Acetylene-free synthesis of vinyloxy pyridine and quinoline

Article abstract of DOI:10.1016/j.tetlet.2016.11.061

Copper-catalyzed vinylation of 2- and 4-hydroxy pyridine and quinoline affords exclusively N-vinylation products. However, vinyl ethers of 4-hydroxy pyridine and quinoline can be prepared via a three-step sequence involving copper-catalyzed C-O cross coupling reaction of the corresponding N-heteroaryl bromides with ethylene glycol, chlorination of the terminal alcohol, and dehydrohalogenation of the β-chloro ethers. Although not efficient in 2-hydroxy series, this method can be conveniently applied to the preparation of various aza-aryl vinyl ethers in moderate to good overall yields.

Full text of DOI:10.1016/j.tetlet.2016.11.061

Accepted Manuscript
Acetylene-free synthesis of vinyloxy pyridine and quinoline
Abdelrahman Hamdi, Amany S. Mostafa, Cedric Nana Watat, Mathieu Y.
Laurent, Kawther Ben Ayed, Khalid B. Selim, Gilles Dujardin
PII:
S0040-4039(16)31529-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.061
TETL 48347
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 September 2016
10 November 2016
14 November 2016
Please cite this article as: Hamdi, A., Mostafa, A.S., Nana Watat, C., Laurent, M.Y., Ben Ayed, K., Selim, K.B.,
Dujardin, G., Acetylene-free synthesis of vinyloxy pyridine and quinoline, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.11.061
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1
Tetrahedron Letters
Acetylene-free synthesis of vinyloxy pyridine and quinoline
Abdelrahman Hamdia, Amany S. Mostafaa, Cedric Nana Watatb, Mathieu Y. Laurentb, Kawther Ben Ayedb,
Khalid B. Selima, and Gilles Dujardinb,
a Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
b Université du Maine, IMMM-UMR 6283 CNRS, MSO Team, Faculté des Sciences, 72085 Le Mans, Cedex 9, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper-catalyzed vinylation of 2- and 4-hydroxy pyridine and quinoline affords exclusively N-
vinylation products. However, vinyl ethers of 4-hydroxy pyridine and quinoline can be prepared
via a three-step sequence involving copper-catalyzed C-O cross coupling reaction of the
corresponding N-heteroaryl bromides with ethylene glycol, chlorination of the terminal alcohol,
and dehydrohalogenation of the β-chloro ethers. Although not efficient in 2-hydroxy series, this
method can be conveniently applied to the preparation of various aza-aryl vinyl ethers in
moderate to good overall yields.
Available online
Keywords:
N-Heteroaryl vinyl ethers
Copper-cross coupling
Pyridines
2016 Elsevier Ltd. All rights reserved.
Quinolines
Isoquinolines
While the preparation of phenol-derived vinyl ethers has been
extensively studied, the preparation of aza-aryl vinyl ethers has
been far less developed. To our knowledge, the O-vinylation of
hydroxy aza-aromatic compounds by a direct vinylation transfer
method is limited to two examples of 3-hydroxypyridines under
copper-mediated conditions involving: (i) vinyl iodide, which
allowed for O-vinylation of 3-hydroxy-6-methyl-pyridine in 51%
yield,18 (ii) trivinylcyclotriboroxane, which allowed for O-
vinylation of 3-hydroxy-5-acetate-pyridine in 25% yield.19
Importantly, the application of the CuII/O2-procedure employing
tetravinyl stannane was shown to exclusively lead to N-vinylated
products in the case of 4-hydroxypyridine (Scheme 1, eq. 1) and
2-hydroxyquinoline,14 both subjected to tautomerism with the
pyridone form. As a consequence of these features, the only
method available for the synthesis of 4-vinyloxy pyridines (and of
the corresponding benzopyridine analogs) is the O-vinylation
using the Reppe chemistry, a method that was extensively
developed by the Russian group at Irkutsk Institute,20 and which
employs high pressure of acetylene and heavy metal salts.21
Aryl vinyl ethers are promising key intermediates in a wide
variety of reactions (e.g. cyclopropanation,1 cycloaddition,2 and
metathesis processes3) as well as in the production of new
polymeric materials4 and biologically active molecules5. The
synthesis of phenyl vinyl ethers is well documented either
through one step vinylation or multistep protocols.6 Among the
former methods is the base-catalyzed reaction of phenols with
acetylene which has wide scope but requires severe conditions
(strong base, high pressure and temperature) and specific
apparatus.7 More practically, the utilization of iridium-based
catalyst (Ir(cod)Cl)2 allows vinyl transfer to phenols from vinyl
acetate under thermal conditions in high yield.8 O-Vinylation of
alcohols conveniently occurred by several procedures of metal-
based vinyl transfer, involving a vinyl ether as vinyl source.
However, these procedures are reported to be inefficient (PdII)9 or
poorly efficient (AuI/AgII, HgII)10,11 when applied to phenol
substrates. Interestingly, several copper-based cross-coupling
reactions have been reported to proceed efficiently under mild
basic conditions between phenols and different types of vinyl
donors: vinyl halides (CuCl/acac, Cs2CO3, reflux),12
trivinylcyclotriboroxanes (Cu(OAc)2, Cs2CO3, rt),13 or tetravinyl
stannane (Cu(OAc)2, O2, rt).14 On the other hand, an alternative
and indirect way for preparing phenyl vinyl ethers relies on the
base-mediated β-elimination of 2-bromo aryl ethers15 or the
oxidative β-elimination of 2-arylseleno aryl ethers,16 whereas no
reports regarded the regiocontrolled elimination from an
In connection with our research program on the development
of 1,3-dipolar cycloaddition reaction between vinyl ethers and C-
carboxynitrones,22 we needed to prepare several N-aza-aryl vinyl
ethers as dipolarophiles. We present in this letter our efforts to
identify a general acetylene-free method, able to implement a
vinyloxy group to pyridine or (iso)quinoline nucleus, especially at
the -position.
unsymmetrical acetal17 containing an aryloxy moiety.
———
* Corresponding authors. Tel.: +33 43833344.
E-mail address: gilles.dujardin@univ-lemans.fr
Tel.: +20502200242 E-mail address: khbselim@mans.edu.eg

2
Tetrahedron
We thus started our study with 4-hydroxypyridine (1a) as a
haloethoxy)pyridine/quinoline
which would undergo -
model substrate, with the aim to prepare 4-(vinyloxy)pyridine
(2a). However, owing to the weak solubility of 1a in some
organic solvents (MeCN, THF) and to the volatility of the
corresponding vinyl ether 2a (that limit the yield), we have
explored the direct vinylation on 7-methoxy-4-hydroxy quinoline
(1c) in most cases.
elimination reaction under basic condition.
X
OH
N
O
N
O
N
nucleophilic
substitution
-elimination
base
X
+
X
base
X = Br or Cl
In a preliminary study, all our attempts to use iridium-based
8
catalyst (Ir(cod)Cl)2 for such vinyl transfer failed in our hands.
Scheme 2. Proposal of indirect O-vinylation via O-alkylation.
Using direct vinylation reaction through copper-mediated vinyl
transfer from trivinylcyclotriboroxanes13 to 4-hydroxypyridine
(1a) did not give the target vinyl ether 2a but afforded instead the
N-vinylated product 3a (Scheme 1, eq. 2).23 Applying the same
conditions to 7-methoxy-4-hydroxyquinoline (1c) led again to the
sole N-vinylated product 3b (Scheme 1, eq. 3). Similar results
were obtained when 1a and 1c were submitted to the conditions
described by Ellman and coworkers with vinyl iodide.18
Therefore, we concluded that the regiochemical outcome in favor
of the N-vinylation previously reported with 1a,14 was not
attributed to the conditions used by the authors (O2 atmosphere,
polar solvent) (Scheme 1, eq. 1) but should be considered as a
For the alkylation step, we have considered the conditions
described by Harrowfield's group on 2,6-dicarboalkoxy-4-
hydroxypyridine, which used excess dibromoethane and
potassium carbonate in refluxing acetonitrile to afford the O-
alkylated compound in good yield.24 However, even after
optimization of these reaction conditions, the competition
between O- and N-alkylation was found to remain a problematic
issue in order to give 2a or 2b as a sole product in a good yield
after dehalogenation step (Scheme 3). Indeed, in the case of 1a,
the O-alkylated product 4a was obtained in an unseparable
mixture (40:60) with the N-vinyl product 3a, which resulted from
general trend for any copper-based vinyl transfer procedure. This the competitive N-alkylation and subsequent in situ
regioselectivity can be attributed (i) to the tautomerism of 4- dehydrobromination under basic thermal conditions.25 In the case
hydroxypyridine (1a) into 4-pyridone (1b) and of 4-
hydroxyquinoline (1c) into 4-quinolinone (1d), and (ii) to the
azaphilicity of copper towards 1b and 1d, respectively.
of 1c, 3b was produced in minor amount and the main by-product
was the N-bromoethyl compound 4’b.25 Treatment of the
unseparable mixture 4b/4’b/3b by NaH in DMF led to the O-
and N-vinyl products 2b and 3b in low overall yield (~ 10%) for
the two steps.
Br
O
N
K2CO3
O
OH
O
dibromoethane
+
N
N
N
H
MeCN, 90°C, 1 d
50%
1a
1b
4a
40 : 60
3a
(unseparable mixture)
OH
1c
1d
Br
K2CO3
O
N
O
N
MeO
N
dibromoethane
+
MeCN, 90°C, 1 d
31%
MeO
MeO
O
4b
4'b
52 : 48
Br
(unseparable mixture)
MeO
N
H
NaH, DMF, 12 h , rt
O
O
+
MeO
N
MeO
N
3b
2b
(separated)
low overall yields (~ 10%)
Scheme 3. Attempts of indirect vinylation of 1a and 1c via O-
alkylation.
To overcome this problem, we finally decided to use 4-
halopyridine instead of 1a as a starting material based on the work
of Liljefors's group26 who reported the mono dechloro-
vinyloxylation of 3,5-dichloropyridine by a three-step sequence: (i)
mono nucleophilic substitution with ethylene glycol, (ii)
chlorination of the terminal alcohol with thionyl chloride, (iii) β-
elimination of the 2-chloro ether with potassium hydroxide. The
yield of the first step was not given and the 3-chloro-5-
(vinyloxy)pyridine was obtained in 11% yield for the last two
steps. The copper-catalyzed coupling of ethylene glycol with 3-
bromopyridine (5d) was recently described in high yield by Chae
Scheme 1. Direct N-vinylation vs O-vinylation of 4-hydroxypyridine
(1a) and 7-methoxy-4-hydroxyquinoline (1c).
At this stage, we turned our attention to indirect methods. As
shown in scheme 2, the synthesis of 2a and 2b could be carried
out by indirect vinylation of 1a and 1c through O-nucleophilic
substitution
with
1,2-dihaloethane
to
furnish
4-(2-

3
Table 1. 3-Step synthesis of N-heteroaryl vinyl ethers via Cu-
catalyzed C–O coupling of bromides with ethylene glycol,
-chlorination and -elimination reactions.
Satisfied results were observed with 5- and 6-bromoquinolines
(5g and 5h) to give 2g and 2h (Table 1, entries 6,7).
In contrast to these positive results, the present 3-step O-
vinylation method was unsuccessful in the case of α-bromo
pyridine derivatives 5i-k. Indeed, applying the same conditions to
2-bromopyridine (5i) led to the formation of N-vinyl-2-pyridone
(3i) (Table 2, entry 1). The same intriguing regiochemical
outcome was observed when starting from 2-bromoquinoline (5j),
and from 1-bromoisoquinoline (5k) (Table 2, entries 2, 3).
Entry
1
Yield
47%
Yield
50%
6
2
2a
6a
Table 2. N-Vinylation of α-bromo-N-heteroaromatics via 3-step
method.
2
65%
68%
6c
2c
3
4
79%
93%
31%
61%
6d
2d
Entry
1
Yield
96%
Yield
63%
6
3
6e
6i
2e
3i
5
6
7
92%
85%
85%
65%
75%
67%
2
3
61%
76%
24%
75%
6j
6f
2f
3j
6k
3k
6g
2g
6h
2h
The copper-catalyzed coupling step clearly gave the O-
alkylated compounds 6i-k and this is confirmed by comparison of
the 1H NMR data of 6i with the reported one of 2-
hydroxyethoxypyridine28 and N-hydroxyethylpyridone.29 O-
Alkylated pyridine 6i is characterized with a typical deshielded
proton at position 6 with a chemical shift of 8.12 ppm in
comparison with a chemical shift of 7.56 ppm of the same proton
in N-hydroxyethylpyridone. The formation of the N-vinyl
compounds 3i-k results therefore from an unexpected pathway
occurring under the elimination conditions in the last step.
and co-workers.27 Therefore, we chose to use 4-bromopyridine (5a)
for the C-O cross coupling reaction with ethylene glycol under the
catalytic effect of the CuII salt in the presence of K2CO3.
Fortunately, using Chea’s conditions27 (5 mol% CuCl2, 3.0
equiv. K2CO3, 130 °C, 16 h), 6a was obtained in moderate isolated
yield (47%, Table 1, entry 1). The coupled product was easily
chlorinated by SOCl2 in CH2Cl2 under refluxing condition to give
4-(2-chloroethoxy)pyridine in quantitative yield which is pure
enough to go to the next step without further purification. β-
Elimination was smoothly carried out using 3.5 equiv. of NaH in Hypothesis on the possible mechanism of this "O to N migration"
can involve a bicyclic pyridinium intermediate A (Scheme 4)
obtained after neutralization and internal nucleophilic
displacement. Further abstraction of the more acidic pseudo-
benzylic proton gives intermediate B that evolves to 3i by
elimination.
anhydrous DMF under heating for 18 h to give the desired vinyl
ether 2a in 50% yield.
We then applied this 3-step procedure to various N-heteroaryl
bromides 5c-k possessing monocyclic and bicyclic rings with one
nitrogen atom at different positions (Tables 1 and 2).
.Cl
4-Bromoquinoline (5c) was converted to its respective coupled
alcohol 6c and then to the corresponding vinyl ether 2c in good
yield in both steps (Table 1, entry 2). This protocol was
successfully applied to 3 examples of β-bromopyridine derivatives
5d-f for the synthesis of pyridinyl and (iso)quinolinyl vinyl ethers
2d-f in 25–60% yield for the three steps (Table 1, entries 3–5). It is
noteworthy that the low yield of 2a and 2d is due to the high
volatility of these ethers during vacuum evaporation process.
N
N
O
O
N
O
N
O
Cl
H
6'i
A
B
3i
Base
Scheme 4. Proposed mechanism of O- to N- vinyl migration.

4
Tetrahedron
To show the importance of the prepared aza-aryl vinyl ethers
2, unoptimized 1,3-dipolar cycloaddition reaction was performed
between 2f and the chiral nitrone formed in situ from reaction of
L-gulose hydroxylamine30 and ethyl glyoxalate (Scheme 5). The
cycloadduct 7 was obtained as a mixture of 4 diastereomers in
96% yield, which gave a single stereoisomer (dr 98:2) in 41%
yield after column chromatography. The relative and absolute
configurations of 7 were tentatively assigned by analogy with
adducts of known configuration22c obtained from D-mannosyl
nitrone. Removal of the chiral auxiliary will be the next step to
give enantiomerically pure isoxazolidines equipped with both an
ester function and an aza-aryloxy side-chain as 5-aryloxy
oxaproline unit, ready for use in our ingoing project.
6. Winternheimer, D. J.; Shade, R. E.; Merlic, C. A. Synthesis 2010, 15, 2497–
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O
O
N
O
L-gulosyl
EtOOC
O
O
H
L-gulosyl
EtO2C
2f
O
N
N
OH
O
O
N
CHCl3, 80 °C
96% yield
H
L-gulose-NHOH
+
O
diastereomeric mixture
after colum chromatography gave
7, 98:2 dr, 41% yield
H
CO2Et
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1656.
N
18. Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2010, 12, 2978–
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O
HN
O
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21. This unique preparation was reported to afford the target O-vinyl
compounds as sole or main products, combined in this last case with minor N-
vinyl compounds (42 and 15% yields respectively for 2-hydroxypyridine20a).
22. (a) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10,
4493–4496. (b) Nguyen, T. B.; Beauseigneur, A.; Martel, A.; Dhal, R.;
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X. ; Cividino, P.; Poisson, J.-F.; Shpak-Kraievskyi, P.; Laurent, M. Y.; Martel,
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Beauchard, A.; Poisson, J.-F.; Py, S.; Laurent, M. Y.; Martel, A.; Ammar, H.;
Abid, S.; Dujardin, G.; Eur. J. Org. Chem. 2014, 2924–2932. (e) Shpak-
Kraievskyi, P.; Mankou Makaya, A.; Beauchard, A.; Martel, A.; Laurent, M.
Y.; Dujardin, G. Eur. J. Org. Chem. 2015, 2924–2932.
EtO2C
oxaproline derivative
Scheme 5. 1,3-DC reaction of chiral nitrone with vinyl ether 2f.
In conclusion, a 3-step synthesis of vinyl ethers derived from
N-heteroaromatic bromides was developed through a sequential
Cu-catalyzed C-O coupling, chlorination and elimination process.
Although not general, this reaction pattern allows a facile
synthesis of N-heteroaryl vinyl ethers, including those derived
from 4-hydroxypyridine and 4-hydroxyquinoline which are
unavailable compounds by acetylene-free methods.
Acknowledgments
Financial support of this study by Grants from Egypt-France
Scientific and Technological Cooperation Program Hubert Curien
“IMHOTEP” (n° 33165UG), The Academy of Scientific
Research and Technology (ASRT) and Campus France are
gratefully acknowledged.
23. Structures of vinyl ethers obtained in our study (O-vinyl vs N-vinyl) were
1
unambiguously attributed by comparison of H and 13C NMR data with those
described by the Russian group cited before20 for a wide range of O-vinyl and
N-vinyl derivatives of hydroxypyridines and quinolines: (a) Afonin, A. V.;
Andriyankova, L. K.; Pertsikov, B. Z.; Voronov, V. K. Zhur.. Organich.
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Supplementary Material
Supplementary material is available for all experimental
procedures and characterization data of compounds 2a-h, 3a,b,i-
k, 4b, 4’b, 6a,c-k and chlorinated intermediates 6’a,c-k.
25. The crude product contained also significant amounts of dimers resulting
from the coupling of one equivalent of dibromoethane to two equivalents of
the substrate.
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Graphical Abstract
Vinyl ethers of hydroxy pyridine and quinoline, not accessible by direct copper-catalyzed O-vinylation, are prepared via a
three-step sequence from the corresponding N-heteroaryl bromides.
Acetylene-free synthesis of vinyloxy pyridine
and quinoline
Leave this area blank for abstract info.
Abdelrahman Hamdia, Amany S. Mostafaa, Cedric Nana Watatb, Mathieu Y. Laurentb, Kawther Ben
Ayedb, Khalid B. Selima, and Gilles Dujardinb,

Acetylene-free synthesis of vinyloxy pyridine and
quinoline
Abdelrahman Hamdia, Amany S. Mostafaa, Cedric Nana Watatb, Mathieu Y. Laurentb, Kawther
Ben Ayedb, Khalid B. Selima, and Gilles Dujardinb,
a Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
b Université du Maine, IMMM-UMR 6283 CNRS, MSO Team, Faculté des Sciences, 72085 Le Mans, Cedex 9, France
Research highlights
Bullet 1
► State of art reviewed on vinylation methods of hydroxy pyridines / quinolines
Bullet 2
► 2- & 4-Hydroxy pyridines / quinolines : N-vinylation with known copper-based methods
Bullet 3
► First synthesis of 4-vinyloxy pyridine & 4-vinyloxy quinoline from bromides