Catalytic addition reactions of alkylazaarenes to vinylsilanes

Article abstract of DOI:10.1246/cl.180132

Strong Br?nsted-base-catalyzed addition reactions of alkylazaarenes with vinylsilanes are reported. The reactions of alkylpyridines and their analogues with vinylsilanes proceed in moderate to high yields in the presence of catalytic amounts of LiTMP, LiCl, and MS 4?. This is a general method that can be applied to catalytic addition reactions of alkylazaarenes with vinylsilanes.

Full text of DOI:10.1246/cl.180132

Advance Publication Cover Page
Catalytic Addition Reactions of Alkylazaarenes to Vinylsilanes
Yasuhiro Yamashita, Kodai Minami, and Shū Kobayashi*
Advance Publication on the web March 17, 2018
doi:10.1246/cl.180132
© 2018 The Chemical Society of Japan
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1
Catalytic Addition Reactions of Alkylazaarenes to Vinylsilanes
Yasuhiro Yamashita,1 Kodai Minami 1 and Shū Kobayashi*1
1Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Strong Brønsted-base-catalyzed addition reactions of
1
2
3
4
5
6
7
8
9
nucleophiles at their b-positions more easily than alkyl-
substituted alkenes. Catalytic addition reactions of a
vinylsilane with alkylpyridines were reported by Pines et al.
in 1969;8,9 however, sodium or potassium metal was
employed in these reactions, and a significant amount of
byproduct formed under the conditions. General catalytic
addition reactions of alkylpyridines to vinylsilanes have not
yet been established.10 Here, we report the results of our
studies on the catalytic addition reactions of alkylazaarenes
alkylazaarenes with vinylsilanes are reported. The reactions
of alkylpyridines and their analogues with vinylsilanes
proceed in moderate to high yields in the presence of catalytic
amounts of LiTMP, LiCl, and MS 4Å. This is a general
method that can be applied to catalytic addition reactions of
alkylazaarenes with vinylsilanes.
1
Keywords: Strong base, Alkylazaarene, Vinylsilane
10 to vinylsilanes under strongly basic catalyst conditions.11
1
2
3
4
5
6
7
8
9
Azaarenes are one of the most common structural motifs
in natural products and biologically active compounds,
pharmaceuticals, agrochemicals, etc.1 Accordingly, efficient
methods for functionalization of azaarenes are extremely
important in organic synthesis, and various kinds of reactions
have been reported. Among the large number of azaarenes,
pyridine derivatives are the most common family and the
most widely exploited.2 Introduction of carbon units to the a-
positions of alkylazaarenes is a useful method to obtain
1
2
3
4
5
6
1
1
We first investigated the catalytic addition reaction of 4-
ethylpyridine (2a) with triphenylvinylsilane (1a) in the
presence of 10 mol% potassium hexamethyldisilazide
(KHMDS) in diethyl ether (Et2O) at 0 °C (Table 1). Whereas
the reaction proceeded sluggishly when only KHMDS was
used (entry 1), the desired product 3aa was obtained in 61%
Table 1. Optimization of the reaction conditionsa
10 functionalized azaarene derivatives. Catalytic carbon–carbon
11 bond-forming reactions at the a-position of alkylazaarenes
12 have already been investigated.3 However, most of the
13 catalytic reactions require transition-metal catalysts and high
14 reaction temperature; furthermore, the reaction position is
15 limited to the ortho-benzylic C–H bond. Therefore, general
16 methods to functionalize alkylazaarenes at their benzylic
17 positions under mild reaction conditions are highly desired.
Base
catalysts
N
N
Ph3Si
+
Ph3Si
1a
3aa
2a (1.2 eq.)
N
Ph3Si
2
4aa
1
1
2
3
4
5
6
7
8
9
Brønsted-base-catalyzed carbon–carbon bond-forming
reactions are fundamental and traditional methods in
synthetic organic chemistry. The reactions proceed under
proton transfer conditions, and they are regarded as an ideal
chemical process from an atom economy perspective.
However, use of weakly acidic carbon pronucleophiles (pKa
>30 in DMSO) in the Brønsted-base-catalyzed reactions
remains limited. Our group recently reported strong
Brønsted-base-catalyzed carbon–carbon bond-forming
Entry Metal amide
(mol%)
Additive
(mol%)
–
Solvent
Yield
(%)b
3
1
2
KHMDS (10)
Et2O
Et2O
KHMDS (10) 18-crown-6
61c
(11)
–
–
–
–
3
4
5
6
7
8
9
10
LiTMP (10)
LDA (10)
Et2O
Et2O
Et2O
63
59
0
60
57
52
84
quant.
(98)d
68
10 reactions of weakly acidic carbonyl and related compounds
11 as carbon pronucleophiles, where catalytic Mannich-type
12 reactions and 1,4-addition reactions proceeded in high yields
13 with good to high stereoselctivities.4 Furthermore, quite
14 recently we found that catalytic 1,4-addition reactions of
15 alkylazaarenes proceeded smoothly in a similar fashion.5
16 Indeed, although a-hydrogen atoms of alkylazaarenes are not
17 acidic (the hydrogen atom of 4-methylpyridine has pKa 35 in
18 DMSO),6 the reactions proceeded well. On the other hand,
19 however, available electrophiles in the system were limited
20 to only N-arylimines and a,b-unsaturated carbonyl
21 compounds, and expansion of available electrophiles is
22 highly desired. Vinylsilanes are stable substituted alkenes,
23 and the silyl groups can be converted into several functional
24 groups.7 The silyl groups are also known to stabilize anions
25 formed at their a-positions; therefore, vinylsilanes can accept
LiHMDS (10)
LiTMP (10)
LiTMP (10)
LiTMP (10)
LiTMP (10)
LiTMP (10)
THF
–
–
CPME
toluene
Et2O
LiCl (10)
LiCl (10),
MS 4Å
MS 4Å
LiCl (5),
MS 4Å
Et2O
11
12
LiTMP (10)
LiTMP (5)
Et2O
Et2O
79
a
1
2
3
4
5
1
The reaction of 1 (0.30 mmol) with 2 (0.36 mmol) was
performed in 0.6 M at 0 °C for 18 h under Ar atmosphere unless
otherwise noted. The yield was determined by 1H NMR
b
analysis using durene as internal standard. c Double adduct 4aa
(10%) was obtained. d Isolated yield.

2
1
2
3
4
5
6
7
8
9
yield by using KHMDS and 18-crown-6 ether; however,
undesired byproduct 4aa was obtained in a significant
amount (entry 2). On the other hand, remarkably, lithium
2,2,6,6-tetramethylpiperidide (LiTMP) was found to promote
the reaction effectively in the absence of a crown ether
without formation of 4aa (entry 3). Other lithium amides,
namely lithium diisopropylamide (LDA) and lithium
hexamethyldisilazide (LiHMDS), were also employed as
catalysts. Whereas LDA showed almost the same reactivity
60 then
examined.
The
reaction
of
2a
with
61 dimethylphenylvinylsilane (1b) proceeded in good yield
62 under heating conditions because of the low reactivity of 1b.
63 The number of phenyl groups on the silicon atom might affect
64 the stabilizing ability of the a-anion and influenced the total
65 reactivity. It was found that many alkylazaarenes could be
66 employed for the catalytic addition reactions with
67 vinylsilanes in the presence of the LiTMP catalyst system.
68
69
70
Table 2. Scope of the reaction with respect to alkylazaarenes
10 (entry 4), LiHMDS did not catalyze the reaction at all because
11 of its lower Brønsted basicity (entry 5). The effect of solvents
12 was then examined. Slightly lower yield was obtained when
13 a less polar solvent, toluene, was used, but the use of
14 alternative ether solvents THF and cyclopentyl methyl ether
15 (CPME) gave almost the same results as obtained with Et2O
16 (entries 6–8). Interestingly, it was found that addition of a
17 lithium salt improved the yield; thus, when 10 mol% lithium
18 chloride (LiCl) was used, an increased yield of 84% was
19 obtained (entry 9). LiCl might affect an aggregation state of
20 LiTMP to enhance its reactivity.12 Further improvement of
21 the yield was achieved by using molecular sieves 4Å (MS
22 4Å), and the desired adduct was obtained in 98% isolated
23 yield (entry 10). The combined use of LiCl and MS 4Å was
24 essential (entry 11). A good yield was also obtained when the
25 catalyst loading was decreased to 5 mol% (entry 12). It was
26 thus established that the LiTMP–LiCl–MS 4Å system
27 promoted the desired addition reaction effectively without
28 formation of byproduct 4aa.
LiTMP (10 mol%)
LiCl (10 mol%)
Ph3Si
AAr
Ph3Si
1a
R
AAr
+
Et2O (0.6 M),
MS 4A
0 oC, 18 h
R
2 (1.2 eq.)
3
N
N
N
Ph3Si
Ph3Si
Ph3Si
3ab 73%
4 eq. of 4-methylpyridine
3aa 98%
3ad 95%
3ac 89%
3af 88%
Ph3Si
Ph3Si
Ph3Si
N
N
N
C
3ae 75%
4 eq. of 2-methylpyridine,
THF, 0.3 M
(o/m = >99/1)
THF, 0.3 M, 40 o
N
N
Ph3Si
Ph3Si
N
Me
Ph3Si
N
29
The substrate scope of the addition reaction was then
3ag 88%
(o/p = 8/92)
THF, 0.3 M
3ai 43%
20 mol% of LiTMP and LiCl
3ah 94%
30 examined (Table 2). When 4-methylpyridine (2b, 4-picoline)
31 was used as azaarene instead of 4-ethylpyridine, the desired
32 reaction proceeded, but formation of the double adduct was
33 observed. A good yield of the product 3ab was obtained when
34 4 equivalents of the pyridine 2b was used to suppress the side
35 reaction. 4-Propylpyridine (2c) also worked well to afford
36 3ac in high yield. Next, 2-alkylpyridines were examined as
37 pronucleophiles. When 2-ethylpyridine (2d) was employed,
38 the reaction proceeded in high yield to afford the product 3ad.
39 In the reaction of 2-methylpyridine (2e), the use of 4
40 equivalents of 2e was also effective to suppress byproduct
41 formation, and the desired product 3ae was obtained in good
42 yield. Regioselective reactions were then investigated. When
43 2,3-dimethylpyridine (2f) was used as pronucleophile, the
44 desired reaction proceeded only at the 2-methyl group to
45 afford 3af in high yield. The selectivity could be explained
46 based on much more acidic nature of an a-hydrogen atom of
47 the 2-methyl group than that of the 3-methyl group due to
48 different stabilization pattern of the formed anion via
49 delocalization after deprotonation. Furthermore, when 2,4-
50 dimethylpyridine 2g was used, the reaction proceeded with
51 high regioselectivity at the 4-position to afford the product
52 3ag. That is also because a-hydrogen atom of the 4-methyl
53 group could be more acidic than that of 2-methyl group.13
54 Other types of alkylazaarenes were then employed. 2-Ethyl-
55 1-methylimidazole (2h) reacted with 1a to afford the product
56 3ah in high yield. When 1-methylisoquinoline (2i) and 2-
57 ethylquinoline (2j) were used, the reactivities were decreased
58 in both cases, and the desired products 3ai and 3aj were
59 obtained in moderate to good yields. Other vinylsilanes were
CPME, 60 oC, 48 h
N
Ph3Si
PhMe2Si
N
3aj 78%
20 mol% of LiTMP and LiCl
CPME, 60 o
3ba 75%
20 mol% of LiTMP and LiCl
CPME, 60 oC, 48 h
C
71
72
73
The obtained productwasconvertedinto alcohol 5aa under
74 oxidative conditions (Scheme 1). By treating 3aa with
75 tetrabutylammonium fluoride (TBAF) and subsequently with
76 KF and H2O2, the silyl group was oxidized to afford 5aa in
77 high yield. The pyridine nitrogen atom was not oxidized
78 under the reaction conditions.
79
1) TBAF (5 eq.)
THF, reflux, 3 h
SiPh3
OH
2) KF (2 eq.)
H2O2 (3 eq.)
NaHCO3 (1 eq.)
THF, reflux, 3 h
N
N
5aa
94%
3aa
80
81
82
83
Scheme 1 Transformation of 3aa
In conclusion, strong Brønsted-base-catalyzed addition
84 reactions of alkyl azaarenes with vinylsilanes were developed.
85 The reactions of alkylpyridines and their analogues with
86 vinylsilanes proceeded in moderate to high yields in the
87 presence of catalytic amounts of LiTMP, LiCl, and MS 4Å.
88 This is a general method to perform catalytic addition
89 reactions of alkylazaarenes with vinylsilanes. The

3
66
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73
74
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77
78
79
80
81
82
83
84
85
86
87
88
89
90
6
7
The pKa values are shown in Bordwell pKa table
(http://www.chem.wisc.edu/areas/reich/pkatable/). See also: F. G.
Bordwell, Acc. Chem. Res. 1988, 21, 456-463.
1
2
3
4
5
6
7
8
9
triphenylsilyl group was successfully converted into a
hydroxyl group under oxidative conditions without any effect
on the pyridine nitrogen atom. Further studies on reactions
with other alkenyl compounds as well as asymmetric
catalysis are ongoing.
This work was partially supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promotion
of Science (JSPS) and Ministry of Education, Culture, Sports,
Science and Technology (MEXT), and the Japan Science and
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10 Technology Agency (JST).
11
12 Supporting
8
9
Information
is
available
on
13 http://dx.doi.org/10.1246/cl.
14 References and Notes
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91 10
92
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95 11
96
Presented at the 98th Annual Meeting of the Chemical Society of
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The acidity difference between 2-methyl and 4-methylpyridine
can be anticipated by the reported pKa values of 2-benzylpyridine
(28.2 in DMSO) and 4-benzylpyridine (26.7 in DMSO). The pKa
97 12
98
99
100 13
101
102
103
values
are
shown
in
Bordwell’s
pKa
table
104
(http://www.chem.wisc.edu/areas/reich/ pkatable/). See also: a) F.
G. Bordwell Acc. Chem. Res. 1988, 21, 456. Related information,
see b) H. Pines, N. E. Sartoris, J. Org. Chem. 1969, 34, 2113, and
ref. 5.
105
106
107
108
4
5
H. Suzuki, R. Igarashi, Y. Yamashita, S. Kobayashi, Angew. Chem.
Int. Ed. 2017, 56, 4520.