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Synthesis of Novel Biaryl-Type P=C-N-Heterocyclic σ2P,N- and σ2P,σ3P-Hybrid Ligands

  • Phosphines are highly versatile ligands for transition metal catalysts because of wide tuning abilites of their stereoelectronic properties. Bulky and basic phosphines, to a smaller extend also π-acidic phosphites were intensively studied whereas dicoordinated trivalent phosphorus compounds were comparatively little investigated in this respect. In part this may go back to the limited stability of many P=C compounds, in the case of the stable benzazaphosphole to low stabilityof complexes with non-zero-valent transition metals. With the availability of suitable chelate complexes this problems may be overcome. Because biaryl phosphines proved particularly useful as chelate ligands this work is focused on the development of convenient syntheses of new biaryl-type N-heterocyclic or functionally aryl substituted 1,3-benzazaphosphole P,N- P,P- and P,O-chelate ligands and the characterization of their structures. The pivotal point was to find an applicable synthetic route to the title ligands. Because currently transition metal catalyzed cross-coupling reactions are a hot field in catalytic research, the initial target of my work was the investigation of the applicability of suitable biaryl coupling reactions on 1,3-benzazaphospholes. There are several types of transition metal catalyzed biaryl couplings. One reaction, which is currently in the main focus by use of non-toxic and air stable coupling partners, often allowing water as environmental friendly solvent, is the Pd-catalyzed Suzuki-Miyaura coupling of an aryl halide with an arylboronic acid. To apply the Suzuki coupling to the synthesis of biaryl-type benzazaphospholes, the synthesis of either benzazaphosphol-2-boronic acids or reactive 2-halogen-benzazaphospholes have to be performed. Because of the successful introduction of functional groups in position 2 of benzazaphospholes via lithiation and reaction with electrophiles, the 2-lithiation of suitably available N-substituted benzazaphospholes and introduction of boryl groups or halogen by reaction with boronic acid esters or with a halogenating reagent like dibromoethane appeared as a realistic route and was chosen for closer study. N-Neopentyl-benzazaphosphole was selected by its relatively easy access and N-mesityl-benzazaphosphole as a N-aryl representative. From the two principal methods developed to synthesize 1,3-benzazaphospholes, only the synthesis and reduction of o-aniline phosphonic acid esters to o-phosphinoanilines and subsequent [4+1] cyclocondensation is promising to access N-substituted 2-CH benzazaphospholes. My first investigations targeted to improve the synthesis of the benzazaphosphole precursors. The invention of a Cu- instead of the earlier used Pd-catalyzed P-C coupling allows a more economical access to anilinophosphonates which were then transformed to 2H-1,3-benzazaphospholes by the established orthoformamide cyclocondensation. Several attempts of the coupling with careful control of dryness of all reagents and solvents were made in order to obtain pure 1,3-benzazaphosphole-2-boronic acid ester and, after mild hydrolysis, to isolate 1,3-benzazaphosphole-2-boronic acid. The coupling worked with N-mesityl-1,3-benzazaphosphole 13e, but the benzazaphosphol-2-boronic acid could not be obtained in pure form because of easy B-C bond cleavage during crystallization, certainly by the two ‘OH groups. For attempts with a reverted methodology, the synthesis of a 2-bromo-substituted benzazaphosphole was studied, which should be coupled with (hetero)arylboronic acids via Suzuki-Mijaura reaction. However, the 2-bromo-benzazaphosphole also could not be obtained in pure form, and a coupling experiment with phenyl boronic acid and catalysis with ligand free Pd/C failed. Therefore, other routes to biaryl-type benzazaphospholes were envisaged. Direct C-H functionalization has emerged over the past few years as an attractive strategy to enhance molecular complexity. This holds also for π-excess-type heterocycles like indoles, benzoxazoles or purines which allow direct CH-arylation in 2-position. These reactions generally involve palladium based catalysts and in some cases rhodium catalysts. In a series of experiments the catalytic arylation, heteroarylation and later also alkylation were studied with 1,3-benzazaphospholes 13a-e as precursors. The initial studies were carried out with iodobenzene, keeping similar reaction conditions as for 2-CH arylation of indoles. Then transition metal catalysts, bases and conditions were varied. The necessity and influence of a catalyst was established by blind experiments without transition metal catalyst which led to strong decrease of the reactivity. However, the transitional metal catalyzed reactions of N-substituted-1,3-benzazaphosphole with aryl- and heteroaryl halides did not give the desired 2-aryl-substituted 1,3-benzazaphosphole biaryl ligands but revealed a novel oxidative addition at the P=C double bond. In the presence of moisture benzazaphospholine-P-oxides are formed. Further exploration of the scope of this reaction showed that it is applicable to several functionally substituted aryl halides and heteroaryl halides. As besides PdX2 (X = Cl, OAc) also Pd(0)(PPh3)4 was found active as catalyst, it can be assumed, that the reaction occurs via a Pd(0) species and oxidative addition of the aryl halide at Pd(0). Because Pd(0) will coordinate stronger to the π-acidic benzazaphosphole than Pd(II) it is assumed that in the first step small equilibrium amounts of a Pd(0)benzazaphosphole complex will be formed which undergo the oxidative addition and then react to benzazaphospholium salt and furnish back a Pd(0) complex with 1,3-benzazaphosphole ligand. The benzazaphospholium salts are highly sensitive to moisture and react with traces of water to form benzazaphospholine-P-oxides 20 and acid, neutralized by the base. A cyclic species RR’P(OH)=CHR”, where the halogen is replaced by OH, may be assumed as intermediate which undergoes a rearrangement to the more stable RR’P(=O)-CH2R” tautomer, driven by the high P=O bond energy. After various investigations of the optimum conditions for the reaction, a number of new functionally substituted P-aryl or P-heteroaryl benzazaphospholine P-oxides and 1,3-dineopentyl-benzazaphospholine-3-oxide were isolated and characterized by 1H, 31P, 13C and HRMS data and two by crystallography. The biaryl-type 2-phenyl-1,3-benzazaphosphole is known since the earliest reports of these heterocycles, synthesized by cyclocondensation of 2-phosphinoaniline with benziminoester hydrochloride or in low yield with benzaldehyde. The latter method was further developed because of the compatibility of the aldehyde group with various donor functions. 2-Phosphinoaniline (12a) and 2-phosphino-4-methylaniline (12b) were heated with pyridine-2-carboxaldehyde under varied conditions, and a crucial role of acid catalyst was observed in the investigation. The results showed that the dehydrogenating cyclocondensation, if catalyzed by a suitable type and amount of acid catalyst, works well for primary phosphinoanilines 12a,b and a variety of reactive aldehydes, including N-heterocyclic and o- or m-functionally substituted arylaldehydes. In an equimolar ratio, on heating usually hydrogen is eliminated, at least formally, to furnish the aromatically stabilized 1H-1,3-benzazaphosphole ring systems of 35 whereas in other cases reductive side reactions occur, e.g. the N-CH2R substitution to 36 in reactions with two equivalents of aldehyde. Thus the synthesis of 1,5-dimethyl-1,3-benzazaphosphole (36a) was achieved by double cyclocondensation of 12b and formaldehyde in a 1:2 molar ratio. This provides the so far shortest way to synthesize N-substituted 1,3-benzazaphospholes and suggests, that the reaction is generally applicable in reactions with two equivalents of monoaldehyde. This puts the question if N-secondary o-phosphinoanilines such as N-neopentyl-2-phosphinoaniline (12d) can be cyclocondensed with aldehydes to benzazaphospholes or if a primary amino group is required. The successful experiment shows that cyclocondensation of N-secondary o-phosphinoanilines with suitable aldehydes is possible. N-Neopentyl-2-pyrido-1,3-benzazaphosphole was obtained in high yield. An interesting extension of the above reaction are cyclocondensations with compounds bearing two aldehyde groups. Double condensation of 12b with o-phthaldialdehyde was performed. It proceeded fast and gave tetracyclic-1,3-benzazaphosphole in high yield. Based on the NMR monitored primary formation of organoammonium phosphino glycolates from amines, phosphines and glyoxylic acid, followed by conversion to phosphinoglycines, it is assumed that the reaction proceeds by initial attack of the primary phosphino group of 12b at the carbonyl carbon atom of R-CHO, polarized with the help of the acid catalyst. The resulting P-C bonded secondary phosphine, containing an α-hydroxy group, may release water after transfer of a proton to oxygen in equilibrium, followed by attack of amine. This leads to formation of the dihydro-intermediate 34, observed by NMR reaction monitoring in several cases. Possible ways are releasing of H2 during reflux, directly giving 2-substituted NH-1,3-benzazaphospholes 35, or hydrogen transfer, connected e.g. with N-substitution leading to 1,2-disubstituted 1,3-benzazaphospholes 36. The second path is observed mainly when excess or double molar quantities of aldehydes are used at the start of the reaction. The two hydrogen atoms at P and C2 are consumed during the second condensation and formation of the NCH2R group and generate the P=C double bond. Finally, cyclocondensation of o-phosphinoanilines with aldehydes has proven as a useful method for the synthesis of biaryl type benzazaphosphole ligands. After thorough investigations, N-primary and secondary phosphino anilines were found cyclisable with various heteroaryl aldehydes upon refluxing in toluene in the presence of a suitable acid catalyst, and 11 new compounds were synthesized following this procedure and characterized by 1H, 31P, 13C NMR and HRMS data. For two compounds crystal structures were also obtained. First attempts to synthesize chelate complexes with the 2-(hetero)aryl-1,3-benzazaphospholes were started. A soluble 2-(o-diphenylphosphinophenyl)-1,3-benzazaphoasphole-Cr(CO)4 chelate complex was detected by NMR spectroscopy, whereas most products of the new ligands with Rh(COD) or NiCp complexes were insoluble in usual NMR solvents and require further efforts for synthesis and full analytical and structural characterization.
  • Routes to functionally substituted biaryl-type 1H-1,3-benzazaphospholes, ligands with π-acidic dicoordinated phosphorus and a second donor atom at the 2-aryl group, were investigated. In a first approach the synthesis of benzazaphosphole-2-boronic acids for subsequent Suzuki coupling was studied by C2-lithiation of N-substituted benzazaphospholes, reaction with excess B(OMe)3 and hydrolytic workup. N-Mesitylbenzazaphosphole-2-boronic acid was detected by NMR but hydrolyzed to the starting material on repeated crystallization for purification. Therefore, direct arylation of 2-unsubstituted 1,3-benzazaphospholes was investigated. The C-P diagonal related indoles react preferably in 2-position. For the benzazaphospholes, however, P-arylation was observed with Pd catalysts in the presence of bases. The primary products are highly sensitive to moisture and could not be obtained pure, but in the presence of small (or larger) amounts of moisture a variety of P-aryl benzazaphospholine-P-oxides was obtained and structurally characterized. Neopentyl iodide reacts even without a transition metal catalyst. Finally, a broadly applicable route to the target molecules was found in the condensation of 2-phosphinoanilines with (hetero)arylaldehydes, which tolerate various functional groups. Refluxing in a 1:1 molar ratio in toluene in the presence of a suitable catalyst, e.g. p-tolylsulfonic acid, provided the functionally substituted 2-(hetero)arylbenzazaphospholes with 2-pyrid-2-yl-, imidazol-2-yl-, o-diphenyl- or o-dicyclohexylphosphinophenyl group in rather good yields via unstable intermediate dihydrobenzazaphospholes. The fate of hydrogen is not yet clear. In a 1:2 molar ratio cyclization and reductive N-substitution occurs, e.g. with formaline to N-methyl-1,3-benzazaphosphole. With formylbenzonitrile and, in better yield and purity, with o-phthalbiscarbaldehyde a planar tetracyclic benzazaphosphole with N-CH2-bridge to the o-position of the 2-phenyl group was formed. One CHO group of glyoxal is reduced to methyl by the intermediate dihydrobenzazaphosphole producing 2-methyl-1,3-benzazaphosphole. Pyridine-2,6-bis(carbaldehyde) reacts with partial cleavage of PH3 to a mixture of the wanted 2,6-bis(benzazaphospholyl)pyridine pincer ligand (minor) and a 2-benzazaphospholyl-6-tolylaminomethyl-pyridine P,N,N-pincer ligand (major). In preliminary studies on complex formation a 2-pyridyl-1,3-benzazaphosphole Cr(CO)4 P,N-chelate complex and a W(CO)5-complex of the tetracyclic benzazaphosphole were obtained. The structures of the compounds were elucidated by multinuclear NMR- and HRMS-spectra and for three compounds by X-ray structure analysis. Kurze Inhaltszusammenfassung in deutsch (2745 Buchstaben) Synthesewege zu funktionell substituierten Biaryl-Typ 1H-1,3-Benzazaphospholen, Liganden mit π-acidem zweifach koordiniertem Phosphor und einem zweiten Donoratom an der 2-Arylgruppe, wurden untersucht. In einem ersten Ansatz wurden Synthesen von Benzazaphosphol-2-boronsäuren für eine nachfolgende Suzuki-Kopplung über C2-Lithiierung von N-substituierten Benzazaphospholen, Reaktion mit überschüssigem B(OMe)3 und hydrolytische Aufarbeitung versucht. N-Mesitylbenzazaphosphol-2-boronsäure wurde NMR-spektroskopisch nachgewiesen, zersetzt sich aber bei der Reinigung durch wiederholtes Umkristallisieren unter C-B-Bindungsspaltung zur C-H Ausgangsverbindung. Deswegen wurde die direkte Arylierung von 2-unsubstituierten 1,3-Benzazaphospholen studiert. Die nach der C-P-Schrägbeziehung verwandten Indole reagieren vorzugsweise in 2-Position. Bei den Benzazaphospholen wurde jedoch unter vergleichbaren Reaktionsbedingungen mit Pd-Katalysatoren in Gegenwart von zwei Äquivalenten Base P-Arylierung beobachtet. Die primären Produkte sind sehr feuchtigkeitsempfindlich und konnten nicht rein erhalten werden. In Gegenwart schon geringer Mengen von Feuchtigkeit wurden eine Reihe P-arylsubstituierter Benzazaphospholin-P-oxide erhalten, deren Struktur durch NMR, HRMS und Kristallstrukturanalyse gesichert ist. Schließlich wurde auch ein breit anwendbarer Zugang zu den Zielmolekülen durch Cyclokondensation von 2-Phosphinoanilinen mit (Hetero)Arylaldehyden gefunden, die eine Reihe funktioneller Gruppen tolerieren. Umsetzung in einem Molverhältnis 1:1 führt beim Erhitzen in Toluol in Gegenwart eines geeigneten Katalysators, z.B. p-Toluolsulfonsäure, in relativ guten Ausbeuten über wenig stabile, intermediäre Dihydrobenzazaphosphole zu funktionell substituierten 2-(Hetero)arylbenzazaphospholen mit 2-Pyrid-2-yl-, Imidazol-2-yl-, o-Diphenyl- or o-Dicyclohexylphosphinophenyl-Gruppen. Der Verbleib des Wasserstoffs ist hier noch unklar. In einem Molverhältnis 1:2 erfolgt die Cyclokondensation verbunden mit einer reduktiven N-Substitution, z.B. mit Formalin unter Bildung von N-Methyl-1,3-benzazaphosphol. Mit 2-Formylbenzonitril und, in besserer Ausbeute und Reinheit, mit o-Phthalbis(carbaldehyd) wird ein planares tetracyclisches Benzazaphosphol mit N-CH2-Brücke zur o-Position der 2-Phenylgruppe gebildet. Bei Reaktion mit Glyoxal wird eine CHO-Gruppe durch das intermediäre Dihydrobenzazaphosphol zu CH3 reduziert, wodurch 2-Methyl-1,3-benzazaphosphol entsteht. Pyridine-2,6-bis(carbaldehyd) reagiert unter partieller Abspaltung von PH3 zu einer Mischung des erwünschten 2,6-Bis(benzazaphospholyl)pyridin Pincerliganden (Nebenprodukt) und dem P,N,N-Pincerligand 2-Benzazaphospholyl-6-tolylaminomethyl-pyridin (Hauptprodukt). In vorläufigen Studien zur Komplexbildung wurde ein 2-Pyridyl-1,3-benzazaphosphole Cr(CO)4 P,N-Chelatkomplex und ein W(CO)5-Komplex des tetracyclischen Benzazaphosphols erhalten. Die Strukturen der Verbindungen wurden durch Multikern-NMR- und HRMS-Spektren und für drei Verbindungen durch Röntgenstrukturanalyse charakterisiert.

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Author: Basit Niaz
Title Additional (English):Synthesis of Novel Biaryl-Type P=C-N-Heterocyclic σ2P,N- and σ2P,σ3P-Hybrid Ligands
Title Additional (German):Synthese neuartiger Biaryl-Typ P=C-N-heterocyclischer σ2P,N- und σ2P,σ3P-Hybridliganden
Advisor:Prof. Dr. Joachim W. Heinicke
Document Type:Doctoral Thesis
Date of Publication (online):2012/03/31
Granting Institution:Ernst-Moritz-Arndt-Universität, Mathematisch-Naturwissenschaftliche Fakultät (bis 31.05.2018)
Date of final exam:2011/03/18
Release Date:2012/03/31
Tag:Azaphospholderivat; Biaryle; Cyclisation; Ligand; Phosphine
Benzazaphosphole; Dehydrocyclisation; Hybrid ligand; P-Arylation; Phosphinoaniline
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie
DDC class:500 Naturwissenschaften und Mathematik / 540 Chemie