Letter pubs.acs.org/OrgLett
Chemo‑, Regio‑, and Enantioselective Rhodium-Catalyzed Allylation of Pyridazinones with Terminal Allenes Shaista Parveen,†,‡ Changkun Li,† Abbas Hassan,†,‡ and Bernhard Breit*,† †
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg im Breisgau, Germany Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
‡
S Supporting Information *
ABSTRACT: The rhodium-catalyzed addition of pyridazinones to terminal allenes furnished the corresponding branched N2-allylated products in good yields with high regio- and enantioselectivities. A broad functional group compatibility was observed, and assorted synthetic transformations of the N-allylpyridazinones led to the preparation of a small library of N2-functionalized pyridazinones. Labeling experiments with deuterated substrates provided insights into the underlying reaction mechanism.
N
itrogen-containing heterocycles such as chiral N2alkylated pyridazinones are found as pharmacophores in a large number of drug candidates displaying a vast array of physiological activities. Among them are antiasthmatic agents,1 HCV inhibitors (a),2 antidiabetics (b, d),3 gamma secretase modulators (c),4 and agents exhibiting cyctotoxic,5 antihypertensive,6 and antinociceptive7 properties (Figure 1).1
Scheme 1. Synthesis of N-Substituted Pyridazinones
regio-, and enantioselective addition of pyridazinones to terminal allenes providing access to secondary α-chiral N2allylated pyridazinones. Initial reactivity assays were carried out using 6-chloro-2Hpyridazin-3-one (1a) and 3-phenylpropylallene (2b) in the presence of 2.5 mol % [{Rh(COD)Cl}2] and 5 mol % of racBINAP in 1,2-dichloroethane (DCE) at 80 °C (Table 1). To our delight the N2-allylated product (3aa) was obtained as the exclusive isomer in 92% yield, as well as in highly branched regioselectivity. Based on this promising result we initiated a screening of various chiral bidentate biphosphine ligands.14 Most of the employed ligands gave satisfying results in terms of regio- and chemoselectivity as well as conversion and yields but exhibited poor enantioselectivities. Fortunately, we found a class of biaryl biphosphine ligands that provided promising enantioselectivities (75−89%). Among them the 3,5-diisoprop4-dimethylamino-substituted MeObiphep ligand (L5) proved
Figure 1. Bioactive molecules with N2-alkyl pyridazinone scaffold.
N-Substituted pyridazinones are usually prepared either by condensation of substituted hydrazines with diacids8 or by alkylation of pyridazinones with alkyl or aryl halides.9 α-Chiral N2-alkylated derivatives require alkylation reactions with preformed chiral electrophiles (Scheme 1).10 These methods either necessitate multiple steps, generate a stoichiometric amount of waste, require the preparation of chiral electrophiles, or suffer from structural restraints. We recently reported on the rhodium-catalyzed, atomeconomic, and highly regioselective addition of different pronucleophiles to allenes and alkynes,11 a methodology that can be regarded as an alternative to transition-metal-catalyzed allylic substitution12 and oxidation13 to generate branched allylic products. We herein report on the rhodium-catalyzed chemo-, © 2017 American Chemical Society
Received: March 23, 2017 Published: April 19, 2017 2326
DOI: 10.1021/acs.orglett.7b00718 Org. Lett. 2017, 19, 2326−2329
Letter
Organic Letters Table 1. Ligand Screening for Regio- and Enantioselective N-Allylation of Pyridazinone 1a with Allene 2aa
entry
ligand
B:Lb
yieldc (%)
eed (%)
1 2 3 4 5 6
rac-BINAP L1 L2 L3 L4 L5
9:1 10:1 4:1 17:1 9:1 19:1
92 92 91 82 77 96
− 64 30 75 82 89
Table 2. Allylation of 6-Chloro-2H-pyridazin-3-one with Different Terminal Allenes
a c
0.2 mmol scale reaction. bThe ratio determined from crude 1H NMR. Yields of isolated product. dDetermined by chiral HPLC analysis.
a
7.5 mol % L5 was used. bee after recrystallization.
Table 3. N-Allylation of Various Substituted Pyridazinonesa,b to be the best ligand for asymmetric allylation of pyridazinones with allenes, exhibiting a good combination of yield, B:L ratio, and enantioselectivity (Table 1, entry 6). With the optimized reaction conditions in hand, we started to explore the reaction scope by initially coupling 6-chloro-2Hpyridazin-3-one (1a) with a range of structurally diverse allenes (Table 2). Various substituents like alkyl (3aa, 3ag, 3aj) or cycloalkyl (3af, 3ad) reacted smoothly to furnish the corresponding N-allylated products not only in excellent yields and B:L ratios but also in good enantioselectivities. Protected hydroxy functions such as silyl ethers (3ab) and benzoyl ethers (3ac) as well as ketones (3ae), sulfonyl (3ai), phthalimidoyl moieties (3ak) were well tolerated as were free hydroxy functions (3ah). Elaborating the scope and practicality of the present allylation methodology, we further investigated the coupling reactions of various substituted pyridazinones with the standard allene 3c (Table 3). Besides monosubstituted 2H-pyridazinones, disubstituted analogues could be allylated smoothly with excellent yields and good enantioselectivities. To highlight the synthetic utility of the newly synthesized Nallyl pyridazinones, we performed assorted transformations, converting the allylic moiety into various useful functional groups (Scheme 2). Hydrogenation, using 10% wt Pd/C at 0 °C, gave Nalkylpyridazin-one (4a) in 96% yield while hydroxylation via hydroboration/oxidation furnished 78% of the anti-Markovnikov alcohol (4b). N-Allyl pyridazinone was also found to be compatible with our hydroformylation and ozonolysis conditions, giving the corresponding aldehydes (4c and 4d), by using either our self-assembly [Rh(CO)2acac]/6-DPPon
a
The B:L ratio was determined from crude 1H NMR. bee values were determined by chiral HPLC analysis. c7.5 mol % ligand was used.
catalyst system15 or O3/PPh3, in 91% and 82% yields, respectively. To gain insights into the reaction mechanism, labeling studies with N2-deuterated pyridazinone 5a were performed (Scheme 3). As previously observed with other nitrogen pronucleophile systems, we observed deuterium incorporation at both the terminal and internal position of the allylic double bond. This is in agreement with a reaction mechanism as proposed for other pro-nucleophiles involving a reversible hydrometalation/β-hydride elimination of the less substituted 2327
DOI: 10.1021/acs.orglett.7b00718 Org. Lett. 2017, 19, 2326−2329
Letter
Organic Letters
Synthetic procedures for new compounds as well as their analytical data, involving 1H NMR, 13C NMR spectra and scanned HPLC chromatograms for chiral compounds (PDF)
Scheme 2. Assorted Transformations of N-Allyl Pyridazinone 3aa
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Bernhard Breit: 0000-0002-2514-3898 Notes
The authors declare no competing financial interest. Single-crystal X-ray crystallographic data supporting this publication can be accessed at www.ccdc.cam.ac.uk/data_ request/cif under CCDC deposition number 1511721.
Scheme 3. Labelling Experiments with N2-Deuterated 5a
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ACKNOWLEDGMENTS We acknowledge DFG (Deutsche Forschungsgemeinschaft) for supporting our program and also Dr. Daniel Kratzert for crystallographic analysis. S.P. acknowledges DAAD Germany for a research fellowship.
π-bond of the allene, passing rhodium-vinyl intermediate B (Scheme 4). Hydrometalation of the more substituted allene πbond generates π-allyl complex C which, after reductive elimination, liberates the allylation product D.
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Scheme 4. Proposed Mechanism for the Rhodium-Catalyzed Synthesis of N-Allyl Pyridazinones via Hydroamination of Allenes
In summary, rhodium-catalyzed asymmetric allylation of the pyridazinone scaffold via addition to terminal allenes proved to be a mild, efficient, and functional-group-tolerant methodology for the syntheses of N-allyl-1,2-diazinones in excellent yields, with high levels of chemo-, regio-, and enantiocontrol under neutral conditions. A broad range of new chiral N2-allylated pyridazinones were prepared by coupling various functionalized allenes with a wide variety of substituted pyridazinones in an essentially byproduct-free manner. Furthermore, assorted transformations of the allylated products furnished a variety of N2-functionalized pyridazinones representing valuable pharmaceutical building blocks rendering this new methodology a valuable addition to the toolbox of asymmetric allylation chemistry.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00718. 2328
DOI: 10.1021/acs.orglett.7b00718 Org. Lett. 2017, 19, 2326−2329
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DOI: 10.1021/acs.orglett.7b00718 Org. Lett. 2017, 19, 2326−2329
