Intramolecular carbolithiation of N-allyl-ynamides: An efficient entry to 1,4-dihydropyridines and pyridines - Application to a formal synthesis of sarizotan

Article abstract of DOI:10.3762/bjoc.8.250

We have developed a general synthesis of polysubstituted 1,4-dihydropyridines and pyridines based on a highly regioselective lithiation/6-endo-dig intramolecular carbolithiation from readily available N-allyl-ynamides. This reaction, which has been successfully applied to the formal synthesis of the anti-dyskinesia agent sarizotan, further extends the use of ynamides in organic synthesis and further demonstrates the synthetic efficiency of carbometallation reactions.

Full text of DOI:10.3762/bjoc.8.250

Intramolecular carbolithiation of N-allyl-ynamides: an
efficient entry to 1,4-dihydropyridines and pyridines –
application to a formal synthesis of sarizotan
Wafa Gati1,2, Mohamed M. Rammah2, Mohamed B. Rammah2
and Gwilherm Evano*3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2214–2222.
1Institut Lavoisier de Versailles, UMR CNRS 8180, Université de
Versailles Saint-Quentin-en-Yvelines, 45, avenue des Etats-Unis,
78035 Versailles Cedex, France, 2Laboratoire de Chimie Organique
Hétérocyclique LCOH/LCOHSNR-LR11ES39, Département de
Chimie, Faculté des Sciences de Monastir, Université de Monastir,
avenue de l’environnement, 5019 Monastir, Tunisia, and 3Laboratoire
de Chimie Organique, Service de Chimie et PhysicoChimie
Organiques, Université Libre de Bruxelles, Avenue F. D. Roosevelt
50, CP160/06, 1050 Brussels, Belgium
doi:10.3762/bjoc.8.250
Received: 15 November 2012
Accepted: 11 December 2012
Published: 21 December 2012
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
Email:
© 2012 Gati et al; licensee Beilstein-Institut.
License and terms: see end of document.
Gwilherm Evano* - gevano@ulb.ac.be
* Corresponding author
Keywords:
carbolithiation; carbometallation; dihydropyridines; organolithium
reagents; pyridines; sarizotan; ynamides
Abstract
We have developed a general synthesis of polysubstituted 1,4-dihydropyridines and pyridines based on a highly regioselective lithi-
ation/6-endo-dig intramolecular carbolithiation from readily available N-allyl-ynamides. This reaction, which has been successfully
applied to the formal synthesis of the anti-dyskinesia agent sarizotan, further extends the use of ynamides in organic synthesis and
further demonstrates the synthetic efficiency of carbometallation reactions.
Introduction
Since the discovery of the carbometallation reaction by Ziegler magnesium, zirconium, titanium, palladium and other metals
and Bähr in 1928 [1], this reaction has evolved as a most are suitable for this transformation and considerable progress
powerful tool to construct carbon–carbon bonds. An ever has recently been made in this area. Among these systems, the
increasing number of organometallic species have been shown carbometallation of alkynes constitutes a most efficient entry to
over the years to be suitable reagents for the carbometallation of polysubstituted alkenes, provided that both the regioselectivity
various carbon–carbon multiple bonds. Lithium, copper, zinc, and the stereoselectivity can be controlled [2-5]. In this context,
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an efficient strategy to control these selectivity issues is the intermediate and the less-stable allyllithium 3, an intramolec-
incorporation of a heteroatom directly attached to the triple ular carbometallation may then occur to yield a chelation-stabi-
bond, which can dramatically affect both the regio- and stereo- lized vinyllithium 4 and drive the overall process to the forma-
chemical outcomes due to the polarization of the triple bond tion of the heterocyclic ring system. Further reaction with an
and/or the formation of chelation-stabilized vinylmetal species. electrophile followed by aqueous workup or hydrolysis under
The carbometallation of O-, N-, P-, S-, and Si-substituted acidic and oxidative conditions would then afford the highly
alkynes has indeed been quite extensively studied and shown to substituted dihydropyridine or pyridine derivatives 5 and 6, res-
provide most efficient entries to polysubstituted, stereodefined pectively. While there were no examples of such exclusive
heteroatom-substituted alkenes and has been implemented in anionic 6-endo-dig cyclizations reported to the best of our
remarkably elegant processes [6]. Intramolecular versions are knowledge [39], we felt that the presence of the chelating group
especially attractive and provide most useful entries to highly on the nitrogen may allow such a selective process and a clean
substituted carbo- and heterocycles.
formation of the (dihydro)pyridine ring system. We have indeed
demonstrated the efficiency of this strategy [40] and now report
Based on our recent interest in the chemistry of ynamides [7-18] in this manuscript a full account on this work as well as the
and inspired by recent reports from Meyer and Cossy [19-21], application of our pyridine synthesis to a formal synthesis of the
Marek [22-24] and Lam [25,26] on their carbopalladation, anti-dyskinesia agent sarizotan.
carbocupration and carbozincation, respectively, we decided to
Results and Discussion
study the intramolecular carbolithiation of ynamides, which
Feasibility of the deprotonation/intramolec-
ular carbolithiation
may provide an interesting entry to highly functionalized 1,4-
dihydropyridines [27-29] and pyridines [30-33], most useful
building blocks in organic synthesis and medicinal chemistry as
well. Our strategy is summarized in Scheme 1 and is based on
the following assumptions: According to the remarkable work
of the Beak group on the α-lithiation of Boc-protected amines
[34-38], N-allyl-ynamides 1 should be readily deprotonated to
afford a transient chelation-stabilized allyllithium 2 and,
provided that a metallotropic equilibrium exists between this
To first evaluate the compatibility of the ynamide moiety with
the lithiation step and address potential problems associated
with competitive carbolithiation of the activated alkyne, we first
reacted N-benzyl-ynamide 7 with one equivalent of sec-butyl-
lithium and tetramethylethylenediamine (TMEDA) in THF at
−78 °C for 15 minutes, followed by the addition of methyl
iodide. The corresponding N-phenylethyl-ynamide 8 was
Scheme 1: Strategy for the synthesis of (1,4-dihydro)pyridines by deprotonation/intramolecular carbolithiation.
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obtained in nearly quantitative yield, therefore demonstrating Hsung’s second-generation synthesis based on the copper-medi-
the compatibility of the ynamide group with the deprotonation ated cross-coupling between bromoalkynes 9 and nitrogen
step (Scheme 2a), although longer reaction times before the nucleophiles [42] turned out to be the most convenient one, the
addition of methyl iodide resulted in much lower yields and use of terminal alkynes [43], gem-dibromoalkenes [7], potas-
extensive degradation: The intramolecular carbolithiation of sium alkynyltrifluoroborates [8] or copper acetylides [12] being
N-allyl-ynamides to 1,4-dihydropyridines might therefore be less efficient when bulky N-Boc-allylamines 10 were used as
possible, provided that the overall reaction rate is not too slow. nucleophiles. By using a slightly modified Hsung’s procedure, a
To further test this hypothesis, N-allyl-ynamide 1a was reacted series of N-allyl-ynamides 1 could be readily prepared in
under similar reaction conditions and to our delight, a smooth acceptable yields using a combination of copper(II) sulfate
cyclization occurred, the expected 1,4-dihydropyridine 5a being pentahydrate (40 mol %) and 1,10-phenanthroline (80 mol %)
virtually formed as virtually the sole product (Scheme 2b), a with potassium phosphate in refluxing toluene, the major side
clean reaction being a strict requirement for the development of reaction observed in all cases being the competitive dimeriza-
a general route to 1,4-dihydropyridines devoided of an electron- tion of the starting bromoalkynes (Scheme 3).
withdrawing group at C-3, due to the instability of these acid-
Intramolecular carbolithiation of N-allyl-
and oxygen-sensitive molecules. In situ conversion of the inter-
ynamides to 1,4-dihydropyridines and
pyridines: scope and limitations
mediate dihydropyridine to the corresponding pyridine by
replacing the saturated aqueous ammonium chloride solution,
used for the workup, by a combination of acetic acid and
o-chloranil [41] was equally successful and provided the
expected pyridine 6a in 81% yield (Scheme 2c).
With this set of ynamides in hand, we next evaluated their
cyclization to the corresponding 1,4-dihydropyridines 5 or
pyridines 6 using the lithiation/intramolecular carbolithiation
sequence. All N-allyl-ynamides 1 shown in Scheme 3 were
therefore treated with s-butyllithium and TMEDA in THF at
−78 °C for one hour followed by the addition of an aqueous
saturated solution of ammonium chloride (Scheme 4, condi-
tions A) or acetic acid and o-chloranil (Scheme 4, conditions
B), yielding the corresponding 1,4-dihydropyridines 5 or
Synthesis of the starting N-allyl-ynamides
Before moving to the evaluation of the scope and limitations of
this intramolecular carbolithiation, we had to prepare a set of
ynamides possessing representative substituents on both the
ynamide and allyl groups. Among all the methods evaluated,
Scheme 2: Feasibility of the deprotonation/intramolecular carbolithiation.
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Scheme 3: Synthesis of the starting N-allyl-ynamides.
pyridines 6, respectively. Results from these studies are afford the cyclized products, which could also not be obtained
collected in Scheme 4, yields being indicated only in the pyri- either when starting from a TIPS-protected primary ynamide (5/
dine series due to the high sensitivity of the 1,4-dihydropyri- 6k), the silicon protecting group being readily cleaved under the
dine derivatives, which were obtained in virtually pure form in reaction conditions. The influence of the substitution pattern of
crude reaction mixtures. As evidenced with these results, 3-aryl- the allyl moiety was next carefully examined and substitution at
1,4-dihydropyridines and pyridines (5/6a–f and l–r) are readily the β-, γ-positions, or both, was well tolerated, yielding the 3,5-
obtained from the corresponding aryl-substituted N-allyl- disubstituted- (5/6l–o), 3,4-disubstituted- (5/6p–q) and 3,4,5-
ynamides regardless of the substitution pattern or the electronic trisubstituted- (5/6r) 1,4-dihydropyridines and pyridines in
properties of the aromatic ring. The reaction is also efficient in good yields, respectively, compounds that are rather chal-
the case of an alkenyl group (5/6g) and the presence of an alkyl lenging to obtain using other synthetic routes. In addition, the
group was, as expected, more problematic due to competitive reaction can be performed on a gram-scale with similar effi-
propargylic lithiation. Indeed, while a tert-butyl group was well ciency. This was indeed briefly evaluated for the anionic
tolerated (5/6h), the presence of secondary or primary alkyl cyclization of ynamide 1a and the exact same yield of the
chains such as cyclohexyl (5/6i) or n-hexyl (5/6j) groups did not corresponding pyridine 6a (81%) was obtained on a gram scale.
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Scheme 4: Intramolecular carbolithiation of N-allyl-ynamides to 1,4-dihydropyridines and pyridines.
With a chelation-stabilized vinyllithium being formed after the conditions and then treated with deuterated water (Scheme 5a)
anionic 6-endo-dig cyclization, we next considered the possi- or methyl iodide (Scheme 5b) before the acidic and oxidative
bility of trapping this vinyllithium with an electrophile, which workup. While the desired 2,3-disubstituted 6s and 6t were
might allow the introduction of an additional C-2 substituent. indeed formed under these conditions, they could only be
N-Allyl-ynamide 1a was therefore cyclized under our standard isolated in modest yields (30–33%), even in the presence of
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Beilstein J. Org. Chem. 2012, 8, 2214–2222.
additional HMPA, which might may constitute the major limita-
tion of our process. Other attempts involving electrophiles such
as acid chlorides and allyl bromide or transmetallation with zinc
chloride and Negishi cross-coupling were unsuccessful, which
does confirm that our deprotonation/carbometallation sequence
is not suitable for the preparation of C-2-substituted (1,4-
dihydro)pyridines.
Application to a formal synthesis of sarizotan
To further probe the synthetic utility of our pyridine synthesis,
we next envisioned its use for the synthesis of the 3,5-disubsti-
tuted pyridine core of the antidyskinetic drug, 5-HT1A receptor
agonist, dopamine D2 receptor ligand sarizotan 19 (Scheme 6).
The pyridinyl-chroman sarizotan (also called EMD-128130)
was originally developed by Merck KGaA in the late 1990’s
[44] and was found to be a dual selective 5-HT1A receptor
agonist and D2 receptor antagonist displaying a strong efficacy
in the reduction of dyskinesia resulting from long-term
antiparkinsonian treatment with levodopa [45-50]. Although its
development was stopped by Merck KGaA in 2006 after
Scheme 5: 2,3-Disubstituted pyridines by trapping of the intermediate
metallated 1,4-dihydropyridine.
Scheme 6: Formal synthesis of the anti-dyskinesia agent, 5-HT1A receptor agonist, dopamine D2 receptor ligand sarizotan.
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Beilstein J. Org. Chem. 2012, 8, 2214–2222.
analysis of data from Phase III clinical trials failed to confirm
its efficiency [51], sarizotan is still under intense investigation
[52-54] and was recently licensed to Newron Pharmaceuticals
for further testing in new indications [55].
Supporting Information
Experimental details and copies of NMR spectra for all new
compounds.
Supporting Information File 1
Experimental.
Motivated by the high potential of sarizotan and by the clear
lack of structure-activity relationship studies on the pyridine
core of this bioactive compound [56], we designed an efficient
and modular synthesis of the disubstituted pyridine core of sari-
zotan that should enable the preparation of sarizotan analogues
with different substitution on the pyridine ring. This synthesis is
shown in Scheme 6 and starts from commercially available
2-methylene-1,3-propanediol (11). Mono-protection of this diol
as a TBS ether and activation of the remaining alcohol as a
mesylate according to previously reported procedures [57,58],
gave allylic mesylate 12, which was next reacted with potas-
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-250-S1.pdf]
Supporting Information File 2
Copies of 1H and 13C NMR spectra for new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-250-S2.pdf]
sium phthalimide in DMF at 90 °C, affording the corres- Acknowledgements
ponding N-allylphthalimide. Deprotection of the phthalimide by The authors thank the CNRS, the Universities of Versailles,
hydrazinolysis followed by protection of the resulting primary Monastir and Brussels, the ANR (project DYNAMITE ANR-
amine as a tert-butyl-carbamate gave the Boc-protected amine 2010-BLAN-704) and the CMCU/PHC Utique (grant 10G1025)
13 required for the synthesis of the substrate of the anionic for support. We are grateful to Ms. Estelle Galmiche and Mr.
cyclization. Indeed, this amine 13 was engaged in a copper- Flavien Bourdreux (Lavoisier Institute) for their assistance with
catalyzed cross-coupling with 1-(bromoethynyl)-4-fluoroben- HRMS and NMR analyses and to Mr. Guillaume Boissonnat
zene (14) and gave the corresponding ynamide 15 in a modest, (Université Libre de Bruxelles and Ecole Polytechnique Paris-
unoptimized 36% yield. This set the stage for the key lithiation/ Tech) for technical assistance.
intramolecular carbolithiation/oxidation step for the formation
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