Alkyl lithium-catalyzed benzylic C-H bond addition of alkyl pyridines to α-alkenes

Article abstract of DOI:10.1039/d0ob01499k

Br?nsted base catalyzed C-C bond formation reactions have been extensively utilized as reliable, efficient, and atom economical methods in organic synthesis. However, the electrophiles were mostly limited to polar ones such as imines, carbonyl compounds,

Full text of DOI:10.1039/d0ob01499k

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DOI: 10.1039/D0OB01499K
COMMUNICATION
Alkyl Lithium-Catalyzed Benzylic C–H Bond Addition of Alkyl
Pyridines to α-Alkenes
Yan-Long Luo,a Yu-Feng Liua and Bing-Tao Guan*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A
Deprotonation and functionalization of alkyl pyridines
Brønsted base catalyzed C–C bond formation reactions have been
extensively utilized as reliable, efficient, and atom economical
methods in organic synthesis. However, the electrophiles were
mostly limited to polar ones such as imines, carbonyl compounds,
α, β-unsaturated compounds, styrenes and conjugated dienes. The
use of α-alkenes as electrophiles in C–C bond formation reaction
always needs transition metal catalysts. Herein, we reported an
alkyl lithium-catalyzed benzylic C–H bond addition of alkyl
pyridines to α-alkenes. The alkyl lithium catalyst displayed quite
different selectivity from the transition metal catalysts.
R
R
R
R
B-
E+
N
N
N
H
R
E
B
Early transition metal catalyzed functionalization of alkyl pyridines
R
R'
N
R1
R2
cationic
Y, Hf, Zr catalysts
R'
N
R1
R2
H
+
C
D
Potassium amide catalyzed alkylation of alkyl pyridines with styrenes
R
An alkyl pyridine motif exists widely and behaves importantly in
many natural products, pharmaceuticals, ligands, and functional
materials.1 In various approaches to the alkyl pyridines synthesis, the
benzylic C–H bond functionalization reaction is the most frequently
used method. The deprotonation of an alkyl pyridine with a strong
base could easily afford a benzylic anion, which could successfully
undergo the substitution or addition reactions with a series of
electrophiles such as halides,2,3 carbonyl groups,1,4 imines5 and α, β-
unsaturated carbonyl compounds (Scheme 1A).6 Using Lewis acid
catalysts or transition metal catalysts, the catalytic alkylation of alkyl
pyridines could be achieved but mostly with highly reactive imines
and enones.5, 6e It was not until the early transition metal complexes
got involved as catalysts that the scope of electrophiles was greatly
extended to simple alkenes and alkynes (Scheme 1B).7 Hou and co-
workers reported the catalytic addition of benzylic C–H bonds of alkyl
pyridines to various alkenes with cationic yttrium catalysts.7b,c Yao
and co-workers later reported the similar alkylation reactions with
cationic zirconium catalyst.7d,e Mashima and co-workers reported
the coupling of 2,6-lutidine with internal alkynes catalyzed by
alkylhafnium complexes.7f,g However, the early transition metal
N
N
KHMDS catalyst
Ar
H
Ar
+
styrenes
this work)
Alkyl lithium-catalyzed alkylation of alkyl pyridines with -alkenes (
R
R
H
N
H
N
R1
LiCH2TMS catalyst
R1
H
+
-alkenes
Scheme 1 C–H Functionalization of Alkyl pyridines.
were inhibited, the benzylic C–H bonds underwent the catalytic
alkylation reactions.8
Brønsted base catalyzed C–C bond formation reactions had
been widely used in organic synthesis for their reliability,
efficiency, and atom economy.9 With the great efforts from
Kobayashi, Walsh and Schneider groups, the pronucleophiles
scope was greatly extended from carbonyl compounds to alkyl
pyridines and even toluenes.10 The electrophiles, however,
were mainly limited to imines, α, β-unsaturated amides,
styrenes and conjugated dienes. Actually as early as 1956, Pines
and co-workers reported the alkylation of alkyl pyridines with
alkenes using metal sodium or potassium as catalysts.11 The
alkylation reactions of picoline with ethylene and propene were
carried out under harsh conditions, giving the products in low
yields and in poor selectivity from the multi-alkylation
reactions.11a-c We recently reported the catalytic alkylation of
alkyl pyridines with styrenes by using potassium amide as
catalyst (Scheme 1C).12 Herein, we report the alkyl lithium-
catalyzed benzylic alkylation of alkyl pyridines with α-alkenes
(Scheme 1D).
catalysts prefers the alkylation of the ortho-pyridyl C–H bond rather
than the benzylic ones. Thus, only if the ortho-pyridyl C–H bonds
aState Key Laboratory and Institute of Element-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 30071, China.
bDepartment of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438,
China
E-mail: bguan@fudan.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
Table 1 Catalytic Alkylation of 2-Methylpyridine with 1-Octene.a
N
CH3
N
R
LiCH2TMS (30 mol%)
View Article Online
+
R
DOI: 10.1039/D0OB01499K
CH3
TMEDA, THF
125 °C, 48 h
N
CH3
N
C6H13
CH3
catalyst (10 mol%)
2
1a
3
+
C6H13
2a
additive, 100 °C, 24 h
Ph
1a
3aa
N
C5H11
N
C8H17
CH3
70%
N
C10H21
CH3
70%
N
entry
1
catalyst
LDA
additive
Et2O
3aa yield (%)b
CH3
CH3
3ae
78%
9
3ab
3ac
3ad
58%
2
LiTMP
LiHMDS
NaDA
KDA
Et2O
9
N
N
N
3
Et2O
NR
NR
NR
10
3
3
+
CH3
CH3
4
Et2O
3ag
3ag'
a
b
3af
3ag 3ag'
91%
55% (
/
= 1 / 3)
5
Et2O
H3C
6
n-BuLi / hexane Et2O
N
N
N
7
LiCH2TMS
LiCH2TMS
LiCH2TMS
LiCH2TMS
LiCH2TMS
LiCH2TMS
Et2O
17
5
5
+
CH3
30%a,c (12:1, d.r.)b
CH3
CH3
8
––
11
3ah
3ah'
b
3ai
3ah / 3ah'
57% (
= 4.6 / 1)
9
19
THF
Scheme 2 Substrate Scope of Alkenes. Conditions: 2-methylpyridine
(1a) (1.0 mmol), alkenes (2) (7.0 mmol), LiCH2TMS (30 mol%), THF
(0.2 mL), TMEDA (0.2 mL), 125 °C, 48 h, isolated yields are based on
the amount of (1a). aTHF (0.2 mL), 100 °C, 48 h. bRatios determined
by 1H NMR. c47% yield with 50 mol% of LiCH2TMS.
10
11
12
25
THF + TMEDA
THF + TMEDA
THF + TMEDA
29c
81 (76)d
aConditions: 2-methylpyridine (1a) (0.5 mmol), 1-octene (2a) (1.0
mmol), catalyst (10 mol%), additive (0.1 mL), 100 °C, 24 h. bNMR
reaction but failed to provide any alkylation product. For the
yields based on 2-methylpyridine with 2-methoxynaphthalene as an dienes such as 1,7-octadiene and 1,9-decadiene, only one of the
internal standard, isolated yield in parenthesis. cLiCH2TMS (20 mol%).
two double bonds reacted with 2-methylpyridine to afforded
pyridine substituted alkenes (3ag and 3ah), accompanying with
their alkene isomerization products (3ag’ and 3ah’). In the case
of 1,5-hexadiene, however, both of the double bonds
underwent the alkylation reaction with the benzylic C–H bonds
to form a substituted cyclopentane product 3ai in a low yield of
30% (see Supporting Information). Quite different from the
scandium catalyzed continuous insertion reaction of 1,5-
hexadiene,13 the alkyl lithium catalyst achieved twice alkylation
at the same benzylic position, revealing that there was an
intramolecular deprotonation before the insertion of the
second double bond. We carried out this reaction further with
50 mol% of LiCH2TMS, and got the cyclopentane product in 47%
yield, suggesting a stoichiometric reaction based on the alkyl
lithium reagent. A possible reason for the change from the
catalytic reactions to this stoichiometric one is the tertiary
lithium intermediate, which is crowd enough to prevent the
coordination and deprotonation with another 2-
methylpyridine.
Beside 2-methylpyridine, some other alkyl pyridines including
2-ethylpyridine, 2-propylpyridine, 2-pentylpyridine and 2-(3-
phenylpropyl)pyridine were also allowed to react with 1-
octene. With the increase of the steric hindrance at the benzylic
position, the alkyl pyridine products bearing a tertiary alkyl
group were isolated in moderate to low yields (Scheme 3, 3ba-
3ea). Multi-substituted 2-methylpyridines such as 2,3-
dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine,
5-ethyl-2-methylpyridine, 2-methyl-5-phenylpyridine and 2-
methyl-6-phenylpyridine were also subjected into the catalytic
alkylation reactions and the alkylation products were obtained
in good to high yields (3fa-3ka). 2,6-Dimethylpyridine and 2,4,6-
trimethylpyridine smoothly reacted with 1-octene to give the
alkylation products in 45% and 36% yields (3la and 3ma), along
with some 2,6-dialkylation by-products (3la’ and 3ma’, see
dLiCH2TMS (30 mol%), 1-octene (2a) (3.5 mmol), 125 °C, 48 h.
We firstly carried out the reaction between 2-methylpyridine
and 1-octene at 100 °C with lithium amides as catalysts and Et2O
as additive (Table 1, entries 1-3). Lithium diisopropylamide
(LDA) and lithium 2,2,6,6-tetramethylpiperidine (LiTMP), 24
hours later, afforded the alkylation product 3aa in 9% yields,
suggesting a stoichiometric reaction of the lithium amides
rather than a catalytic one. Sodium and potassium amides as
catalysts were tested in the reaction but failed to give any
alkylation product (entries 4 and 5). Alkyl lithium compounds
were also subjected into the reaction as catalysts (entries 6 and
7); to our delight, LiCH2TMS achieved the alkylation reaction
catalytically even though the turn over number is pretty low
(entry 7, 17% yield). The reaction in absence of the additive
Et2O, however, gave the alkylation product in a lower yield of
11% (entry 8). THF as additive under the same conditions
resulted in a yield of 19% (entry 9). The further addition of
TMEDA as another additive gave an even better yield of 25%
(entry 10). Under the enhanced conditions of more catalyst and
1-octene, higher temperature and longer reaction time, we
could finally complete the catalytic alkylation of 2-
methylpyridine and get the product in a good yield of 81%
(entry 12).
With the optimized conditions in hand, we next evaluated the
scope of alkenes in the alkyl lithium-catalyzed alkylation of 2-
picoline (Scheme 2). Olefins such as 1-heptylene, 1-decene, 1-
laurylene and 4-phenyl-1-butene reacted smoothly with 2-
methylpyridine, and afforded the corresponding alkylation
products in good yields (3ab-3ae). Norbornene exhibited high
activity and gave the alkylation product in 91% yield (3af).
Cyclopentene and cyclohexene were also subjected into the
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
R3
(0.63 H) (0.76 H) (0.63 H)
CD3
N
(0.76 H)
D
D
View Article Online
Hex
DOI: 10.1039/D0OB01499K
H
N
CD3
D
N
D
N
N
CH3
LiCH2TMS (20 mol%)
1-octene
THF, 100 °C, 5 h
R3
LiCH2TMS (30 mol%)
+
R2
R2
(eq 1)
+
C6H13
2a
CH2D
C6H13
TMEDA, THF
125 °C, 48 h
Ph
Ph
Ph
1k-d
1k-d' 82%
3ka-d 10%
1
3
Me
Et
Bu
Ph
N
N
CH3
N
Hex
CH3
1a-Li
(30 mol%)
N
Me
N
Me
C6H13
N
Me
N
Me
(eq 2)
+
Hex
THF, TMEDA
125 °C, 48 h
C6H13
65% (1:1.1, d.r.)
C6H13
C6H13
1a
3aa
72%
a
a
a
a
3ba
3ca
3da
3ea
35% (1:1, d.r.)
40% (1:1, d.r.)
45% (1:1, d.r.)
1) LiCH2TMS (1 equiv.)
1-octene, TMEDA
THF, 100 °C, 12 h
Et
Et
N
Me
N
Me
N
Me
N
Me
CH3
N
CH3
N
C6H13
C6H13
C6H13
C6H13
(eq 3)
3aa
+
+
Me
Me
Et
Hex
2) EtI (2 equiv.), rt, 12h
Me
N
3fa
3ga
3ha
3ia
92%
86%
86%
87%
24%
1a
3ca
23% (1.6:1, d.r.)
1c
48%
Ph
N
Me
Me Me
C6H13
N
Me Me
C6H13
N
Me
Scheme 4 Control Experiments.
C6H13
C6H13
Li
Ph
Li
b
c
3ja
3ka
3la
3ma
36%
Me
54%
80%
45%
H
N
CH3
H
N
N
CH3
CH2
LiCH2TMS
SiMe4
Scheme 3 Substrate Scope of Alkyl pyridines. Conditions: alkyl
pyridines (1) (1.0 mmol), 1-octene (2a) (7.0 mmol), LiCH2TMS (30 mol
% of 1), THF (0.2 mL), TMEDA (0.2 mL), 125 °C, 48 h, isolated yields
based on the amount of alkyl pyridines. aDetermined by GC analysis.
1a
1a-Li
1a-Li'
3aa
C6H13
2a
bDialkylation product 3la’ was obtained in 33% yield. Dialkylation
c
1a
C6H13
Li
Li
N
product 3ma’ was obtained in 47% yield.
N
Supporting Information). It is worthy to note that this
transformation displayed good selectivity: only the 2-methyl
groups undergo the C–H bond alkylation reaction. The 4-methyl
group of the alkyl pyridine, which has even more acidic C–H
bonds, was inert in the catalytic alkylation reaction. These
results suggested that the coordination between the nitrogen
atom and the lithium catalyst is crucial for the addition
(insertion) reaction with alkenes.
C6H13
3aa-Li'
3aa-Li
Scheme 5 A Plausible Reaction Pathway.
The deprotonation of 2-methylpyridine with alkyl lithium
catalyst takes place easily to afford the benzylic lithium
intermediate 1a-Li. Although there is an equilibrium between
benzylic lithium species (1a-Li) and pyridyl lithium species (1a-
Li’), only the former slowly undergoes the following addition to
1-octene to generate a new alkyl lithium intermediate (3aa-Li).
This intermediate quickly goes through an intramolecular
deprotonation reaction to afford a more stable benzylic lithium
intermediate 3aa-Li′, which would further undergo the
deprotonation equilibrium with another 2-methylpyridine to
give the alkylation product and regenerate the benzylic lithium
species.
In the reaction of deuterated 2-methyl-5-phenylpyridine (1k-
d) with 1-octene, the H–D exchange between the benzylic C–D
bond and the ortho-pyridyl C–H bond was observed (Scheme 4,
eq 1), suggesting there is an equilibrium between benzylic metal
species and pyridyl metal species, similarly with the cationic
early transition metal complexes.8c,e However, distinct from the
early transition metal catalysts, alkyl lithium catalyst prefers the
alkylation of the benzylic C–H bond rather than the ortho-
pyridyl C–H bond of the alkyl pyridine. The similar deuterium
distribution (ortho-pyridyl position: 0.63H; benzylic position:
0.76H) of the alkylation product 3ka-d and recovered reactant
1k-d’ revealed the fast equilibrium between the reactant and
the product. To further explore the reaction mechanism, we
carried out the direct deprotonation of 2-methylpyridine with
n-BuLi in diethyl ether at -20 ˚C to prepare the intermediate 2-
picolyllithium (1a-Li), which was reported to exist in a dimer
structure in its solid state.14 2-Picolyllithium can efficiently
catalyze the alkylation reaction, suggesting that 2-picolyllithium
intermediate is possibly involved in the catalytic cycle (Scheme
4, eq 2). The in-situ quenching of a reaction with iodoethane
gave the ethylation products at the benzylic position of both the
reactant and product (Scheme 4, eq 3), suggesting that the two
benzylic lithium intermediates exist as the privilege species in
the catalytic cycle.
Conclusions
In summary, we for the first time achieved the alkyl lithium-
catalyzed benzylic C–H bond addition of alkyl pyridines to α-
alkenes. The alkyl lithium catalyst displayed quite different
selectivity with early transition metal catalysts in the selective
benzylic C–H bond alkylation of 2-alkyl pyridine as well as the
reaction with 1,5-hexadiene. Considering the easy availability
and good selectivity of the alkyl lithium catalyst, this method
could provide a practical approach for synthesis of alkyl
pyridines.
Conflicts of interest
There are no conflicts to declare.
On the basis of these observations, we proposed a possible
process for the catalytic alkylation reaction shown in Scheme 5.
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(e) G. Luo, Y. Luo, J. Qu and Z. Hou, OrganometalVliicews,A2rt0ic1le2O,n3lin1e,
Acknowledgments
3930.
DOI: 10.1039/D0OB01499K
9 (a) I. Fleming and B. M. Trost, Comprehensive organic synthesis:
selectivity, strategy, and efficiency in modern organic chemistry,
Pergamon Press, Oxford, England, 1st ed., 1991. (b) Y. Yamashita
and S. Kobayashi, Chem. Eur. J. 2018, 24, 10.
This project was supported by the National Natural Science
Foundation of China (No. 21372123) and the National Natural
Science Foundation of Tianjin (No. 19JCYBJC20100).
10 (a) Y. Yamashita, H. Suzuki and S. Kobayashi, Org. Biomol. Chem.,
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01499K
The alkyl lithium catalyst successfully achieved the benzylic C–H bond addition of alkyl
pyridines to α-alkenes, and displayed distinct selectivity from the transition metal
catalysts.