Alkylation of pyridines at their 4-positions with styrenes plus yttrium reagent or benzyl grignard reagents

Article abstract of DOI:10.1002/chem.201404635

A new regioselective alkylation of pyridines at their 4-position was achieved with styrenes in the presence of yttrium trichloride, BuLi, and diisobutylaluminium hydride (DIBAL-H) in THF. Alternatively, similar products were more simply prepared from pyridines and benzyl Grignard reagents. These reactions are not only a useful preparation of 4-substituted pyridines but are also complementary to other relevant reactions usually giving 2-substituted pyridines.

Full text of DOI:10.1002/chem.201404635

DOI: 10.1002/chem.201404635
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Alkylation |Hot Paper|
Alkylation of Pyridines at Their 4-Positions with Styrenes plus
Yttrium Reagent or Benzyl Grignard Reagents
Tomoya Mizumori, Takeshi Hata, and Hirokazu Urabe*[a]
Abstract: A new regioselective alkylation of pyridines at
their 4-position was achieved with styrenes in the presence
of yttrium trichloride, BuLi, and diisobutylaluminium hydride
(DIBAL-H) in THF. Alternatively, similar products were more
simply prepared from pyridines and benzyl Grignard re-
agents. These reactions are not only a useful preparation of
4-substituted pyridines but are also complementary to other
relevant reactions usually giving 2-substituted pyridines.
Introduction
Pyridines are the most fundamental heterocyclic compounds
and hence important constituents for pharmaceuticals, organic
materials, and naturally occurring products.[1] Their synthetic
methods rely on traditional reactions include nucleophilic[1–6]
or radical[1,7] additions to pyridines, metalation of pyridines,[1,8]
and multicomponent coupling reactions from acyclic starting
materials.[1,9] In addition to these, new syntheses through CÀH
bond activation of pyridines have recently appeared.[10–12]
When the synthesis starts with pyridines, an issue on the regio-
selection and its selectivity for the introduction of a side chain
or a functional group arises. For example, nucleophilic addition
of organometallic reagents to pyridines takes place mostly at
their 2- or 4-positions, among which the former appears more
Scheme 1. Yttrium-mediated regioselective alkylation of pyridines with styr-
enes.
feasible, but the selectivity is often difficult to control.[1–5]
A
of 4-(1-arylethyl)pyridines 4 as shown in Scheme 1. The other
possible regioisomers 5–7 were not detected.
similar issue is also found in the alkylation of pyridines through
CÀH bond activation, in which the reaction preferentially
occurs at the 2-position of pyridines,[11,12] likely facilitated by
the initial interaction between the metal reagents and the pyri-
dine nitrogen. Thus, the highly regioselective substitution of
pyridines at the 4-position has been less frequently encoun-
tered[4,5,12] and still calls for newer, simpler, or more dependa-
ble methods using inexpensive reagents.
Table 1 shows optimization of the above reaction, using 2-
ethylpyridine (1a) and styrene (2a) as representative sub-
strates and YCl3, BuLi, and DIBAL-H as reagents under the con-
ditions shown in Equation (1). The reaction with one equiva-
lent each of these reagents gave only a trace amount of the
desired product 4a (Table 1, entry 1). Although two equivalents
of BuLi slightly increased the yield (Table 1, entry 2), the use of
further equivalents of BuLi completely inhibited the reaction
(Table 1, entry 3). Alternatively, increasing the equivalents of
DIBAL-H improved the yield to 29% (Table 1, entry 4), but fur-
ther addition did not (entry 5). The most fruitful results were
attained with the increased amount of YCl3 together with the
other reagents, affording the desired pyridine 4a in 72% yield
(Table 1, entries 6 and 7). A careful NMR spectroscopic analysis
of the crude reaction mixture did not show the presence of
other isomeric products 5–7 (Scheme 1) regarding the regiose-
lection of both pyridine and styrene. It should be noted that
the absence of YCl3 under the optimum conditions of Table 1,
entry 7 did not produce pyridine 4a at all (entry 8), clearly indi-
cating an important role of the yttrium reagent in this reaction.
Other hydrides (Table 1, entries 9 and 10) and solvents (Table 1,
entries 11–14) proved unsatisfactory.
Results and Discussion
During our studies on yttrium-mediated organic synthesis,[13,14]
we found that pyridines 1 were alkylated with styrenes 2 in
the presence of a tri-metallic reagent 3 comprising YCl3, BuLi,
and DIBAL-H (iBu2AlH), allowing the regioselective preparation
[a] T. Mizumori, Prof. Dr. T. Hata, Prof. Dr. H. Urabe
Department of Biomolecular Engineering
Graduate School of Bioscience and Biotechnology
Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho
Midori-ku, Yokohama, Kanagawa 226-8501 (Japan)
E-mail: hurabe@bio.titech.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404635.
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Table 1. Optimization of the yttrium-mediated coupling reaction.
Table 2. Preparation of 4-substituted pyridines from styrenes.
Entry
YCl3
[equiv]
BuLi
[equiv]
DIBAL-H
[equiv]
Solvent
Yield [%][a]
of 4a
1
2
4
Entry
R
Ar
Yield [%][a]
1
2
3
4
5
6
7
8
1
1
1
1
1
2
3
0
3
3
3
3
3
3
1
2
3
2
2
4
6
6
6
6
6
6
6
6
1
1
1
2
3
4
6
6
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2-MeTHF[c]
DME[c]
toluene[c]
1
8
0
1
2
3
4
5
6
7
8
9
H
Me
Et
b
c
C6H5À
a
a
a
b
c
d
e
f
b
c
a
d
e
f
g
h
i
0
56
65
64
53
45
53
61
(33)
a
a
a
a
a
a
d
29
13
38
72 (65)
0
36
0
54
7
p-MeC6H4À
m-MeC6H4À
o-MeC6H4À
p-BuC6H4À
p-tBuC6H4À
C6H5À
9
LiBEt3H[b]
PhSiH3
6
6
6
6
C6H13
a
[b]
10
11
12
13
14
1
[a] Yields of the isolated product based on 1. Yield determined by H NMR
spectroscopy using trichloroethylene as an internal standard is shown in
parentheses.
36
0
[c]
PhCF3
[a] Determined by 1H NMR spectroscopy using trichloroethylene as an in-
ternal standard. Yield of the isolated product based on 1 is in parenthe-
ses. [b] Six equivalents of this reagent used instead of DIBAL-H. [c] The re-
action was performed at 808C.
tion (5) formulates the aforementioned stoichiometry of 1a
versus 2 f+3, hence that of 1a versus active species 9.
Table 2 summarizes the results of the preparation of 4-sub-
stituted pyridines under the optimal conditions determined in
entry 7, Table 1. Although pyridine itself (1b) did not partici-
pate in the reaction (entry 1), 2-alkylpyridines 1a and 1c af-
forded the desired products 4a, c, and d–h (Table 2, entries 2–
8). As far as the styrenes are concerned, yields from methylstyr-
enes decreased in the following order: p->m->o-methylstyr-
ene (2b>2c>2d), due perhaps to the increasing steric hin-
drance around the benzylic position (Table 2, entries 4–6).
Other p-alkylstyrenes such as 2e and 2 f gave 4g and 4h in
similar yields to 4a (Table 2, entries 7 and 8). In these reactions,
the depicted 4-(1-arylethyl)pyridines 4 were always exclusively
formed. Whereas a pyridine having a higher 2-alkyl substituent
such as 1d gave the desired product 4i in a lower yield (33%,
entry 9), 2,6-dimethylpyridine (1e) no longer afforded the de-
sired product under these reaction conditions.
To propose a mechanism of this reaction, we performed the
following experiments. Treatment of pyridine 1a with the re-
agent 3 followed by deuteriochloric acid did not result in the
incorporation of deuterium to 1a, negating the initial metala-
tion to the pyridine [Eq. (3)]. Instead, when styrene 2 f was
submitted to the same sequence, ethylarene 8 of 32% deuter-
ation at its benzylic position was produced in 66% yield, the
rest being a small amount of unreacted and non-deuterated
2 f [Eq. (4)]. This observation most likely indicates the active
species in this coupling reaction to be a benzyl metal reagent
9 ([M] refers to a metal portion involving Y, Al, or Li). The mod-
erate efficiency in the generation of active species 9 (21%
from 2 f, estimated by the yield and deuteration of 8 [Eq. (4)])
should account for the fact that 2 and 3 must be used in
excess to pyridines 1 to obtain a good product yield. Equa-
Considering these observations, we propose the mechanism
of this reaction as in Scheme 2, which involves: 1) The genera-
tion of benzylmetal reagent 9’ through the hydrometalation of
2 with 3;[15] 2) The addition of 9’ to pyridine 1 at its 4-position
to give 11, and 3) the aromatization of 11 through elimination
of metal hydride species ([M]ÀH) eventually giving 4. In the
second step, activation of the pyridine through its coordina-
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tion to metallic Lewis acid-like 10 appears crucial, because in-
creasing steric hindrance around the pyridine nitrogen as
found in 2-hexyl- and 2,6-dimethylpyridines (1d and e) consid-
erably retarded the desired reaction. On the contrary, a reason
for the fact that pyridine itself (1b) did not enter the reaction
(Table 2, entry 1) may be attributable to its strong coordination
to the starting metal reagent 3, blocking the first hydrometala-
tion of styrenes. The last step (3) was separately confirmed by
the interception of the released metal hydride in the reaction
using Grignard addition (see below).
Table 3. Preparation of 4-substituted pyridines from Grignard reagents.
1
12
4
Entry
R
Ar
R2
Yield [%][a]
1
2
3
H
Me
Et
b
c
a
p-tBuC6H4À
Me
a
a
a
j
k
h
72
82
74, 64[b]
65,[c] 60[d]
4
5
6
7
8
9
10
a
a
a
a
a
d
d
C6H5À
H
Me
Pr
Me
Me
Me
Me
b
c
d
e
f
l
72
79
75
63
70
60
61
C6H5À
a
m
n
o
p
i
C6H5À
p-MeOC6H4À
m-MeOC6H4À
p-tBuC6H4À
C6H5À
C6H13
a
c
[a] Yields of the isolated products based on 1. [b] Reaction period was
12 h. [c] Compound 12 (1.5 equiv) was used and the reaction period was
24 h. [d] Compound 12 (1.0 equiv) was used and the reaction period was
24 h.
Scheme 2. A proposed reaction course.
The above mechanism and also the pharmaceutical utility of
diarylmethane derivatives such as 4, which are becoming more
and more important,[16,17] prompted us to investigate the possi-
bility of direct addition of benzyl metal species to pyridines. As
nucleophilic addition at the 2-position of pyridines is more
common than that at 4-position,[1–5] the exclusive addition of
benzylmetal species at the 4-position as shown in Scheme 2
should be synthetically quite useful.
For the benzylmetal species, we chose the convenient ones,
Grignard reagents,[1–5] and initiated the investigation, results of
which are summarized in Table 3. When 2-ethylpyridine (1a)
(1 equiv) and 1-[p-(tert-butyl)phenyl]ethylmagnesium chloride
(12a) (2 equiv) were heated at reflux in THF for 18 h (Table 3,
entry 3), the desired 4-alkylated pyridine 4h was isolated in
74% yield. A shortened reaction period or the use of less
equivalents of Grignard reagent 12a decreased the product
yield (Table 3, entry 3), thus the reaction conditions shown in
Equation (6) being optimal. Pyridine itself (1b) and 2-hexylpyri-
dine (1d) are now acceptable substrates for alkylation (see en-
tries 1 and 9 in Table 3 versus entries 1 and 9 in Table 2).
Grignard reagents 12b and 12d having a shorter or longer
alkyl side chain (R2) than methyl (12c), which could not be re-
alized in the styrene method described above and by other
groups,[12b,c] afforded the desired products 4l and m (Table 3,
entries 4 and 6). Likewise, Grignard reagents 12e and f having
a functionalized aryl group could be used equally well to give
desired products 4n and o (Table 3, entries 7 and 8).
The proposed reaction course has been already shown in
Scheme 2, involving the addition of Grignard reagents to pyri-
dines 1 at their 4-position, followed by the aromatization of 11
through elimination of a metal hydride species to give 4-alkyl-
pyridines 4. The last step was confirmed by the interception of
a metal hydride with an externally added aldehyde as shown
in Scheme 3. To a reaction of mixture of 1a and 12b, anisalde-
hyde (14) was added. After the usual workup, anisyl alcohol
(15) was detected in 31% yield based on starting pyridine 1a.
Nonetheless, it should be noted that we were unable to isolate
dihydropyridines formed by hydrolysis of 11 in Scheme 2 or 13
in Scheme 3 throughout all the experiments.
More importantly, the above transformation was found ap-
plicable to various disubstituted pyridines such as 2,3-, 2,5-,
and 2,6-lutidines (1e–g) to give desired products 4q–s in
good yields [Eqs. (7)–(9)]. The exclusive addition at the 4-posi-
tion was again uniformly observed. Thus, the Grignard method
is of wider applicability than the initial styrene-based one for
the alkylation of pyridines.
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was separated and the aqueous layer was extracted with diethyl
ether (2 mL). The combined organic extracts were washed with
water (2 mL) and brine (2 mL), dried over Na2SO4, and concentrated
in vacuo to give a crude oil, 1H NMR spectroscopic analysis of
which showed the presence of a single alkylated pyridine. The
crude oil was chromatographed on amino-silanized silica gel
(hexane) to afford the title compound (49.4 mg, 82%) as a single
regioisomer and as a colorless oil.
Acknowledgements
This work was supported in part by JSPS KAKENHI Grant Num-
bers 25288018 and 26410112.
Scheme 3. Interception of the metal hydride with aldehyde.
Keywords: alkylation
regioselectivity · yttrium
·
Grignard reagents
·
pyridine
·
Conclusion
We report a new regioselective alkylation of pyridines at their
4-position with styrenes and the yttrium-based reagent, which
was then extended to the simpler Grignard-based method.
These reactions are not only a useful preparation of 4-substi-
tuted pyridines but also complementary to other relevant reac-
tions usually giving 2-substituted pyridines. Further investiga-
tion on extension and application of this reaction is in progress
in our laboratory.
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Experimental Section
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A typical procedure for the styrene-based alkylation
2-Ethyl-4-(1-phenylethyl)pyridine (4a): nBuLi (1.13 mL, 1.60m in
hexane, 1.80 mmol) was added to a suspension of YCl3 (176 mg,
0.900 mmol) in THF (3.0 mL) at room temperature under argon.
After the mixture was stirred for 30 min to give a homogeneous
red/brown solution, DIBAL-H (1.76 mL, 1.02m in hexane,
1.80 mmol) was added at room temperature. After the stirring was
continued for 30 min at the same temperature, 2-ethylpyridine
(1a; 0.035 mL, 0.30 mmol) and styrene (2a; 0.103 mL, 0.900 mmol)
were added in this order. After the reaction mixture was stirred at
reflux for 24 h and was cooled to 08C, the reaction was terminated
by the addition of an aqueous saturated solution of potassium
sodium tartrate (10 mL). The heterogeneous mixture was stirred at
room temperature for 1 h. The organic layer was separated and
the aqueous layer was extracted twice with diethyl ether (10 mL
each). The combined organic extracts were washed with brine
(10 mL), dried over Na2SO4, and concentrated in vacuo to give
a crude oil, 1H NMR spectroscopic analysis of which showed the
presence of a single alkylated pyridine. The crude oil was chroma-
tographed on amino-silanized silica gel (hexane) to afford the title
compound (41.0 mg, 65%) as a single regioisomer and as a color-
less oil.
A typical procedure for the Grignard-based alkylation
4-[1-(4-tert-Butylphenyl)ethyl]-2-methylpyridine (4k): To a stirred
solution of [1-(p-(tert-butyl)phenyl)ethyl]magnesium chloride (12a)
(1.37 mL, 0.35m in diethyl ether, 0.480 mmol) in THF (0.48 mL) was
added 2-methylpyridine (1c) (0.024 mL, 0.24 mmol) at room tem-
perature under argon to give a homogeneous pale-yellow solution.
After the reaction mixture was stirred at reflux for 18 h, the reac-
tion was terminated by the addition of an aqueous saturated solu-
tion of NH4Cl (2 mL) and diethyl ether (2 mL). The organic layer
Chem. Eur. J. 2015, 21, 422 – 426
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3298.
Received: July 29, 2014
Published online on October 28, 2014
Chem. Eur. J. 2015, 21, 422 – 426
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