Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights

Article abstract of DOI:10.1021/acs.joc.6b02986

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.

Full text of DOI:10.1021/acs.joc.6b02986

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Article
Intramolecular Inverse Electron-Demand [4+2] Cycloadditions
of Ynamides with Pyrimidines: Scope and DFT Insights
Guillaume Duret, Robert Quinlan, Boyang Yin, Rainer E Martin, Philippe
Bisseret, Markus Neuburger, Vincent Gandon, and Nicolas Blanchard
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02986 • Publication Date (Web): 06 Jan 2017
Downloaded from http://pubs.acs.org on January 6, 2017
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Intramolecular Inverse Electron-Demand [4+2] Cycloadditions of
Ynamides with Pyrimidines: Scope and DFT Insights
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†
†
†
‡
†
Guillaume Duret, Robert Quilan, Boyang Yin, Rainer E. Martin, Philippe Bisseret, Markus
§
*, ,
∥ ⊥
*,†
Neuburger, Vincent Gandon,
and Nicolas Blanchard
†
Université de Strasbourg, CNRS, Laboratoire de Chimie Moléculaire UMR 7509, Fꢀ67000 Strasbourg,
France
‡
Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation
Center Basel, F. HoffmannꢀLa Roche Ltd, Grenzacherstrasse 124, CHꢀ4070 Basel, Switzerland
§
Department of Chemistry, University of Basel, Spitalstrasse 51, CHꢀ4056 Basel, Switzerland
∥Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Univ. ParisꢀSud, Université
ParisꢀSaclay, bâtiment 420, 91405 Orsay cedex, France
⊥Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. ParisꢀSud, Université Parisꢀ
Saclay, 1 av. de la Terrasse, 91198 GifꢀsurꢀYvette, France
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ABSTRACT:
ꢀAminopyridines are valuable scaffolds for the chemical industry in general, from life sciences
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to catalysis. We report herein a collection of structurally diverse polycyclic fusedꢀ and spiroꢀ4ꢀ
aminopyridines that are prepared in only three steps from commercially available pyrimidines.
The key step of this short sequence is a [4+2]/retroꢀ[4+2] cycloaddition between a pyrimidine
and an ynamide, which constitutes the first examples of ynamides behaving as electronꢀrich
dienophiles in [4+2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in
continuous mode in superheated toluene to overcome the limited scalability of MW reactions,
results in a notable production increase compared to batch mode. Finally, DFT investigations
shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA
sequence.
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GRAPHICAL ABSTRACT:
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I. INTRODUCTION
Ynamides are versatile building blocks in synthetic organic chemistry, as they possess the
delicate balance between stability and reactivity, associated with an everꢀincreasing ease of
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1,2,3,4
preparation from commercially available reactants.
Cycloaddition and formal cycloaddition
reactions involving ynamides have been the focus of many research groups, and this field has
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been thoroughly reviewed up to early 2013 by Hsung. In the past three years, elegant studies
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continued to be reported on all classes of pericyclic reactions of ynamides, including [2+2],
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[2+2+2], [3+2],
[4+2],
[4+3], benzannulation strategies and hexadehydroꢀ[4+2]
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DielsꢀAlder reactions.
In this arsenal of pericyclic reactions of ynamides, the interꢀ and intramolecular [4+2] Dielsꢀ
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Alder,
and formal DielsꢀAlder
reactions are of special note since they lead to valuable
nitrogenated heterocycles such as pyridines, quinolines, carbazoles, dihydroindolines or anilines.
In almost all of these instances, the ynamide π system comprises the electron deficient 2π
component of the [4+2] cycloaddition reaction, and only a few examples of (formal) inverse
electronꢀdemand heteroꢀDielsꢀAlder (ihDA) of ynamides have been reported to the best of our
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knowledge (Scheme 1). Indeed, Hsung, Nakada and Chang and Wang have reported that
ynamides could undergo an ihDA reaction with methylvinylketone, cyclic αꢀalkylidene βꢀoxo
imides or with orthoꢀquinone methides under Lewis acid catalysis (Scheme 1, eq 1).
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Movassaghi reported an efficient synthesis of polysubstituted 4ꢀaminopyridines starting from
amides that are activated using triflic anhydride and 2ꢀchloropyridine (Scheme 1, eq 2). The
ensuing activated iminium is then trapped by an ynamide, leading to a keteniminium ion of which
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π electrocyclization delivered a 4ꢀaminopyridine. Besides this elegant cascade reaction, Ma
described the synthesis of 2ꢀsulfonamidoꢀ1,4ꢀdihydropyridines through a threeꢀcomponent
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reaction between a sulfonyl azide, a terminal alkyne and an electronꢀdeficient 1ꢀazaꢀdiene that
rely on the in situ generation of a metalated ynamide (Scheme 1, eq 3). This formal ihDA also
uncovered the crucial role of a Lewis acid (e.g. the cesium cation in Scheme 1, eq 3) on the
outcome of the reaction. Finally, it should be noted that an oxazolidinoneꢀderived ynamide was
reported by Kozmin and Rawal to be unreactive in ihDA with 1,2ꢀdiazines under Ag(I) catalysis,
which stands in sharp contrast with the comparably nucleophilic silyloxy alkynes that delivered a
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collection of silyl protected 2ꢀnaphthols in good yields at room temperature (Scheme 1, eq 4).
This last study demonstrates that [4+2] cycloadditions of ynamides with diazines could be
particularly challenging.
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Scheme 1. Inverse electronꢀdemand (formal) [4+2] cycloaddition reactions of ynamides.
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[
4+2] Cycloadditions of heterocyclic azadienes such as diazines, triazines and tetrazines are
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enabling transformations that allow rapid access to nitrogen containing heterocycles. The
reactivity of the azadiene is directly correlated to the number of nitrogen atoms, each nitrogen
reducing the activation barrier of the [4+2] cycloaddition due to favorable orbital interaction and
to a reduction in distortion energy that is correlated to the outꢀofꢀplane bending of the
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heteroaromatic diene in the transition state.
Among the heterocyclic azadienes, pyrimidines
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are prototypical lowꢀreactivity electronꢀdeficient azadienes and their cycloaddition reactions have
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been only scarcely studied compared to triazines or tetrazines.
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Scheme 2. Inverse electronꢀdemand [4+2] cycloaddition reactions of pyrimidines and alkynes
A) and ynamines (B).
(
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21c,25
In the 1970s and 80s, the groups of Neunhoeffer and van der Plas
explored the interꢀ and
intramolecular ihDA cycloaddition of pyrimidines with terminal alkynes (Scheme 2, A). The first
pericyclic event is followed by a spontaneous retroꢀDielsꢀAlder (rDA) that delivers (fused)
pyridines. This ihDA/rDA sequence proceeds at elevated temperature (up to 210 °C) in
nitrobenzene as the preferred solvent to give moderate yields after an extended period of time (up
to several days). To overcome the use of such solvents and the extended heating at elevated
temperature, Martin showed that van der Plas' ihDA/rDA reaction could be conducted under
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continuous flow in superheated solvents (toluene, 310 °C). However, a nonꢀsolved limitation of
van der Plas' ihDA/rDA sequence is the nature of the dienophile: the terminal alkyne accounts for
the vast majority of the reported 2π components and only a handful of methylꢀ, silylꢀ or arylꢀ
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substituted alkynes were reported.
Along the same lines, heterosubstituted alkynes have rarely
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been used in this ihDA/rDA reaction. Ynol ethers are not reactive partners and only a few
examples of intermolecular cycloadditions using two ynamines, (1ꢀdiethylamino)propꢀ1ꢀyne
(Scheme 2, eqs 2ꢀ4) and (1ꢀdiethylamino)ꢀ2ꢀphenylpropꢀ1ꢀyne (Scheme 2, eq 3), have been
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reported (Scheme 2, B).
Finally, with a quite narrow functional group tolerance and
harsh reaction conditions, this ihDA/rDA reaction has not found a widespread use in medicinal
chemistry or total synthesis besides a few reports to construct pentaꢀsubstituted pyridines such as
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scaffold of some chainꢀbreaking antioxidant. Applications of this sequence can also be found in
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the elaboration of the tetraꢀsubstituted pyridine rings of the monoterpenic alkaloid actinidine or
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the 4ꢀaza analog of ramelteon.
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In continuation of our investigations of heteroꢀDielsꢀAlder cycloaddition reactions, we recently
disclosed for the first time the use of ynamides in ihDA reactions for the synthesis of
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aminopyridines (Scheme 3). Pyrimidines were selected as electronꢀdeficient heterodienes since
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a broad range of these nitrogenated heterocycles are commercially available or can be prepared
from simple reactants in a few steps, thus a general ihDA/rDA sequence based on pyrimidines as
dienes is of high interest. Remarkably, starting from C2ꢀsubstituted pyrimidines led to fused 4ꢀ
aminopyridines in high yields, whether tetraꢀ or pentasubstituted, and a good functional group
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tolerance was observed.
Scheme 3. Inverse electronꢀdemand [4+2] cycloaddition reactions of pyrimidines and ynamides.
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Indeed, 4ꢀamino pyridines are privileged scaffolds that have attracted the attention of both the
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agrochemical and pharmaceutical industry due to their intrinsic biological activities and
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potential for skeleton diversity. In spite of their attractiveness, the synthesis of this class of 4ꢀ
amino pyridines is still hampered by shortcomings although insightful methods have been
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recently designed by Macgregor and Whittlesey and Reissig based on the catalytic
hydrodefluorination reaction of fluorinated pyridines. Therefore, a general ihDA/rDA reaction of
ynamides with pyrimidines could be a direct entry into a class of highly valuable but synthetically
challenging aminoꢀpyridines.
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Herein, we report a full account of our investigations, with a thorough study of the scope of the
reaction sequence including a scaleꢀup ihDA/rDA procedure using flow conditions in
superheated toluene. In addition, DFT calculations at the M06ꢀ2X/6ꢀ311+G(d,p) level were used
to gain insights into the mechanism of this reaction.
II. RESULTS AND DISCUSSION
A threeꢀstep sequence to synthesize structurally diverse 4ꢀamino pyridines was thus designed,
starting from pyrimidines of general structure A, possessing a leaving group in the C2ꢀposition
(Scheme 4). Nucleophilic aromatic substitution with homopropargylic alcohols, amines or Nꢀ
hydroxycarbamates leads to alkynyl pyrimidines B, whose terminal alkynes could be further
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transformed into the corresponding ynamides C. The key ihDA/rDA would then allow the
formation of polycyclic 4ꢀaminopyridines D. To evaluate the relevance and generality of this
threeꢀstep sequence to nitrogenꢀcontaining heterocycles D, we first focused on the synthesis of
the cycloaddition precursors.
Scheme 4. A threeꢀstep synthesis of structurally diverse 4ꢀaminopyridines using ihDA/rDA as a
key step.
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. Synthesis of cycloaddition precursors
We began our investigations by the synthesis of a diversity of cycloaddition precursors that differ
by the nature of the substituents on the pyrimidine ring as well as the ynamide moiety
(carbamate, sulfonamide, indole and sultam). The length and substitution of the tether between
the azadiene and the ynamide was also investigated. To this end, we focused on a first series of 2ꢀ
alkoxypyrimidines 3, 5, 7 and 9 prepared via a S Ar reaction of the appropriate 2ꢀ
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chloropyrimidine with a sodium alkoxide in THF (Schemes 5 and 6).
For the simplest pyrimidines such as the 2ꢀchloroꢀ and 2ꢀchloroꢀ4ꢀtrifluoromethylpyrimidines 1a
and 1b, the S Ar reaction proceeded smoothly at room temperature, leading to the corresponding
N
alkynylꢀpyrimidines 3a-i in 32ꢀ97% yield (Scheme 5, A).
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Scheme 5. Synthesis of 2,4ꢀ and 2,5ꢀdisubstituted alkynyl pyrimidines 3 and 5.
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a
note: Prepared from 5f, Pd(dba) (10 mol%), dppf (20 mol%), Zn(CN) , DMF, 90 °C, 48 h.
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Pyrimidines substituted in the 5ꢀposition by an electronꢀwithdrawingꢀatom (F in 5a-c, Cl in 5d or
Br in 5e) or electronꢀwithdrawingꢀgroup (CN in 5f, CF in 5g) were also prepared by S Ar of the
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corresponding 2ꢀchloropyrimidines with the relevant homopropargylic sodium alkoxide (Scheme
, B). Heating to 130 °C (microwave irradiation) led to a marginal increase in the yield, as can be
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seen for 5a (79% (A) vs 94% (B)) and 5e (74% (A) vs 89% (B)). Pyrimidine 5f bearing a cyanoꢀ
group in the 5ꢀposition was prepared by the palladiumꢀcatalyzed cyanation reaction of 5e
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Pd(dba) (10 mol%), dppf (20 mol%), Zn(CN) , DMF, 90 °C).
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2,4,5 and 2,4,6ꢀTrisubstituted pyrimidines were prepared from pyrimidines possessing a leaving
group in the 2ꢀposition (either a methanesulfonyl in 6a or a chlorine atom in 6b and 8a-e) and
homopropargylic sodium alkoxide in THF (Scheme 6). For the symmetrical pyrimidines 7a and
7b, the 4ꢀ and 6ꢀpositions were substituted by electronꢀwithdrawing chlorine atoms or electronꢀ
donating methoxy groups respectively (Scheme 6, A). In the case of 2,4,5ꢀtrisubstituted
pyrimidines 9a-e, the 5ꢀfluoro substituent was kept identical while the 4ꢀposition differed by the
nature of the aromatic (phenyl in 9a and 4ꢀfluorophenyl in 9b) or heteroaromatic ring
(imidazo[1,2ꢀa]pyridinyl in 9c, 1ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀyl in 9d and thiophenꢀ3ꢀyl in 9e) (Scheme
6, B).
We finally turned our attention to a last series of three alkynyl pyrimidines 11, 13 and 15 that
possess one or two heteroatoms in the tether (Scheme 7). Methyl NꢀpropargylꢀNꢀ(pyrimidinꢀ2ꢀ
yloxy)carbamat 11 was prepared in two steps from commercially available 2ꢀchloroꢀ4ꢀ
trifluoromethylpyrimidine 1b by S Ar followed by propargylation of the nitrogen atom under
N
basic conditions (eq 1). Starting from 1b, a different strategy was used for the synthesis of Nꢀ
propargylꢀNꢀ(pyrimidinꢀ2ꢀyl)acetamide (13). Nucleophilic displacement of the C2ꢀchlorine atom
of 1b by the sodium anion of butꢀ3ꢀynꢀ1ꢀamine led to 12, whose nitrogen atom was protected
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25b,42
using acetic anhydride with 1 mol% of sulfuric acid (eq 2).
Finally, 2ꢀ(propargylthio)ꢀ4ꢀ
trifluoromethylpyrimidine 15 was prepared in a single step in 93% yield by propargylation of
commercially available 14, under basic heterogeneous conditions (eq 3).
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Scheme 6. Synthesis of 2,4,6ꢀ and 2,4,5ꢀtrisubstituted alkynyl pyrimidines 7 and 9.
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Scheme 7. Synthesis of 2,4ꢀdisubstituted alkynyl pyrimidines 11, 13 and 15.
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With a diversity of alkynylpyrimidines in hand, we next turned our attention to their elaboration
into the corresponding ynamides (Schemes 8ꢀ10). To this end, several classical synthetic
strategies for the copperꢀmediated synthesis of ynamides were evaluated, such as Stahl’s methods
(
C: CuCl , pyridine, Na CO , O in toluene at 70 °C, D: CuCl , Cs CO , O , DMSO, 70 °C) and
2 2 3 2 2 2 3 2
2,3,4,43,44,45
Evano’s method (E: CuI, Cs CO , NH OH/EtOH then TMEDA, MeCN, 20 °C).
It is
2
3
4
worth noting that the ynamides precursors 3, 5, 7, 9, 11, 13 and 15 are challenging substrates for
copperꢀmediated transformations owing to the chelating potential of pyrimidines in general (and
more specifically 2ꢀalkoxypyrimidines) that could negatively impact the yield of the desired
4
6,47
copper mediated CꢀN bond formation.
For most of the substrates, several methods were
screened in parallel and only the best results are reported in Schemes 8ꢀ10. Unfortunately, no
general trends were observed in the synthesis of these ynamides.
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Scheme 8. Synthesis of 2,4ꢀdisubstituted ynamidyl pyrimidines 16.
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Starting from 2,4ꢀdisubstituted alkynyl pyrimidines 3, methods D and E proved the most efficient
using diverse nitrogenated nucleophiles such as oxazolidinone, azetidinone, sultame, 3ꢀ
carboxymethylindole, and Nꢀmethyl arylsulfonamides (Scheme 8). The 16 desired ynamides 16a-
q were obtained in 11ꢀ77% yield. The structures of ynamide 16k was unambiguously confirmed
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by Xꢀray diffraction. In addition to methods D and E, method C was used for the synthesis of
10 additional ynamides 17a-i starting from 2,5ꢀdisubstituted alkynyl pyrimidines 5 (Scheme 9).
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Scheme 9. Synthesis of 2,5ꢀdisubstituted ynamidyl pyrimidines 17.
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Finally, a last set of 10 ynamides was prepared from terminal alkynes 7, 9, 11, 13 and 15
(Scheme 10). Except for the case of ynamide 18e for which none of the desired ynamide was
detected (which could be traced back to the chelation potentials of the imidazo[1,2ꢀa]pyridinyl
and 2ꢀalkoxypyrimidine motifs in 9c), the targeted ynamides 18 were obtained in 25ꢀ79% yield.
The more challenging ynamide 19a was obtained with a low (but reproducible) yield of 12%.
Moderate to good yields were obtained for 19b-d that possess either a 2ꢀacetamido (19b, 54%
and 19c, 75%) or a 2ꢀthio (19d, 69%) substituent on the pyrimidine ring.
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Scheme 10. Synthesis of ynamidyl pyrimidines 18 and 19.
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Having prepared a set of 36 structurally differentiated ynamides (16ꢀ19), the reactivity of these
compounds in the intramolecular ihDA/rDA was evaluated.
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2. Intramolecular ihDA/rDA of ynamides
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The ynamides 16a-q were selected for the first series of intramolecular ihDA/rDA under the
optimized reaction conditions, dry sulfolane using microwave irradiation at 255 °C for 1 min
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33
(
Method F) or 210 °C for 30 minutes (Method G) (Scheme 11). The need for an electronꢀ
withdrawing group on the azadiene partner became quickly evident as none of the pyridine 20a
was obtained from compound 16a under conditions F or G. The latter was fully recovered
without any traces of decomposition. On the other hand, introducing a strongly electronꢀdeficient
motif such as a trifluoromethyl group in the 4ꢀposition of the pyrimidine led to a productive
cycloaddition sequence as evidenced by 4ꢀaminopyridines 20b-e and 20i-n, which were obtained
cleanly and in moderate to good yields. In line with these results, a 4ꢀmethoxy substituent on the
pyrimidine ring, as in 16q, did not lead to the desired fused pyridine 20q. A similar lack of
reactivity was observed with the 2,4,6ꢀtrialkoxy pyrimidine 18a (vide infra, Scheme 13). The
efficiency of this ihDA/rDA sequence is also strongly impacted by the nature of the ynamide,
which should not be too strongly electronꢀdeficient. Indeed, it was found that for comparable
substrates, good yields of the fused 4ꢀaminopyridines were obtained using ynamides derived from
oxazolidinone (20b,i-k,n) azetidinone (20d), sultame (20c) and indole (20e and 20m) whereas
ynamides derived from methylsulfonamide led to poor yield of the cycloadducts (20f, 21%) or
suffer from complete decomposition in the case of strongly electronꢀwithdrawing substituent on
the nitrogen atom of the ynamide (20g and 20h, 0%). A last parameter that influenced the
reactivity in this ihDA/rDA sequence is the nature and length of the tether between the
pyrimidine and the ynamide. Whereas a threeꢀatoms tether was perfectly tolerated (as in 20b for
example), a fourꢀ or fiveꢀatoms tether was detrimental to the reactivity, no cycloadducts being
formed in the case of 20o and 20p (for a DFT investigation of the reactivity of 20o, see Section 4
and Supporting Information). Quite logically, substitution of the tether entropically favored the
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first, rateꢀlimiting [4+2] cycloaddition step (vide infra, Figure 2). Tricyclic pyridines 20i-n were
thus obtained and in some cases with greatly improved yields (20b, 60% vs 20k, 91%; 20e, 49%
vs 20m, 86% and 20f, 21% vs 20l, 60%). Finally, it should be noted that an Xꢀray structure of
cycloadduct 20m was obtained, thus unambiguously establishing the fused 4ꢀaminopyridine
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scaffolds arising from the ihDA/rDA cascade of 16m.
Scheme 11. Intramolecular ihDA/rDA of ynamidyl pyrimidines 16.
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a
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Notes NMR Yield using 1b as internal standard. 30 s. 1 h. 10 min. 3 h.
In a second series of studies, we focused on the 2,5ꢀdisubstituted ynamidyl pyrimidines 17
(Scheme 12) to probe the efficiency of the ihDA/rDA sequence using 5ꢀsubstituents on the
pyrimidine that possess opposite steric and electronic properties. Indeed, substitution of this 5ꢀ
position was reported by van der Plas and Neunhoeffer to have a strong impact on the yields of
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the cycloadducts.
In our observation moderate to excellent yields of the desired 4ꢀ
aminopyridines 21 were obtained in cases of 21a-e whose C5ꢀposition is substituted by a fluorine
atom, except in the case of 21c for which only decomposition of the cycloaddition precursor was
observed. This difference in reactivity could be attributed to the more sterically and electronically
demanding electronꢀwithdrawing group on the nitrogen atom of the ynamide, that severely
impacts the transition state of the initial [4+2] cycloaddition. This hypothesis is further supported
by the decrease in yields observed with the increase of steric bulk of the electronꢀwithdrawing
group of the ynamide (21d 90%, 21a 71%, 21e 54% and 21c 0%).
In addition, low yields were obtained in cases with sterically demanding 5ꢀchloro or 5ꢀ
trifluoromethyl groups or the electronꢀrich 5ꢀmethoxy substituent (leading respectively to 21f,
1
7%, 21i, 11% and 21j, 21%). No cycloadducts were obtained starting from 5ꢀbromo and 5ꢀ
cyano substituted pyrimidines (leading respectively to the putative 21g and 21h). An Xꢀray
structure of cycloadduct 21e revealed unambiguously the structure of the cycloadduct obtained
3
3
from 17e.
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Scheme 12. Intramolecular ihDA/rDA of ynamidylpyrimidines 17.
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a
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Notes 60 min. 2 min. 10 min. NMR yields using 1b or 4a as internal standards
Finally, the ihDA/rDA reaction of ynamides 18 and 19 were studied with the potential to give
access to tetraꢀ or pentaꢀsubstituted pyridines, annulated to an oxygenꢀ, nitrogenꢀ or sulfurꢀ
containing fiveꢀmembered heterocycle (Scheme 13). Cycloaddition reaction of the 2,4,6ꢀ
trisubstituted pyrimidine 18a led to only a low yield of the tetraꢀsubstituted aminopyridine 22a
(
21%) in 5 minutes at 255 °C. Although cycloaddition precursor 18a is quite electronꢀdeficient,
the steric requirement of the two C4ꢀ and C6ꢀchlorine atoms seems to negatively impact the yield
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of the ihDA/rDA sequence. In the case of the 2,4,6ꢀtrisubstituted pyrimidine 18b, the electronics
of the azadiene do not favor the cycloaddition at all and no cycloadduct 20q was detected. This
result is coherent with the lack of reactivity of pyrimidine 16q possessing a single C4ꢀmethoxy
group on the pyrimidine ring (see Scheme 12). It should also be noted that ynamide 18g
possessing a 1ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀyl motif at C4 of the pyrimidine led to complete
decomposition at 255 °C for 1 minute, and no cycloadduct 22f could be detected in the crude
reaction mixture. In sharp contrast, pentasubstituted pyridines 22c, 22d and 22g were obtained in
82%, 72% and 72% yield respectively, thus demonstrating that the ihDA/rDA of ynamides
constitute a valuable approach to these densely functionalized pyridines. When two successive
heteroatoms are present in the tether of the cycloaddition precursor as in 19a, the ihDA/rDA
reaction could be conducted at lower temperature (180 °C) leading to the high value 2,3ꢀ
dihydroisoxazolo[5,4ꢀb]pyridine scaffold, albeit in 21% NMR yield (unoptimized). The last three
cycloadducts, 23b-d, were obtained in good to excellent yields, thus highlighting that this method
could be applied to the preparation of 2,3ꢀdihydroꢀ1Hꢀpyrrolo[2,3ꢀb]pyridines (such as 23b and
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23c) or 2,3ꢀdihydrothieno[2,3ꢀb]pyridine (such as 23d).
Scheme 13. Intramolecular ihDA/rDA of ynamidyl pyrimidines 18 and 19.
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a
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Note 5 min 10 min ratio 21a/22a = 82:18 by F NMR ratio 21a/22b = 85:15 by F NMR
e
f
1
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. Scale-up of ihDA/rDA of ynamides under continuous flow conditions
In continuation of our investigations, we were keen to demonstrate that the ihDA/rDA reaction
sequence was easily scalable using continuous flow technology. Even if microwave dielectric
heating is an efficient technology for smallꢀscale experiments, some limitations arise when
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multigrams of products are required within a short time. With regards to scaleꢀup, an
established alternative to microwave irradiation is thermal heating in continuous flow, a safe
synthetic tool that gained momentum in the past few years due to its excellent heat and mass
5
0
transfer capacities. Indeed, Martin et al. demonstrated that inverse electron demand DielsꢀAlder
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cycloadditions, such as the Kondrat'eva reaction, can be conducted efficiently under
continuous flow in superheated solvents (toluene, 230ꢀ310 °C). Our recently reported ihDA/rDA
of ynamides with pyrimidines is also amenable to continuous flow conditions using a very simple
52
setꢀup, as demonstrated in Scheme 14. At 300 °C in superheated toluene, cyanhydric acid
polymers might obstruct the reactor. This potential clogging is efficiently prevented using
2
6b
pentanone (1% v/v) as a cyanide trap. Under these conditions, 16b is efficiently converted to
2
0b on a multigram scale and in a very short reaction time (effective residence time: 7.4 min,
corrected for the 35% thermal expansion of toluene at 300 °C). The increase of yield between
microwave irradiation (60%, Scheme 11) and continuous flow (78%, Scheme 14) is also worth
noting.
This easyꢀtoꢀuse technology thus overcomes the commonly observed limitations of microwave
heating when it comes to synthesis up scaling. Although a systematic comparison of the
cycloaddition yields using microwave irradiations and superheated toluene was beyond the scope
of this study, the rapid preparation of 2.4 g of the fused pyridine 20b proves that this sequence is
relevant to the preparative synthesis of valuable polycyclic pyridines.
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Scheme 14. Continuous flow scaleꢀup of the synthesis of 20b in superheated toluene.
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4
. DFT investigations of the ihDA/rDA sequence of ynamides
Besides developing a practical access to multigrams of the representative cycloadduct 20b, we
have been interested in the understanding of the reaction pathway of the ihDA/rDA of ynamides
with pyrimidines. Actually, the exploration of the DielsꢀAlder reactions of pyridine, diꢀ, triꢀ and
tetrazines with 2π components with density functional theory have been reported recently by Ess
22
23
and Bickelhaupt and Houk. As discussed in the Introduction, it was shown that the reactivity
of azadienes is directly correlated to the number of nitrogen atoms, each substitution of a CꢀH
bond by a nitrogen atom decreasing the σ aromaticity of the heteroaromatics. In addition,
distortion energies and interaction energies of the diene and dienophile were shown to be of
prime importance. To gain some insight into the mechanism of the ihDA of ynamides with
pyrimidines, DFT computations were carried out at the M06ꢀ2X/6ꢀ311+G(d,p) level taking
sulfolane into account (PCM method) using three representative substrates: 3b (Figure 1, A) and
5
2
16b and 17a (Figure 1, B).
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Figure 1. Lowest energy conformations of terminal alkyne 3b and ynamides 16b and 17a.
A. Terminal alkyne 3b
C2
H
0
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7
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9
0
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N
F C
N
O
3
C3
3
b1 (stretched, 0.0)
3b
1
C2: -0.020
C3: +0.750
3b (folded): +0.9
2
3
b2 C2: -0.022
C3: +0.758
B. Ynamides 16b and 17a
O
O
C2
N
R1
N
R2
N
O
C3
1
6b2 (folded, 0.0)
1
2
17a2 (folded, 0.0)
16b R = H, R
= CF3
2
C2: -0.070
C3: +0.766
[
16b1 (stretched): +3.8]
[17a1 (stretched): +1.5]
17a2
R = F, R = H
C2: +0.037
C3: +0.739
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Note: ꢀG528 in kcal/mol; selected distances in Å; selected natural charges.
Determination of the Gibbs free energies and of the geometries of transition states and
intermediates of the ihDA of terminal alkyne 3b are important since they allow a direct
evaluation of the impact of the nitrogen atom connected to the alkyne on reactivity. The most
stable conꢀformations of 3b, 16b and 17a are dependent on the substitution pattern. Figure 1
shows the most stable ground state conformations of the folded and stretched conformers of
terminal alkyne 3b (Figure 1, A) as well as of the folded conformers of ynamides 16b and 17a
(Figure 1, B) at the M06ꢀ2X level. In the terminal alkyne 3b (Figure 1, A), the stretched isomer
3b1 is the most stable by about 1 kcal/mol. This shows that the stabilization of the charge at C3
through alkyne electron transfer is quite negligible (respective charges at C2 and C3 ꢀ0.020 and
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+
0.750). On the other hand, as can be seen in Figure 1 (B), the folded conformer 16b is more
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stable than the stretched one 16b by 3.8 kcal/mol at 528 K (255 °C). Inspection of the maximum
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electron density reveals a weak interaction between C2 at the alkyne moiety and C3 at the
0
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ꢀ3
pyrimidine fragment (ρmax = 0.009 e.Å ). This is consistent with the fact that C3 has a strong
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positive charge (+0.766) while C2 is more negatively charged (ꢀ0.070) than in 3b.
ꢀ3
Two CF…H hydrogen bonds (ρmax = 0.007 e.Å ) also account for the stabilization of 16b , these
2
hydrogen bonds being mainly responsible for the stabilization of the folded isomer. In 17a , Oꢀ
2
ꢀ3
C5 electron density transfer was found at ρmax = 0.005 e.Å while very weak electron transfer
ꢀ3
from the alkyne moiety to C3 was computed at ρmax = 0.003 e.Å . The stretched isomer 17a is
1
less stable by 1.5 kcal/mol at 528 K.
For these substrates, three steps were considered (Figure 2): (i) [4+2] cycloaddition leading to
A3b (from 3b), A16b (from 16b) and A17a (from 17a), (ii) retroꢀ[4+2] cycloaddition of HCN
(
leading to 24•HCN, 20b•HCN or 21a•HCN) or F CCN (leading to 24’•HCN, 20b’•HCN or
3
21a’•HCN) and (iii) dissociation of the final cycloadduct from the HCN or F CCN complex. As
3
after step ii the two fragments may still interact nonꢀcovalently, step iii is required to get a more
precise estimation of the ꢀG of the reaction. It should also be mentioned that even though only
one product can be obtained from 17a, two distinct HCN fragments can be eliminated from A17a
1
since R = H.
Figure 2 summarizes the computed Gibbs free energies at 528 K related to steps iꢀiii for
compounds 3b (grey lines), 16b (light blue lines) and 17a (black lines). All values are relative to
the most stable conformers 3b , 16b and 17a .
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