Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates

Article abstract of DOI:10.1016/j.tetlet.2018.07.053

Ynamides are versatile 3-atoms building blocks for organic synthesis as they participate in a variety of ionic, radical and pericyclic processes. Converting ynamides into 5-atom building blocks, such as the yet unreported N-vinyl ynamides, would open new avenues in this fascinating chemistry. We describe herein our efforts towards such goal and demonstrate that the cross-coupling between N-vinyl carbamates and bromo-alkynes using copper(I) thiophene carboxylate, 1,10-phenanthroline and tBuOK in DMSO is a reactive system with an improved profile compared to the classical ynamides syntheses. The advantages and limitations of this copper-mediated reaction are discussed.

Full text of DOI:10.1016/j.tetlet.2018.07.053

Accepted Manuscript
Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates
Vincent Le Fouler, Guillaume Duret, Philippe Bisseret, Nicolas Blanchard
PII:
S0040-4039(18)30934-1
https://doi.org/10.1016/j.tetlet.2018.07.053
TETL 50162
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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28 May 2018
18 July 2018
23 July 2018
Please cite this article as: Fouler, V.L., Duret, G., Bisseret, P., Blanchard, N., Copper-mediated synthesis of N-vinyl
ynamides from N-vinyl carbamates, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.053
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Copper-mediated synthesis of N-vinyl
ynamides from N-vinyl carbamates
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Vincent Le Fouler, Guillaume Duret, Philippe Bisseret and Nicolas Blanchard

1
Tetrahedron Letters
Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates
Vincent Le Foulera, Guillaume Dureta, Philippe Bissereta and Nicolas Blancharda,
aUniversité de Haute-Alsace, Université de Strasbourg, CNRS, LIMA, UMR 7042, 68000 Mulhouse, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ynamides are versatile 3-atoms building blocks for organic synthesis as they participate in a
variety of ionic, radical and pericyclic processes. Converting ynamides into 5-atom building
blocks, such as the yet unreported N-vinyl ynamides, would open new avenues in this
fascinating chemistry. We describe herein our efforts towards such goal and demonstrate that the
cross-coupling between N-vinyl carbamates and bromo-alkynes using copper(I) thiophene
carboxylate, 1,10-phenanthroline and tBuOK in DMSO is a reactive system with an improved
profile compared to the classical ynamides syntheses. The advantages and limitations of this
copper-mediated reaction are discussed.
Available online
Keywords:
Ynamide
Copper-mediated
Cross-coupling
Diels-Alder
2009 Elsevier Ltd. All rights reserved.
Ynamide -systems can participate in a variety of pericyclic
processes such as [4+2] and formal [4+2] cycloadditions, thus
delivering structurally diverse nitrogen-containing heterocycles.1-
6
We have recently shown that ynamides could behave as
competent electron-deficient dienophiles in intramolecular
inverse electron demand Diels-Alder cycloadditions with
pyrimidines, leading to complex 4-aminopyridines fused with a
5-membered ring after a spontaneous retro-[4+2] step (Scheme 1,
A).7-9
Further investigations of this reaction, in particular of the
connectivity within the cycloaddition precursor, demonstrated
that 4-azaindolines such as 4 could be obtained in good yields
when the nitrogen atom of the ynamide was placed within the
tether between the azadiene and the dienophile (“internal”
ynamides 3, Scheme 1, B). The activation energy for this domino
[4+2]/retro-[4+2] is not as high as for the “external” ynamides 1,
that required a temperature between 210 and 255 °C.7,8 This
promising result encouraged us to explore the scope of this
transformation, as 4-azaindoles in general are relevant scaffolds
for the chemical community and in particular for medicinal
chemistry.10,11
The main challenge in the synthesis of 4-azaindolines using
this strategy was rapidly identified as the synthesis of the
cycloaddition precursors themselves (such as 3). Indeed, a
preliminary screening of copper-mediated and copper-catalyzed
reactions for the elaboration of the N-C7a -bond of ynamide 6
from -ethylamino pyrimidines 5 led to dramatically poor yields
(Scheme 1, C).
———
 Corresponding author. Tel.: +33-389336824; e-mail: n.blanchard@unistra.fr

2
Tetrahedron
these motifs are the most classical protecting groups for
ynamides nitrogen atoms. The synthesis of N-alkenyl carbamates
has been achieved using copper(I)-catalyzed N-vinylation of
carbamates17,18 or transition-metal catalyzed isomerization of N-
allylcarbamates.19,20 When considering the simpler N-vinyl motif,
two methods were reported relying on the Curtius rearrangement
of acryloyl azide (followed by trapping with an alcohol)21-24 or
protection/deformylation of N-vinyl formamide 9.25 For practical
reasons, we selected the latter method that delivered N-vinyl
carbamate 7a in good yield (Scheme 2, Eq. 1). Note that the
Scheme 1. Ynamides in inverse electron demand Diels-Alder
cycloadditions (A, B), synthetic challenge associated with the
cycloaddition precursors (C) and working hypothesis (D).
Indeed, established methods2-6 were extensively screened
using gem-dibromoalkenes, bromoalkynes or copper acetylides
and
tert-butyl
(2-(4-(trifluoromethyl)pyrimidin-2-
yl)ethyl)carbamate 5a or N-((1-(4-(trifluoromethyl)pyrimidin-2-
yl)cyclopropyl)-methyl)methanesulfonamide 5b, leading to 10%
yield of the desired ynamides 6a,b in the best cases. Glaser type
homocoupling was usually the major product of these cross-
coupling reactions. This outcome could be logically attributed to
the strongly coordinating effect of pyrimidines,12-14 which could
lead to unproductive copper complexes (Scheme 1, C).
corresponding benzyloxycarbamate 7b is
a commercially
available compound (Scheme 2, Eq. 2).26 Also, it was observed
that the synthesis of the corresponding N-vinyltosylamide 7c
proved impossible, which might be traced back to the high
electrophilicity of the imine -carbon, in equilibrium with the N-
vinylsulfonamide.24,27
Having in hand the desired nitrogen nucleophiles 7a,b, we
turned our attention to their reactivity in ynamide formation
using known methods such as the ones reported by Evano, Stahl
or Danheiser.2-6 Unfortunately, no traces of the desired ynamides
8 could be detected; diyne formation arising from the copper-
mediated Glaser homocoupling of the alkyne partner was
observed as the only side product. The use of Hsung’s
conditions2 on the other hand delivered 8a in moderate yields
(377%) (Scheme 2, Eq. 3).
A second strategy for the synthesis of “internal” ynamides 6
would call for the construction of the C3-C3a -bond thanks to a
transition metal-catalyzed cross-coupling reaction (Scheme 1, D).
The reactive metallated intermediate would be obtained through a
regio- and chemoselective hydrometallation reaction of N-vinyl
ynamide 8, itself prepared from the easily accessible (and
commercially available in some cases) N-vinyl carbamate 7. This
strategy is reminiscent of previous research by Overman15,16 who
reported highly efficient hydroboration reaction/Suzuki cross-
coupling of N-vinyl carbamates, although in the specific context
of ynamide 8, two -systems would compete for the
hydrometallation step.
Although N-vinyl ynamides 8 are not reported to the best of
our knowledge, this class of ynamides combining two different
-systems whose electronics and sterics could be finely tuned,
would represent a fascinating playground for a diversity of ionic
or pericyclic reactions. We report herein the development of a
copper-mediated synthesis of N-vinyl ynamides 6 that, although
not of a broad scope, allows the synthesis for the first time of
these small and promising building blocks.
Scheme 2. Synthesis of N-vinyl carbamate 7a (Eq. 1),
availability of 7b and unstability of 7c (Eq. 2) and preliminary
study of ynamide 8a formation (Eq. 3).
Table 1. Optimisation of the copper(I)-mediated C-N bond
formation. a 1.5 equiv. b 3 equiv. c 2.2 equiv. d Isolated yield.
Synthesis of ynamides 6 relies first on an easy access to
nitrogen nucleophiles 7 possessing an alkoxycarbonyl or a
sulfonamide group as the electron-withdrawing substituent, as

3
Unsatisfied by these moderate yields, we embarked on the
screening of copper-mediated reaction conditions able to convert
vinyl carbamates 7 to the corresponding N-vinyl ynamide 8 in
good yields. Table 1 is a highlight of extensive research efforts
that evaluated copper(I) salts, ligands, bases, solvents and
temperatures, as well as the effect of syringe pump addition of
the bromo-alkyne 11a or N-vinyl carbamate 7. Using copper
thiophene carboxylate, 1,10-phenanthroline and tBuOK at 55 °C
as the initial catalytic system,28 various solvents (THF, NMP,
DMF and DMSO, entries 1-4) were screened, leading to 75% of
the desired N-vinyl ynamide 8a in DMSO (entry 4). It should be
noted that variations in the ligands (absence of ligand, trans-1,2-
diaminocyclohexane, DMEDA and neocuproine, entries 5-8), the
temperature (entry 9), the base (entry 10) and the copper(I)
source (entry 11) were studied but led in all cases to the recovery
of the starting materials or to lower yields.
Scheme 3. Yield of 8 as a function of the 12/CuTC ratio
(top) and proposed mechanism (bottom).
Having identified the most promising combination of
copper(I) salt, ligand, base and solvent, we next turned our
attention to the efficiency of the cross-coupling reaction as a
function of the ratio of the nucleophile 12 versus CuTC. Indeed,
a reasonable mechanistic picture2-6,18 (Scheme 3) of copper-
catalyzed/mediated C-N bond forming reaction should take into
account that multiple ligations of the N-nucleophile 12 to
copper(I) can result in unproductive anionic copper complexes
such as 14.28 The role of phenanthroline is key in the equilibrium
between productive 13 and unproductive 14. Indeed, variation of
the 12/CuTC ratio demonstrated that a maximum yield (80%
NMR yield, 71% isolated yield) was reached for a 12/CuTC ratio
of 1.34. In line with previous studies related to Goldberg
coupling, a rapid decrease in yield was observed at higher
ratios.29 Taken into account all these parameters, a final short
optimization of the reaction conditions (not shown) identified
that the best yield was obtained using 2 equivalents of the N-
nucleophile 7, CuTC (1.5 eq.), 1,10-phenanthroline (3 eq.) and
tBuOK (2.2 eq.) (Table 1, entry 12).
Scheme 4. Scope of the formation of N-vinyl ynamides 8.
The scope of this copper(I)-mediated N-vinyl ynamide
synthesis was then explored, using two types of N-
vinylcarbamates (7a,b) and ten different bromo-alkynes30 (11a-j)
(Scheme 4). It was rapidly observed that the reaction possesses
some limitations as bromoalkynes substituted by an ester (11b),
an alkyl- or cycloalkyl (11c,d) or a triphenylsilyl (11e) led only
to traces amount of the desired N-vinyl ynamides 8. On the other
hand, (bromoethynyl)triisopropylsilane 11f led to 8f in a
moderate 43% yield. As already seen in Table 1,
(bromoethynyl)benzene 11a led to 71% of the desired 8a but
subtle structural variations in the alkynyl moiety, such as a para-
substitution with a phenyl group (8g) or a meta-substitution with
a methyl group (8h) led to a decrease in yield (30 and 35%
respectively), the reason of which being not clear at the moment.
para-Chloro substitution was tolerated and delivered the
corresponding N-vinyl ynamide 8i in 49%. Switching from a tert-
butoxy carbamate to a benzyl carbamate proved detrimental to
the yield, as 8j was isolated in 27% yield only. In all cases and as
previously observed (vide supra), diyne formation was observed
as the only side product.
Although the scope of this new class of ynamide is not as
wide as one can expect, their stability over time, even exposed to
open air for more than 12 months at room temperature, makes
them attractive small-building blocks for further transformation
of their two different -systems, whether in transition-metal
catalyzed processes or in pericyclic reaction.
Preliminary hydrometallation and cross-coupling reactions
with 2-halopyrimidines as presented in Scheme 1 (D) are
underway and will be reported in due course.

4
Tetrahedron
13. Navarro, J. A. R.; Barea, E.; Galindo, M. A.; Salas, J. M.;
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Acknowledgments
We thank the CNRS, the Université de Strasbourg (doctoral
contract for VLF), the Région Grand-Est (doctoral contract for
GD) and the Université de Haute-Alsace. We also thank the
referees for their suggestions.
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5
Highlights



The first synthesis of N-vinyl ynamides has been
demonstrated
The method is a Cu(I)-mediated process
between N-vinyl carbamates and bromoalkynes
The screening optimization is discussed