpyridine (1.2 equiv) was used. The concentration of the
reaction was 0.4 M.
Table 3: Substrate scope with respect to alkylazaarene 2.[a]
(Table 2, entries 1–3). The electronic nature of the substitu-
ents on the aromatic ring of the a,b-unsaturated amide had
some effects, and amides with an electron-rich methoxy group
Table 2: Substrate scope of the reaction with respect to a,b-unsaturated
amide 1.[a]
Entry
R1
3
Yield [%]
1
2
3
4
5
o-MeC6H4 (1b)
m-MeC6H4 (1c)
p-MeC6H4 (1d)
p-MeOC6H4 (1e)
p-FC6H4 (1 f)
p-ClC6H4 (1g)
p-BrC6H4 (1h)
2-Furyl (1i)
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
quant.
80
89
98
quant.
61
85
75
91
95
6
7
8[b]
9
1-Naphthyl (1j)
2-Naphthyl (1k)
tBu (1l)
10[b,c]
11
12
13
80
64
86
2-Allylpropan-2-yl (1m)
Ph (1n)[d]
[a] The reaction of 1a (0.40 mmol) with 2 (0.48 mmol) was performed in
THF (0.4m) at 08C for 18 h in the presence of KHMDS (10 mol%) and
18-crown-6 ether (11 mol%) under Ar atmosphere unless otherwise
noted. [b] The compound 2 (2.0 equiv), KHMDS (20 mol%), and 18-
crown-6 (22 mol%) were used. [c] The reaction was conducted for 20 h.
[d] KHMDS (5 mol%) and 18-crown-6 ether (5.5 mol%) were used, and
the reaction time was 3 h.
[a] The reaction of 1 (0.40 mmol) with 2a (0.48 mmol) was performed in
THF (0.4m) at 08C for 3 h in the presence of KHMDS (5 mol%) and 18-
crown-6 ether (5.5 mol%) under an Ar atmosphere unless otherwise
noted. [b] The reaction was conducted with 10 mol% of KHMDS and
11 mol% of 18-crown-6 ether for 18 h. [c] The concentration was 0.13 M.
[d] N-Cinnamoylpyrrolidine (1n) was used as an electrophile.
2
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1,4-addition reactions of di- and trialkylpyridines. Given that
the acidity of the a-hydrogen atom at the para-methyl group
of 2a is higher than that at the ortho-methyl group of 2b,[13] we
anticipated that the acidity difference of the a-hydrogen
atoms between the para- and ortho-positions would make
regioselective reactions possible. As we expected, both 2,4-
dimethylpyridine (2d) and 2,4,6-trimethylpyridine (2e)
reacted selectively at the para-position to afford 3ad and
3ae, respectively. To our knowledge, these are the first
À
examples of highly para-selective catalytic C C bond-forma-
tion reactions using alkylazaarenes.[9c,f,m] When 4-ethylpyri-
dine (2 f) was used as a pronucleophile, the desired product
3af was obtained in high yield with good diastereoselectivity.
Other alkylazaarenes were then surveyed (Table 3). 2-
Methylpyrazine (2g) showed similar reactivity to that of 2b,
and the desired product 3ag was obtained in high yield by
using an increased amount of catalyst. The methylquinolines
2h and 2i, and 1-methylisoquinoline (2j) were also good
pronucleophiles, and the desired products 3ah, 3ai, and 3aj
were obtained in high yields with 5 or 10 mol% catalyst
loading, even when the methyl group was positioned at the
ortho-position relative to the nitrogen atom. The KHMDS/
crown ether catalyst system was applicable not only to
pyridine-type pronucleophiles but also to oxazole-, thiazole-,
and imidazole-type compounds. Although 2-methylbenzoxa-
zole (2k) showed low reactivity to afford 3ak, substrates 2-
methylbenzothiazole (2l), 2-methyl-4-phenylthiazole (2m),
and 1,2-dimethylbenzimidazole (2n) reacted with 1a well to
afford the desired products 3al, 3am, and 3an, respectively, in
high yields. Notably, a wide substrate scope with respect to the
alkylazaarenes was demonstrated in the catalytic 1,4-addition
reactions.
Scheme 2. Transformation into a biologically active compound.
Scheme 3. Preliminary investigation of catalytic asymmetric 1,4-addi-
tion reactions of alkylazaarenes. M.S.=molecular sieves.
Not only a,b-unsaturated amides but also an a,b-unsatu-
rated ester was successfully employed (Scheme 1). The 1,4-
addition reaction of 2i with tert-butyl cinnamate (1o) gave the
desired product in good yield.
effective asymmetric environment around the potassium
cation of KHMDS. We have also shown that catalytic
asymmetric direct-type 1,4-addition reactions of simple
amides, promoted by K/34-C-10, can be achieved with high
enantioselectivities.[4c] The catalytic asymmetric 1,4-addition
reactions of 2j were conducted by using KHMDS and 34-C-
10, and the desired products were obtained with good to high
enantioselectivities. Those results suggest that catalytic asym-
metric 1,4-addition reactions of alkylazaarenes were possible
under the base-catalyzed reaction conditions. This reaction is
the first example of catalytic asymmetric 1,4-addition reaction
of non-activated alkylazaarenes with a,b-unsaturated
amides.[16–18] Further improvement of the enantioselectivity
is ongoing.
Scheme 1. The catalytic 1,4-addition reaction with a,b-unsaturated
ester.
4-Heterocyclic-3-arylbutanoic acids are key structures of
allosteric protein kinase modulators.[14] The current catalytic
1,4-addition reaction can provide the main framework of 4-
heterocyclic-3-arylbutanoic acids in two steps. As an example,
4-(2-benzothiazolyl)-3-(4-chlorophenyl)butanoic acid (4gl)
was synthesized (Scheme 2). The desired 1,4-addition reac-
tion proceeded under the optimized reaction conditions, and
subsequent hydrolysis afforded the desired compound 4gl in
good yield.
Finally, a preliminary investigation on asymmetric var-
iants of this reaction was conducted (Scheme 3).[15] We have
already reported that a chiral macrocyclic crown ether,
binaphtho-34-crown-10 (34-C-10), could be used to form an
Acknowledgments
This work was partially supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promotion of
Science (JSPS), the Global COE Program, the University of
Tokyo, MEXT, Japan, and the Japan Science and Technology
Agency (JST). H.S. thanks the MERIT program in the
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University of Tokyo and acknowledges a JSPS Research
Fellowship for Young Scientists for financial support.
Conflict of interest
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Keywords: anions · arenes · Brønsted bases ·
crown compounds · 1,4-addition
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4
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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Angewandte
Communications
Chemie
e) M. Meazza, V. Ceban, M. B. Pitak, S. J. Coles, R. Rios, Chem.
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Manuscript received: November 20, 2016
Revised: February 1, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heteroarenes
H. Suzuki, R. Igarashi, Y. Yamashita,
S. Kobayashi*
&&&& — &&&&
Catalytic Direct-type 1,4-Addition
Reactions of Alkylazaarenes
Going strong: A strong Brønsted base
catalyzes 1,4-addition reactions of alkyla-
zaarenes for the first time. The desired
reactions with a,b-unsaturated amides
proceed under mild reaction conditions
to afford the 1,4-adducts in high yields.
KHMDS=potassium hexamethyldisila-
zide, THF=tetrahydrofuran.
6
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!