Intramolecular inverse electron-demand [4+2] cycloadditions of ynamidyl-tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane

Article abstract of DOI:10.1016/j.crci.2017.01.007

Three representative 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines were synthesized using an intramolecular inverse electron demand hetero–Diels–Alder/retro–Diels–Alder sequence between pyrimidines (acting as azadienes) and ynamides (acting as dienophiles). Two solvents of this reaction, sulfolane and trifluorotoluene, were compared at 210 °C and the former consistently led to higher yields. In addition, these studies confirmed the importance of the steric bulk of the C5-position of the pyrimidinyl cycloaddition precursor.

Full text of DOI:10.1016/j.crci.2017.01.007

C. R. Chimie xxx (2017) 1e5
Contents lists available at ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
ꢀ
Full paper/Memoire
Intramolecular inverse electron-demand [4þ2] cycloadditions
of ynamidyl-tethered pyrimidines: Comparative studies in
trifluorotoluene and sulfolane
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ꢁ
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Cycloaddition [4þ2] intramoleculaire a demande electronique inverse
ꢀ
ꢁ
d'ynamidyl pyrimidine : etudes comparatives dans le trifluorotoluene et
le sulfolane
,
Morgan Donnard a b, Guillaume Duret c, Philippe Bisseret c,
,
*
Nicolas Blanchard c
a
ꢀ
Laboratoire de Chimie organique et bioorganique, EA4566, Universite de Haute-Alsace, Institut de recherche Donnet, 3bis,
rue Alfred-Werner, 68093 Mulhouse cedex, France
b
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ꢀ
ꢀ
Laboratoire d'innovation therapeutique, Universite de Strasbourg, CNRS UMR 7200, Faculte de pharmacie, 74, route du Rhin, 67401
Illkirch, France
c
ꢀ
ꢀ
Laboratoire de chimie moleculaire, Universite de Strasbourg, CNRS UMR 7509, ECPM, 25, rue Becquerel, 67087 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Three representative 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines were synthesized
using an intramolecular inverse electron demand heteroeDielseAlder/retroeDielseAlder
sequence between pyrimidines (acting as azadienes) and ynamides (acting as dienophiles).
Two solvents of this reaction, sulfolane and trifluorotoluene, were compared at 210 ꢀC and
the former consistently led to higher yields. In addition, these studies confirmed the
importance of the steric bulk of the C5-position of the pyrimidinyl cycloaddition precursor.
© 2017 Académie des sciences. Published by Elsevier Masson SAS. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Received 29 September 2016
Accepted 23 January 2017
Available online xxxx
Keywords:
Alkynes
Heterocycles
Nitrogen heterocycles
Cycloaddition
Pericyclic reactions
r é s u m é
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ꢀ ꢀ
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Mots cles:
Trois 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines representatives ont ete synthetisees par
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ꢀ ꢀ
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ꢁ
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Alcynes
une reaction d'heterocycloaddition [4þ2] intramoleculaire a demande electronique inverse
ꢀ ꢀ
ꢀ ^ ꢁ
(ihDA)/retro-DielseAlder (rDA) entre des pyrimidines (jouant le role d'azadienes) et des
Heterocycles
ꢀ ꢀ
ꢀ
^ ꢀ
Heterocycles azotes
Cycloaddition
ynamides (jouant le role de dienophiles). Deux solvants de cette transformation, le sulfolane et
ꢀ
ꢁ
ꢀ ꢀ
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ꢁ
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le trifluorotoluene, ont ete compares a 210 C; le premier des deux a conduit systematique-
ꢀ
ꢀ
ꢁ ꢀ
ment a de meilleurs rendements. De plus, ces etudes confirment l'importance de
Reactions pericycliques
ꢀ
ꢀ
l'encombrement sterique delaposition C5 du precurseurde cycloaddition de type pyrimidinyl.
© 2017 Académie des sciences. Published by Elsevier Masson SAS. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
* Corresponding author.
E-mail address: n.blanchard@unistra.fr (N. Blanchard).
http://dx.doi.org/10.1016/j.crci.2017.01.007
1631-0748/© 2017 Académie des sciences. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: M. Donnard, et al., Intramolecular inverse electron-demand [4þ2] cycloadditions of ynamidyl-
tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane, Comptes Rendus Chimie (2017), http://dx.doi.org/
10.1016/j.crci.2017.01.007

2
M. Donnard et al. / C. R. Chimie xxx (2017) 1e5
1. Introduction
sultame, sulfonamide, and indole). We also demonstrated
that various types of tethers between the pyrimidine and
the ynamide could be successfully used in this ihDA/rDA
sequence, such as ethyloxy, ethylamino, and ethylthio
linkers. The corresponding cycloadducts C were pyridines
fused to oxygen-, sulfur-, and nitrogen-containing five-
membered heterocycles.
The rapid access to polysubstituted 4-amino pyridines is
a central endeavor in chemical sciences, owing to the
importance of these nitrogenated heterocycles as building
blocks or lead compounds in medicinal and agrochemical
chemistries [1], as ligands in organometallic complexes [2]
or as efficient catalysts [3]. Among the strategies leading
to pyridines, cycloaddition reactions proceed under neutral
conditions and have been used as key steps in numerous
syntheses of biologically relevant organic compounds [4]. In
line with our interest in alkyne [5] and heterosubstituted
alkyne chemistry, we have recently reported that poly-
substituted 4-aminopyridines C could be synthesized in
three simple steps from A (Scheme 1) via an inverse electron
demand heteroeDielseAlder (ihDA)/retroeDielseAlder
(rDA) cycloaddition between a pyrimidine and a ynamide,
In the late 1980s, the pioneering work of van der Plas [7]
has demonstrated that a fully carbon-substituted tether
between an alkyne and a pyrimidine was tolerated in the
ihDA/rDA sequence, leading to 6,7-dihydro-5H-cyclopenta
[b]pyridine in moderate yields. In continuation of our in-
vestigations of this ihDA/rDA sequence between ynamides
and pyrimidines, we were keen to study if a carbon tether,
such as a propyl unit, was also tolerated in this reaction. This
would constitute a novel approach to biologically important
6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines that are
found, for example, in some tacrineerhein hybrids [8] and
some fructose-1,6-bisphosphate inhibitors [9] (Fig. 1). We
report therein that such fused pyridines are indeed attain-
able using the intramolecular ihDA/rDA sequence between
pyrimidines and ynamides, and that sulfolane performs
better as a solvent compared to trifluorotoluene.
the latter acting as the electron-rich 2p partner [6].
This intramolecular cycloaddition/cycloreversion of B is
general and tolerates various electron-withdrawing groups
on the nitrogen atom (such as oxazolidinone, azetidinone,
2. Results and discussion
To investigate the relevance of a carbon-tether between
the pyrimidine (4
p component) and the ynamide (2p
component), we synthesized a small subset of representa-
tive cycloaddition precursors 5 that differ only by the na-
ture of the C5-substituent of the pyrimidine (5a, C5eH; 5b,
C5eBr; and 5c, C5eCl), according to two different strategies
Scheme 1. A three-step synthesis of pyridines C via the first ihDA/rDA of
ynamides and pyrimidines [6].
(Schemes
2 and 3). In a first approach, the bis-
homopropargyl derivative 1 [10] was converted into the
corresponding organozinc iodide using the zinc/copper
amalgam [11] in a dimethylacetamide (DMA)-benzene
(1:15) mixture at 80 ꢀC. 2-Iodo pyrimidines 2a and 2b were
added, followed by PdCl2(PPh3)2 (5 mol %). This Negishi
cross-coupling reaction delivered the expected C2-
alkylated pyrimidines 3a and 3b in 80% and 73% yields,
respectively [12]. The latter were then treated with potas-
sium carbonate in methanol, and the intermediate terminal
Fig. 1. Selected biologically relevant compounds possessing the 4-
aminopyridine motif (in light blue) [8,9].
Scheme 2. Synthesis of ihDA/rDA precursors 5a and 5b.
Please cite this article in press as: M. Donnard, et al., Intramolecular inverse electron-demand [4þ2] cycloadditions of ynamidyl-
tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane, Comptes Rendus Chimie (2017), http://dx.doi.org/
10.1016/j.crci.2017.01.007

M. Donnard et al. / C. R. Chimie xxx (2017) 1e5
3
investigations [6]. It should be noted that sulfolane per-
formed systematically better in terms of yields in these ihDA/
rDA sequences, which could be attributed to its increased
relative permittivity and dipolar moment compared with
trifluorotoluene. These observations are in agreement with
the known solvent effect on this class of pericyclic reactions
[4c,6,7]. Combined with its ease of removal (by simple
aqueous washings of the reaction mixture with hot water
followed by extraction with tert-butylmethylether), this
makes sulfolane a practical solvent for this transformation.
Scheme 3. Synthesis of ihDA/rDA precursor 5c.
3. Conclusions
alkynes were submitted to a cupration reaction using
copper(I) iodide and potassium carbonate in dime-
thylformamide (DMF) [13]. In the last step, the copper
acetylides 4a and 4b were transformed into the corre-
sponding ynamides 5a and 5b using Evano's method [13]
(N,N,N0,N0-tetramethylethylenediamine (TMEDA), oxygen
atmosphere in acetonitrile at room temperature) in good
yields (81% and 76%, respectively).
The third cycloaddition precursor 5c was prepared from
alkynyl-amidinium salt 6 and the iminium salt 7 in three
steps (Scheme 3). The initial condensation of 6 and 7 forged
the pyrimidine ring substituted in C5 by a chlorine atom
and in C2 by the desired pent-1-ynyl chain [14]. The yna-
mide motif was then introduced using Evano's method [13],
delivering the cycloaddition precursor 5c in 83% over two
steps.
Following our previous studies on the ihDA/rDA
sequence of pyrimidines tethered with ynamides, we have
reported in this letter that 6,7-dihydro-5H-cyclopenta[b]
pyridin-4-amines were easily accessible in three steps from
simple starting materials. In addition, comparative studies
between two solvents, trifluorotoluene and sulfolane,
demonstrated that the latter leads to higher-yielding re-
actions, while being practical to discard from the reaction
mixture by simple aqueous washings. Further studies
aiming at exploring further the nature of the tether be-
tween the pyrimidine and the ynamide are in progress and
will be reported in due course.
Having in hand the three cycloaddition precursors 5aec,
their reactivity in the ihDA/rDA sequence was evaluated
(Scheme 4). On the basis of our preliminary screening of
reaction conditions [6], we selected two solvents having
different dipolar moments, trifluorotoluene (relative
permittivity, 9.18; dipolar moment, 2.86 D) and sulfolane
(relative permittivity, 43.4; dipolar moment, 4.69 D) [15].
Systematic studies demonstrated that the optimal condi-
4. Materials and methods
4.1. General consideration
All reagents, chemicals, and dry solvents were pur-
chased from commercial sources and used without pu-
rification. Reactions were monitored by thin-layer silica
gel chromatography using Merck silica gel 60 F254 on
aluminum sheets. Thin-layer silica gel chromatography
plates were visualized under ultraviolet light and
revealed with acidic p-anisaldehyde stain or KMnO4
stain. Crude products were purified by flash column
ꢀ
tions were 210 C for 2 h in trifluorotoluene (conditions A)
and for 30 min in sulfolane (conditions B). The best results
were obtained with the cycloaddition precursor 5a, because
the fused pyridine 8awas obtained in 43% in trifluorotoluene
and 59% in sulfolane. On the other hand, pyrimidines 5b and
5c lead to a more sterically demanding [4þ2]-transition
state and the impact of the C5 substituents (a bromine
atom in 5b and a chlorine atom in 5c) is obvious from the
isolated yields of the fused pyridines 8b and 8c (12e29%).
These results are in agreement with our previous
chromatography on Merck silica gel Si 60 (40e63 mm). All
NMR spectra were recorded in CDCl3 on Bruker spec-
trometers at 300 or 400 MHz for 1H analyses and 75 or
100 MHz for 13C analyses. Proton chemical shifts are re-
ported in ppm
(d), relatively to residual CHCl3 (d
7.27 ppm). Multiplicities are reported as follows: singlet
Scheme 4. ihDA/rDA sequence of ynamidyl-pyrimidines 5aec.
Please cite this article in press as: M. Donnard, et al., Intramolecular inverse electron-demand [4þ2] cycloadditions of ynamidyl-
tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane, Comptes Rendus Chimie (2017), http://dx.doi.org/
10.1016/j.crci.2017.01.007

4
M. Donnard et al. / C. R. Chimie xxx (2017) 1e5
(s), doublet (d), triplet (t), quartet (q), broad singlet (br s),
combinations of those, or multiplet (m). Coupling con-
stants values J are given in Hz. Carbon chemical shifts are
4.1.3. 5-Chloro-2-pent-4-ynyl-pyrimidine (3c)
To a mixture of hex-5-ynamidine hydrochloride 6 (1 g,
5.3 mmol) and (Z)-N-(2-chloro-3-(dimethylamino)allyli-
dene)-N-methylmethanaminium hexafluorophosphate 7
(1.1 g, 3.6 mmol) in methanol (30 mL) was added sodium
methoxide (0.49 g, 9 mmol) and the solution was subse-
quently refluxed for 2 h. Then, it was cooled down to
room temperature and the reaction mixture was
concentrated under vacuum. The residue was then dis-
solved in DCM (20 mL) and washed with brine (10 mL).
The organic layer was dried over MgSO4, filtrated,
concentrated, and finally purified by silica gel flash
chromatography (cyclohexane/EtOAC 8:2) to give the
desired alkyne 3c in 74% yield (482 mg, 2.7 mmol). 1H
NMR (300 MHz, CDCl3): 8.62 (s, 2H), 3.08 (t, J ¼ 8.1 Hz,
2H), 2.37 (td, J ¼ 8.1 Hz, 3.5 Hz, 2H), 2.05 (m, 2H), 1.98 (t,
J ¼ 3.5 Hz, 1H). These data are in accordance with the
values reported in the literature.
reported in ppm (
d), relatively to the internal standard
(CDCl3, 77.23 ppm). High-resolution mass spectral
d
analysis (HRMS) was performed using an Agilent 1200
RRLC high pressure liquid chromatography (HPLC) chain
coupled with an Agilent 6520 Accurate mass quadrupole
time of flight (QToF).
4.1.1. Negishi coupling reaction leading to 2-alkylated
pyrimidines 3a and 3b
A mixture of ZneCu couple (230 mg) and 5-iodo-1-
trimethylsilylpent-1-yne 1 (500 mg, 1.9 mmol) in ben-
zene/DMA (15:1, 4 mL) was stirred at 80 ꢀC for 4 h. Sub-
sequently, to this solution, Pd(PPh3)2Cl2 (74 mg, 0.01 mmol)
and 2-iodopyrimidine 2a or 2b (0.75 mmol) were added,
and the reaction was let to stir at the same temperature for
48 h. The reaction mixture was cooled down to room
temperature, washed with water (5 mL), and dried over
MgSO4. The organic layers were filtered, concentrated, and
purified by silica gel flash chromatography (DCM/EtOAc
9:1) to give the targeted product 3.
4.1.4. Synthesis of alkynyl copper 4aec
Under Argon, to a suspension of CuI (518 mg, 2.7 mmol)
in DMF (68 mL) was added a solution of alkyne 3
(2.7 mmol) in DMF (5 mL) followed by potassium carbonate
(166 mg, 1.2 mmol). The reaction was let to stir at room
temperature for 3 h and the yellow precipitate formed
during the reaction was collected by filtration and succes-
sively washed with ammonium hydroxide (10% NH4OH
solution, 2 ꢂ 8 mL), water (2 ꢂ 8 mL), absolute ethanol
(2 ꢂ 8 mL), and finally diethyl ether (2 ꢂ 8 mL). The yellow
solid was then dried under vacuum overnight to afford the
desired alkynyl copper 4.
4.1.1.1. 2-(5-(Trimethylsilyl)pent-4-yn-1-yl)pyrimidine
(3a). Yield 80% (131 mg, 0.6 mmol). 1H NMR (300 MHz,
CDCl3): 8.69 (d, J ¼ 4.9 Hz, 2H), 7.15 (t, J ¼ 4.9 Hz, 1H),
3.09 (t, J ¼ 7.6 Hz, 2H), 2.37 (t, J ¼ 7.6 Hz, 2H), 2.08 (tt,
J ¼ J0 ¼ 7.6 Hz, 2H), 0,15 (s, 9H); 13C NMR (100 MHz,
CDCl3): 171.0, 157.3 (2C), 118.8, 106.9, 85.2, 38.6, 27.4, 19.9,
0.4 (3C).
4.1.4.1. (5-(Pyrimidin-2-yl)pent-1-yn-1-yl)copper
(4a). 479 mg, 2.3 mmol, 85%.
4.1.1.2. 5-Bromo-2-(5-(trimethylsilyl)pent-4-yn-1-yl)pyrimi-
dine (3b). Yield 73% (163 mg, 0.55 mmol). 1H NMR
(300 MHz, CDCl3): 8.43 (s, 2H), 2.76 (t, J ¼ 7.2 Hz, 2H), 2.09
(t, J ¼ 6.9 Hz, 2H), 1.77 (tt, J ¼ 7.2 Hz, 6.9 Hz, 2H), ꢁ0.136 (s,
9H); 13C NMR (100 MHz, CDCl3): 169.0, 157.8 (2C), 118.0,
106.6, 85.3, 37.8, 27.2, 19.7, 0.3 (3C).
4.1.4.2. (5-(5-Bromopyrimidin-2-yl)pent-1-yn-1-yl)copper
(4b). 645 mg, 2.2 mmol, 83%.
4.1.4.3. (5-(5-Chloropyrimidin-2-yl)pent-1-yn-1-yl)copper
(4c). 657 mg, 2.7 mmol, quantitative.
4.1.2. Deprotection of silylalkynes 2a and 2b
To a solution of the pyrimidine 2a or 2b (0.6 mmol) in
methanol (2 mL) was added potassium carbonate (5 mg,
0.04 mmol) in one portion and the mixture was then let to
stir for 2 h at room temperature. The reaction mixture was
then concentrated under vacuum, and the residue was
dissolved in ethyl acetate (5 mL), washed with brine (5 mL),
and dried over MgSO4. After filtration and concentration,
the corresponding terminal alkyne was directly used in the
next step without further purification.
4.1.5. General procedure for the synthesis of ynamides 5aec
To a solution of oxazolidinone (176 mg, 2 mmol) and the
alkynyl copper reagent 4 (0.5 mmol) in acetonitrile (1 mL)
was added N,N,N0,N0-tetramethylethylenediamine (76
mL,
0.5 mmol) and the resulting reaction mixture was vigor-
ously stirred at room temperature and under an atmo-
sphere of oxygen for 18 h. After complete disappearance of
the yellow suspension (to become a homogenous deep blue
solution), the crude reaction mixture was concentrated
under vacuum and purified by flash chromatography over
silica gel (cyclohexane/EtOAC 6:4) to afford the targeted
ynamide 5.
4.1.2.1. Alkyne from 3a. 1H NMR (400 MHz, CDCl3): 8.67 (d,
J ¼ 4.8 Hz, 2H), 7.10 (t, J ¼ 4.8 Hz, 1H), 3.06 (t, J ¼ 7.7 Hz, 2H),
2.37 (td, J ¼ 7.7 Hz, 3.5 Hz, 2H), 2.10 (m, 2H), 1.97 (t,
J ¼ 3.5 Hz, 1H).
4.1.5.1. 3-(5-(Pyrimidin-2-yl)pent-1-yn-1-yl)oxazolidin-2-one
(5a). Yield 81% (95 mg, 0.41 mmol). 1H NMR (300 MHz,
CDCl3): 8.66 (d, J ¼ 5.1 Hz, 2H), 7.13 (t, J ¼ 5.1 Hz,1H), 4.40 (t,
J ¼ 8.1 Hz, 2H), 3.87 (t, J ¼ 8.1 Hz, 2H), 3.07 (t, J ¼ 7.4 Hz, 2H),
2.43 (t, J ¼ 7.4 Hz, 2H), 2.07 (tt, J ¼ J0 ¼ 7.4 Hz, 2H); 13C NMR
4.1.2.2. Alkyne from 3b. 1H NMR (300 MHz, CDCl3): 8.66 (s,
2H), 3.01 (t, J ¼ 7.8 Hz, 2H), 2.25 (td, J ¼ 6.9 Hz, 2.7 Hz, 2H),
2.01 (m, 2H), 1.95 (t, J ¼ 2.7 Hz, 1H).
Please cite this article in press as: M. Donnard, et al., Intramolecular inverse electron-demand [4þ2] cycloadditions of ynamidyl-
tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane, Comptes Rendus Chimie (2017), http://dx.doi.org/
10.1016/j.crci.2017.01.007

M. Donnard et al. / C. R. Chimie xxx (2017) 1e5
5
(75 MHz, CDCl3): 170.8, 157.2 (3C), 118.8, 70.7 (2C), 63.0,
Acknowledgments
47.2, 38.5, 27.6, 18.3.
ꢀ
The authors thank the Universite de Strasbourg, the
ꢀ
CNRS, the Universite de Haute-Alsace, the ANR (project
4.1.5.2. 3-(5-(5-Bromopyrimidin-2-yl)pent-1-yn-1-yl)oxazoli-
din-2-one (5b). Yield 76% (120 mg, 0.38 mmol). 1H NMR
(300 MHz, CDCl3): 8.69 (s, 2H), 4.39 (t, J ¼ 8.1 Hz, 2H), 3.85
(t, J ¼ 8.1 Hz, 2H), 3.02 (t, J ¼ 7.5 Hz, 2H), 2.41 (t, J ¼ 7.3 Hz,
2H), 2.07 (tt, J ¼ 7.5 Hz, 7.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3): 168.9, 157.8 (3C), 118.0, 70.9, 70.5, 63.0, 47.2, 37.8,
27.4, 18.3.
ꢀ
DYNAMITE ANR-2010-BLAN-704), and the Region Alsace.
We are grateful to Dr. Didier Le Nouen (Universite de
Haute-Alsace) for his assistance in NMR experiments.
€
ꢀ
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(1 mL) was transferred in a microwaveable tube and irra-
diated under microwaves (300 W) at 210 ꢀC for 2 h. The
reaction mixture was then cooled down to room temper-
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silica gel (cyclohexane/EtOAC 1:0 to remove the PhCF3 then
6:4) to give the targeted bicyclic pyridine derivative 8.
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4.1.6.1. 3-(6,7-Dihydro-5H-cyclopenta[b]pyridin-4-yl)oxazoli-
din-2-one (8a). Yield 43% (37 mg, 0.18 mmol). 1H NMR
(300 MHz, CDCl3): 8.33 (d, J ¼ 5.7 Hz, 1H), 7.10 (d, J ¼ 5.7 Hz,
1H), 4.52 (t, J ¼ 7.4 Hz, 2H), 4.12 (t, J ¼ 7.4 Hz, 2H), 3.10e2.99
(m, 4H), 2.14 (tt, J ¼ J0 ¼ 7.5 Hz, 2H).
ꢀ
[6] (a) G. Duret, R. Quinlan, R.E. Martin, P. Bisseret, M. Neuburger,
V. Gandon, N. Blanchard, Org. Lett. 18 (2016) 1610e1613;
(b) G. Duret, R. Quinlan, B. Yin, R.E. Martin, P. Bisseret, M. Neuburger,
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Biomol. Chem. 12 (2014) 801e814.
4.1.6.2. 3-(3-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-
yl)oxazolidin-2-one (8b). 1H NMR (300 MHz, CDCl3) (com-
plex multiplicities and broad signals because of rotamers):
8.53 (br s, 1H), 4.59 (m, 2H), 4.28 (m, 2H), 3.15e3.01 (m,
2H), 2.87e2.79 (m, 2H), 2.26e2.11 (m, 2H).
[9] M. Rosini, F. Mancini, A. Tarozzi, F. Colizzi, V. Andrisano,
M.L. Bolognesi, P. Hrelia, C. Melchiorre, Bioorg. Med. Chem. 14
(2006) 7846e7853.
4.1.6.3. 3-(3-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-
yl)oxazolidin-2-one (8c). Yield 23% (21 mg, 0.09 mmol). 1H
NMR (300 MHz, CDCl3): 8.35 (d, J ¼ 6.1 Hz, 1H), 4.56 (t,
J ¼ 7.6 Hz, 2H), 4.19 (t, J ¼ 7.6 Hz, 2H), 3.21 (t, J ¼ 7.5 Hz, 2H),
3.09 (t, J ¼ 7.5 Hz, 2H), 2.20 (tt, J ¼ J0 ¼ 7.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3): 162.9, 154.7, 144.9, 131.0, 129.2126.2, 62.7,
46.5, 33.7, 31.5, 23.5. HRMS (ESI) calculated for
€
ꢀ
[10] S. Brase, H. Wertal, D. Frank, D. Vidovic, A. de Meijere, Eur. J. Org.
Chem. (2005) 4167e4178.
ꢁ
[11] J.P. Despres, A.E. Greene, Org. Synth. 68 (1990) 41.
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(1988) 475e478.
[13] K. Jouvin, J. Heimburger, G. Evano, Chem. Sci. 3 (2012) 756e760.
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Org. Chem. (2012) 47e52.
C
11H12ClN2O2 [MþH]þ: 239.0587; found: 239.0587.
[15] U. Tilstam, Org. Process Res. Dev. 16 (2012) 1273e1278.
Please cite this article in press as: M. Donnard, et al., Intramolecular inverse electron-demand [4þ2] cycloadditions of ynamidyl-
tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane, Comptes Rendus Chimie (2017), http://dx.doi.org/
10.1016/j.crci.2017.01.007