Synthesis of Anionic Phosphorus-Containing Heterocycles by Intramolecular Cyclizations Involving N-Functionalized Phosphinecarboxamides

We report that the 2-phosphaethynolate anion (PCO−) reacts with propargylamines in the presence of a proton source to afford novel N-derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five- and six-membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5-exo-dig or 6-endo-dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus-containing heterocylic systems that are closely related to known organic molecules with interesting bio-active properties.


Synthesis of Anionic Phosphorus-Containing Heterocycles by Intramolecular Cyclizations Involving N-Functionalized Phosphinecarboxamides
Thomas P. Robinson and Jose M. Goicoechea* [a] Abstract: We report that the 2-phosphaethynolate anion (PCO À )r eacts with propargylamines in the presence of ap roton source to afford novel N-derivatizedp hosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five-and six-membered anionic heterocyclesr esulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5-exo-dig or 6-endo-digc yclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. Thiss trategy represents au nique approach to phosphorus-containing heterocylic systems that are closely related to known organic molecules with interesting bio-active properties.
Phosphorus-containing heterocyclesa re molecules of appreciable interest, particularly due to their role as supportingl igands in homogeneous catalysis. [1,2] Nevertheless, the straightforward preparation of such compounds on as ignificant scale remains challenging, largely due to the fact that many of the chemical transformations available for the synthesis of more traditional "organic" heterocycles are not available to phosphorus-containing species. Thisi sp articularly true for systemsw ith av ariety of different functional groups where competing side-reactions may take place. One of the most recent developments in the synthesis of novel phosphoruscarbon heterocycles has been the use of the 2-phospha-ethynolate anion,P CO À (first reported by Becker and co-workers), [3,4] for the synthesis of novel four-, five-and six-membered ring systems. [3, 4b, 5-8] In addition to affording molecules of fundamental importance,t hese recent studies have also produced redox-active systemsw hich may ultimately be employed as components in electronic devices. [8] We have recently developed an interest in designingp hosphorus-containing molecules that may be used as precursors to novel heterocyclesb ye xploiting existing paradigms for ring closure in organic compounds (or Baldwin's rules). [9] This research builds on previous studies by our group demonstrating that PCO À reacts with ammonium salts to afford phosphinecarboxamide, PH 2 C(O)NH 2 (a heavier analogue of urea). [10] Herein we show that this reaction exhibits significant functional group tolerance fort he synthesis of novel N-derivatized phosphinecarboxamides with reactive functional groups (in this case alkynes). Reaction of the 2-phosphaethynolate anion (PCO À )w ith propargylamines (NH 2 CH 2 CCH, NH 2 C(CH 3 ) 2 CCH, and NH 2 CH 2 CC(C 6 H 5 )) in the presence of ap roton source yields N-derivatized phosphinecarboxamides PH 2 C(O)NHCR 2 CCR' (R = R' = H( 1 ); R=CH 3 ,R '=H( 2 ); R=H, R' = C 6 H 5 (3)) as pictured in Scheme 1. [11] These reactions proceed quantitatively and rapidly (by the time NMR data are collected on crude reaction mixtures). The resulting products can be identified by their 31 PNMR spectra which reveal characteristic triplet resonances that collapse to singlets on proton decoupling (d = À132.4, d = À129.6, and d = À132.6 ppm for 1, 2,a nd 3,r espectively, with 1 J H-P coupling constants of approximately 208 Hz). Full experimental details are provided in the Supporting Information. Compound 3 was found to be unstable in solution, decomposing to am ixture of unidentified compounds within an hour,a lthoughi tc an be generated in situ and used fors ubsequent transformations (vide infra). By contrast, 1 and 2 are indefinitely stable in solutiona nd can be isolated in moderate to good yields as compositionally pure solids,a sd etermined by field-ionization mass spectrometry ande lementala nalysis. Both were additionally characterizedb ys ingle-crystal X-ray diffraction confirming the formation of N-(prop-2-yn-1-yl)phosphinecarboxamides ( Figure 1a nd Figure 2). To our knowledge,s uch compounds have not been reported previously,b ut are closely related to N-2-propyn-1-yl-acetamides (or N-propargylamides), which are commonly employed in organic chemistry,m ostn otably for the generation 2,5-oxazoles. [12,13] The structures of 1 and 2 exhibit comparable bond metrics and are closely related to that of PH 2 C(O)NH 2 .T he PÀC( 1 : 1.860(1) ; 2:1 .862(2) ), CÀO( 1:1 .240(2) ; 2:1 .229(3) ), and CÀNd istances (1:1 .332(2) ; 2:1 .331 (3) ) of the phosphinecarboxamide moiety are identicalw ithin experimental error and comparable to those recorded for PH 2 C(O)NH 2 (PÀC: 1.865(1) ; CÀO: 1.230(2) ; CÀN: 1.329 (2) ). [10] Moreover,b oth speciesa lso reveal the presence of aC À Ct riple bond with interatomic distances of 1.188(2) and 1.171(3) f or 1 and 2, respectively.
The optimized computed geometries at the density functional theory (DFT) level for 1-3 display closely related bond metric parameters, and those of 1 and 2 are in good agreement with the crystallographically determined values (see Supporting Information for furtherd etails). [14] The calculations show significant lone pair character on the phosphorus atom for the HOMO of 1 and 2 (42.39 %a nd 36.88 %, respectively) and the HOMOÀ1o f3(40.99 %), and large HOMO-LUMO gaps for all three species(ranging between 5.38 and 6.58 eV).
Deprotonation of 1 at À78 8Cu sing one equivalent of KHMDS reveals amixture of two products by 31 PNMR spectroscopy at d = À4.4 and À34.3 ppm. The former is aq uartet resonance ( 3 J H-P = 8.5Hz), whereas the latter appears as ad oublet of doublets ( 2 J H-P = 41.0 Hz, 3 J H-P = 6.3 Hz)-both of which collapse to singlet resonances on proton decoupling.B ased on these observations we were led to hypothesize that deprotonation of the phosphine moiety (-PH 2 )g ives rise to an anionic phosphide that can attack the alkyne functionality in an intramolecular fashion. The outcomeo fs uch ap rocess can give rise to two different products depending on whether the phosphide attacks the b or g carbon (relative to the amide nitrogen). According to Baldwin's rules, such reactions would either afford the 5-exo-digo r6 -endo-dig cyclization products,r espec-  Due to their comparable solubility,t he isolation of compositionally pure samples of 4 and 5 was not possible. Addition of 18-crown-6 (1,4,7,10,13,16-hexaoxacyclo-octadecane) to the reaction mixture allowed the crystallization of the 6-endo-dig product, 5,w hich wasc rystallographically characterized as [K(18-crown-6)][5]·0.5 THF (Figure 3). The structure confirms the formation of as ix-membered ring containing an intact carboxamide moiety.B ond metric data for this motif are consistent with significant delocalization of negative change between the phosphorus atom and the carbonyl moiety,o bservable in as horter P1ÀC1 and longer C1ÀO1 distance (1.799(2) and 1.269(2) , respectively) relative to that of the N-(prop-2-yn-1yl)phosphinecarboxamidep recursor (PÀC: 1.860(1) ; CÀO: 1.240 (2) ). The ring contains aC = Cb ond whichi sa pparent in the C3ÀC4 distance (1.311 (4) ). This value is notably longer than the alkyne in 1 (1.188 (2) ).
To our knowledge such six-membered phosphorus-containing heterocyclesa re entirely unprecedented. The structure is closely related to analogousc yclic urea systemss uch as 3,4-dihydropyrimidin-2(1 H)-ones. Such heterocyclic systems have attracted considerable interest in the organic chemistry community on account of their antiviral, antitumor, antibacterial, and anti-inflammatory activities. [15] In an effort to selectively target compositionally pure samples of the aforementioned heterocycles, we attempted analogous cyclizations employing the functionalized N-(prop-2-yn-1yl)phosphinecarboxamides PH 2 C(O)NHCR 2 CCR' (R = CH 3 ,R ' = H ( 2 ); R=H, R' = C 6 H 5 (3)). We postulated that introducing steric bulk at the a-carbon would favor the formation of the sixmembered 6-endo-dig product. By contrast, aryl substituents on terminal alkynes have been demonstrated to favor formation of the 5-exo-dig products. [16] Reaction of 2 with one equivalentofK HMDS in the presence of 18-crown-6g ives rise to as inglep roduct exhibiting am ulti-plet resonance in the 31 PNMR spectrum at d = À44.4 ppm (c.f. d = À129.6 ppm for 2). This doublet of doublets ( 2 J H-P = 40.4 Hz, 3 J H-P = 6.7 Hz) collapses to as inglet on proton decoupling. The downfield shift of this resonance compared to that of the phosphinecarboxamide precursor is consistent with the formation of ap hosphide. The chemical shift and coupling constant data for this new speciesa re closely relatedt ot hose recorded for 5 and are consistent with the formation of the 6endo-digc yclization product [cyclo-PC(O)NHC(CH 3 ) 2 CHCH] À (6).
Large colorless crystalso f[ K(18-crown-6)] [6]·THF could be isolated in good yield by cooling ac oncentrated THF solution of the reaction product to À30 8C.
The in situ generation of 3,a nd subsequent reaction with KHMDS in the presence of 18-crown-6 gives rise to as ingler eaction product exhibiting am ultiplet resonance at d = À16.2 ppm (dt, 3 J H-P = 13.4 Hz, 3 J H-P = 4.5 Hz). This speciesw as crystallized from THF at À30 8Ca nd identified as af ive-membered ring containing an exo-doubleb ond[ cyclo-PC(O)NHCH 2 C{CH(C 6 H 5 )}] À (7; Figure 5).  . This finding is consistent with theoretical calculations which show that isomer 8 is À9.9 kJ mol À1 more stable than 7.T he isomerization is accompanied by as hift of the 31 PNMR resonance from d = À16.2 to À3.5 ppm (this value is closely related to that recorded for 4 which was observed at d = À4.4 ppm). Crystals of [K(18-crown-6)][8]·1.5 py suitable for single-crystal X-ray diffraction were grown by diffusion of hexane into ac oncentrated pyridine solution of the product ( Figure 6). On account of the similarity of both isomers, bond metricdetailsare discussed in tandem.
Both crystal structures contain af ive-membered anionic ring system with ap hosphine carboxamide moiety.I nteratomic distances for the PÀC, CÀO, and CÀNb onds of the phosphinecarboxamide core are very similar in both systems (PÀC: 1.817(2) and 1.788(2) ; CÀO: 1.249(3) and 1.277(2) ; CÀN: 1.362(3) and 1.376(2) , for 7 and 8,r espectively). The most notable structuralv ariations involve the exo-substituent, in the case of 7,t he C3ÀC4 bond length is consistent with double bond character 1.359(3) . By contrast, in 8 the bond lengthens significantly to 1.504(3) ; this is accompanied by ac oncomitant shortening of the N1ÀC2 bond to 1.382(3) ( c.f. 1.448(3) i n 7 )a nd of the C2ÀC3 bond to 1.350(3) ( 1.518(3) i n7 ). Both anions are related to P-derivatized 1,3-azaphosphol-2-ones, previously reported in the chemical literature. [17] As with 5 and 6,t he optimized computed geometries from the DFT analysis are in close agreement with the experimentally determined ones. In both cases, there is as ignificant distribution of negative chargeb etween the phosphorus and oxygen atoms of the heterocycle, with ag reater accumulation of chargeo nt he oxygen atoms in both isomers.
We have demonstrated that N-functionalized phosphinecarboxamides (PH 2 C(O)NHR) bearing reactive functional groups are availableu sing the phosphorus-containing analogue of the cyanate anion (PCO À ). Intramolecular transformationsi nvolving these speciesa llow the synthesis of unprecedented five-and six-membered heterocycles. In addition to their fundamental interest, these novel compounds may ultimately be used for the synthesis of chiral phosphines and as precursors to polymeric materials. Studies on the subsequent reactivity of 1-8 are currently on-going.