Lewis basicity modulation of N-heterocycles: A key for successful cross-metathesis

Article abstract of DOI:10.1021/ol502016h

Cross-metathesis involving N-heteroaromatic olefinic derivatives is disclosed. The introduction of an appropriate substituent on the heteroaromatic ring decreases the Lewis basicity of the nitrogen atom, thus preventing the deactivation of the ruthenium-centered catalyst. The reaction is quite general in terms of both N-heterocycles and olefinic partners.

Full text of DOI:10.1021/ol502016h

Letter
pubs.acs.org/OrgLett
Lewis Basicity Modulation of N‑Heterocycles: A Key for Successful
Cross-Metathesis
Kevin Lafaye, Lionel Nicolas, Amandine Guerinot, Sebastien Reymond, and Janine Cossy*
́
́
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231 ESPCI ParisTech, CNRS, PSL*
Research University, 10, rue Vauquelin 75231 Paris Cedex 05, France
S
* Supporting Information
ABSTRACT: Cross-metathesis involving N-heteroaromatic olefinic deriva-
tives is disclosed. The introduction of an appropriate substituent on the
heteroaromatic ring decreases the Lewis basicity of the nitrogen atom, thus
preventing the deactivation of the ruthenium-centered catalyst. The reaction
is quite general in terms of both N-heterocycles and olefinic partners.
partners which incorporated a pyrimidine as well as an
ver the past decades, metathesis reactions have emerged
Oas a powerful tool for the construction of C−C double imidazole group.
The cross-metathesis between the C3-monosubstituted
bonds and is now used for the synthesis of a wide array of
compounds such as polymers, petrochemicals, pharmaceuticals,
and natural products.1 The development of well-defined
ruthenium carbene complexes has allowed great achievements
both in terms of efficiency and chemoselectivity.2 Thus, a large
range of functional groups including alcohols, amides,
carbamates, and sulfonamides are well tolerated under
metathesis conditions.3 However, the use of a substrate
possessing a strong Lewis base such as a free amine or pyridine
remains an issue as the coordination of the nitrogen to the
ruthenium center may cause the deactivation of the catalyst.4
To address this problem, aliphatic amines were protected by
electron-withdrawing groups or protonated before the meta-
thesis reactions; alternatively, additives were used.3a,b,5 The use
of pyridine-, quinoline-, or pyrimidine-containing compounds
in metathesis remains problematic. Some examples of ring-
closing metathesis using N-heteroaromatic-containing olefins
have already been reported,6 but in contrast, to the best of our
knowledge, only a few examples of cross-metathesis involving
olefin possessing a quinoline or a pyridine moiety have been
described.7 Most of these reactions were not optimized as long
reaction time or a large excess of the metathesis partner were
required. In addition, these reactions are quite limited, and no
general study has been conducted. As part of our efforts toward
the development of attractive synthetic tools, our group is
interested in cross-metathesis.8 In particular, we have described
the functionalization of vinyloxazoles9 and -thiazoles10 by cross-
metathesis, and the method was successfully applied to the
synthesis of several myxobacterial antibiotics.10 Pyridine,
pyrimidine, or imidazole moieties are ubiquitous in bioactive
compounds.11 Thus, we decided to embark on the develop-
ment of cross-metathesis involving N-heteroaromatic-contain-
ing olefinic substrates. Herein, we report that a suitable choice
of the C2-substituent on the heteroaromatic ring enables the
use of alkenes bearing a pyridine motif in ruthenium-catalyzed
cross-metathesis. The study was further extended to olefinic
pyridine 1 and methyl acrylate was first investigated. Because
of its performance in cross-metathesis, the second-generation
Grubbs−Hoveyda catalyst (G−H II) was chosen, and the
reaction was carried out at 50 °C in CH2Cl2 (Scheme 1).12
After 24 h, no conversion was observed, and the starting
material was fully recovered. This result was not surprising as
pyridines were found to poison the ruthenium catalyst by
coordination to the metal center.4
Scheme 1. Absence of Cross-Metathesis between Pyridine 1
and Methyl Acrylate
In order to reduce the Lewis basicity of the nitrogen atom of
the pyridine, we decided to introduce an electron-withdrawing
substituent on the pyridine ring (Table 1). Pleasingly, in the
presence of the G−H II catalyst, the 2-chloropyridine
derivative 2a reacted with methyl acrylate to give the cross-
metathesis product 3 in 64% yield (Table 1, entry 1). An
increase of the concentration from 0.1 to 1 M allowed the
reaction to reach an excellent yield of 84% in 3 (Table 1, entry
2). The use of toluene at 80 °C instead of CH2Cl2 resulted in a
lower yield of 3 (35%) (Table 1, entry 3), and the Grubbs II
catalyst (G II) appeared to be less effective for this
transformation (65%) (Table 1, entry 4).
This positive result prompted us to investigate the influence
of the nature of the C2 substituent on the pyridyl moiety. Thus,
a variety of 2,5-disubstituted pyridine derivatives 4a−g were
Received: July 10, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization of the Conditions with
Table 3. Evaluation of Electron-Poor Olefinic Partners
2‑Chloropyridine Derivative 2a
a
entry
1
R1
R2
6 (yield, %)
a
entry
cat.
solvent
temp (°C) [C] (M) 3, yield (%)
H
Ac
6a (78)
6b (52)
6c (62)
6d (0)
6e (0)
b
1
2
3
4
G−H II
G−H II
G−H II
G II
CH2Cl2
CH2Cl2
toluene
CH2Cl2
50
50
80
50
0.1
1
64
84
35
65
2
Me
H
CHO
3
4
Si(OEt)3
P(O)(OEt)2
B(pin)
1
H
c
1
5
H
a
a
b
Isolated yields.
Isolated yields. Crotonaldehyde was used as a 1/20 cis/trans
c
mixture. pin = pinacol.
reacted with methyl acrylate under the above optimized
conditions (Table 2).13 When a halogen atoms was present
at C2 on the pyridine ring (X = Br, Cl, F), the reaction
proceeded smoothly delivering the desired olefins in 67−73%
yields (Table 2, entries 1−3). A trifluoromethyl group was also
suitable for the CM, and the corresponding cross-metathesis
product 5d was obtained in 73% yield (Table 2, entry 4). The
best result was obtained with 4e bearing a triflate at C2 as olefin
5e was isolated with an excellent 85% yield (Table 2, entry 5).14
In the presence of a (−I, +M) methoxy substituent at C2, a
lower yield of 51% in 5f was observed (Table 2, entry 6).
Similarly, when a tert-butyl group was introduced at the C2
position, the cross-metathesis proceeded in a moderate 52%
yield in 5g (Table 2, entry 7).
expected product was isolated in a low 37% yield (Table 4,
entry 1).15 Similarly, the product of the metathesis between 2a
and 4‑fluorostyrene could not be purified, thus disabling the
determination of the isolated yield (Table 4, entry 2). In
contrast, the use of 2-chloro-3-vinylpyridine led to the cross-
metathesis product in 55% yield (Table 4, entry 3).
Table 4. Evaluation of Styrenic Partners
Table 2. Influence of the C2 Pyridine Substituent
a
entry
4
R
X
5 (yield, %)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
H
H
H
H
Ac
H
H
Br
5a (73)
5b (67)
5c (68)
5d (73)
5e (85)
5f (51)
5g (52)
a
Isolated yields.
Cl
F
Finally, several electron-rich olefins were evaluated, and to
our delight, the cross-metathesis between 2a and cis-1,4-
diacetoxy-2-butene proceeded smoothly providing the desired
product in 79% yield (Table 5, entry 1). Similar results were
obtained when the unsaturated acetate 2b (Table 5, entry 2) or
the TBS ether 2c (Table 5, entry 3) were involved in the CM.
Unfortunately, a low yield of 38% was observed for the
formation of the allylic chloride 8d resulting from the cross-
metathesis between 2a and cis-1,4-dichloro-2-butene (Table 5,
entry 4). By contrast, 1-phenylallyl acetate reacted with 2a to
give the corresponding product in 68% yield (Table 5, entry 5).
When the cross-metathesis was conducted between 2a and
allyltrimethylsilane or allyl bromide, a mixture of compounds
with no trace of the desired product was observed (Table 5,
entries 6 and 7).
The reactivity of 2-chloro-3-vinylpyridines was then inves-
tigated (Table 6). Surprisingly, under the optimized conditions,
the cross-metathesis between 9a and methyl acrylate was
sluggish, and after 24 h, 9a, 10a, and 11 were obtained as a 2/
2/1 mixture. A better result was obtained by using cis-1,4-
diacetoxy-2-butene as the cross-metathesis product 10b was
isolated albeit in a moderate yield of 56%.
CF3
OTf
OMe
t-Bu
4g
a
Isolated yields.
In order to evaluate the scope and limitations of the cross-
metathesis, pyridine derivative 2a was reacted with a range of
alkenes under the optimized reaction conditions. Encouraged
by the successful cross-metathesis between 2a and methyl
acrylate (Table 1, entry 2), we first turned our attention to
electron-poor olefinic partners (Table 3). When 3-buten-2-one
was used, the cross-metathesis product 6a was isolated in 78%
yield (Table 3, entry 1). The conditions were compatible with
the use of a disubstituted alkene as the cross-metathesis
between 2a, and crotonaldehyde delivered the expected
product albeit in a moderate 52% yield (Table 3, entry 2).
Triethoxyvinylsilane was also a suitable partner for the
metathesis as a good yield in 6c was obtained (62%) (Table
3, entry 3). Disappointingly, vinyl phosphonates and vinyl
boronates proved unreactive under the reaction conditions
(Table 3, entries 4 and 5).
When the olefinic substituent was moved to the C5 position
on the pyridine ring, the cross-metathesis with cis-1,4-diacetoxy-
2-butene provided the expected product 13a in 61% yield
Styrenic partners were next tested, and when the cross-
metathesis was performed between 2a and 4-vinylanisole the
B
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Table 5. Evaluation of Electron-Rich Olefins
Table 7. Variation of the N-Heterocycles
a
b
c
Isolated yields. Isolated together with some impurities. syn/anti =
50/50.
Table 6. Reaction of 2-Chloro-3-vinylpyridine
a
Isolated yields.
could inhibit the Grubbs−Hoveyda catalyst by strongly
coordinating the ruthenium metal center thus disabling its
reactivity with olefins.4 The introduction of an electron-
withdrawing group at C2 on the N-heteroaromatic ring could
reduce its Lewis basicity facilitating the dissociation step
essential to the activity of the catalyst.16,17 Similarly, the
presence of an hindered substituent such as a tert-butyl group
render the coordination of the nitrogen to the catalyst more
difficult, thus enabling a moderate reactivity (Table 2, entry 7).
To verify our hypothesis, a competitive experiment was carried
out (Scheme 3). Monosubstituted pyridine 1 and 2-
chlorosubstituted pyridine derivative 2a were mixed (1 equiv
of each) in the presence of methyl acrylate (3 equiv) and G−H
II catalyst (10 mol %). Interestingly, no reaction took place and
both olefins 1 and 2a were fully recovered. This result suggests
that pyridine 1 could deactivate the ruthenium catalyst thus
totally inhibiting the cross-metathesis reaction.
a
b
entry
R1
R2
9a/10/11
10 (yield, %)
1
2
H
CO2Me
40:40:20
10a (31)
10b (56)
CH2OAc
CH2OAc
20:80:−
a
b
1
Determined by H NMR on the crude mixture. Isolated yield.
(Scheme 2). Replacing the chlorine atom by a bromine did not
lead to significant improvement of the yield whereas the
presence of a fluorine atom was detrimental to the reaction
(Scheme 2).
Scheme 2. Influence of the Substituent on Vinylpyridine
Reactivity
Scheme 3. Competitive Experiment
The cross-metathesis reaction with methyl acrylate was then
generalized to a range of N-heteroaromatic-containing alkenes
(Table 7). When olefin 14a possessing a 2-chloroisoquinoline
moiety was used, the corresponding product 15a was delivered
in a moderate yield of 53% (Table 7, entry 1). To our delight,
in the presence of dichloropyrimidines, the expected products
were isolated in 70% and 82% yields (Table 7, entries 2 and 3).
When a N-methyl-2-chloro imidazole ring was present, a low
yield of 21% for the cross-metathesis product was obtained-
(Table 7, entry 4). Gratifyingly, an increased yield of 71% was
reached by replacing the methyl group on the nitrogen by a
phenyl substituent (Table 7, entry 5). Finally, compound 15f
possessing a pyrazole ring was obtained in good yield (82%)
(Table 7, entry 6).
The presence of a substituent at C2 could offer opportunities
for further functionalization. As an example, the 2-chloropyr-
idine 3 was used in a Suzuki cross-coupling with p-tert-
butylphenylboronic acid to afford the expected product in a
nonoptimized 51% yield (Scheme 4).
Scheme 4. Suzuki Coupling with Chloropyridine 3
In order to explain the difference of reactivity between
nonsubstituted and C2-substituted N-heterocycles in the cross-
metathesis, we hypothesized that Lewis basic N-heterocycles
C
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In summary, we have shown that the presence of an electron-
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partners. The presence of (pseudo)halogeno substituents could
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Thus, this method appears as a promising synthetic tool which
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agrochemicals, or pharmaceuticals.
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ASSOCIATED CONTENT
* Supporting Information
■
S
́
(h) Ferrie, L.; Amans, D.; Reymond, S.; Bellosta, V.; Capdevielle, P.;
Experimental procedures and spectral data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
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3425. (c) Dash, J.; Melillo, B.; Arseniyadis, S.; Cossy, J. Tetrahedron
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Org. Chem. 2008, 2701. (e) Colon, A.; Hoffman, T. H.; Gebauer, J.;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: janine.cossy@espci.fr.
Notes
The authors declare no competing financial interest.
(11) (a) Pozharskii, A. F.; Soldatenkov, A.; Katritzky, A. R.
Heterocycles in Life and Society: An Introduction to Heterocyclic
Chemistry, Biochemistry and Applications, 2nd ed. Wiley: New York,
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