Photoassisted Diversity-Oriented Synthesis: Intramolecular Cycloadditions of Photogenerated Azaxylylenes with Oxazole Pendants, and Subsequent Postphotochemical Multicomponent Modifications.

Photogenerated aza-o-xylylenes undergo intramolecular cycloaddition reactions to tethered oxazoles, with primary photoproducts featuring a reactive cyclic imine moiety suitable for multicomponent postphotochemical transformations. For example, the reaction of these imine photoproducts with bromoacetyl bromide leads to a key 1,4-dielectrophilic synthon, offering access to diverse polyheterocyclic molecular architectures. This reaction sequence is accompanied by rapid growth complexity in a very few simple synthetic steps, and is in keeping with the philosophy of diversity-oriented synthesis (DOS).

Intramolecular cycloadditions of photogenerated azaxylylenes with oxadiazoles provide direct access to versatile polyheterocyclic ketopiperazines containing a spiro-oxirane moiety.

Photogenerated azaxylylenes undergo intramolecular cycloadditions to 1,3,4-oxadiazole pendants, which are accompanied by concomitant release of dinitrogen, yielding functionalized ketopiperazinoquinolinols containing an oxirane moiety fused to the quinolinole moiety while spiro-connected to diketopiperazine. These primary photoproducts are reactive versatile intermediates which can be further derivatized under nucleophilic SN1- or SN2-like ring opening of the oxirane moiety. The oxidized quinolinones undergo new rearrangements under the conditions of the Schmidt reaction, leading to unprecedented triazacanoindolinones.

Photoassisted diversity-oriented synthesis: accessing 2,6-epoxyazocane (oxamorphan) cores.

The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the aniline nitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.

Intramolecular cycloadditions of photogenerated azaxylylenes: an experimental and theoretical study.

The mechanism of intramolecular cycloadditions of azaxylylenes photogenerated via excited-state intramolecular proton transfer (ESIPT) in aromatic o-amido ketones and aldehydes bearing unsaturated functionalities was studied experimentally and computationally. In time-correlated single-photon counting experiments, no relation was found between lifetimes of singlet species and the nature of the amide pendant, either unsaturated furanpropanamide, capable of photocyclization, or the acetamide control. Steady-state emission for amido-tetralone derivatives showed comparable dual emission bands, but bromo substitution decreased the intensity of the ESIPT band. The most reactive derivatives of amidobenzaldehydes were virtually lacking the ESIPT band. The quantum yield of cycloaddition is decreased in the presence of triplet quenchers, O2 or trans-piperylene, and improved with heavy atom substitution in the aromatic ring, providing further evidence for the initial mechanistic hypothesis in which the fast singlet-state ESIPT is accompanied by the ISC in the tautomer (azaxylylene), which undergoes stepwise addition to the tethered unsaturated pendants.

Photoassisted synthesis of enantiopure alkaloid mimics possessing unprecedented polyheterocyclic cores.

Enantiopure alkaloid mimics are synthesized via high yielding intramolecular cycloadditions of photogenerated azaxylylenes tethered to pyrroles, with further growth of molecular complexity via post-photochemical transformations of primary photoproducts. This expeditious access to structurally unprecedented polyheterocyclic cores is being developed in the context of diversity-oriented synthesis, as the modular design allows for rapid "pre-assembly" of diverse photoprecursors from simple building blocks/diversity inputs.

Photoassisted access to enantiopure conformationally locked ribofuranosylamines spiro-linked to oxazolidino-diketopiperazines.

N-Furoylated L-threonine-, serine-, or cysteine-based aminoacetals are coupled with o-aminoketones or aldehydes to offer rapid access to diverse enantiopure polyheterocycles possessing conformationally locked aminoglycoside-containing molecular scaffolds. The key step involves photogeneration of azaxylylenes which undergo [4 + 4] or [4 + 2] cycloadditions to the tethered furoyl pendants.

Reactivity of allenylphosphonates toward salicylaldehydes and activated phenols: facile synthesis of chromenes and substituted butadienes.

The reaction of salicylaldehydes with allenylphosphonates in the presence of a base leads to a variety of phosphono-chromenes and allylic phosphonates. Optimization of reaction conditions reveals that DBU (base) in DMSO (solvent) is the best combination in most cases, with DBU acting as an organocatalyst. PEG-400 also gave good results, but the yields were slightly lower than that in DMSO. Several of the key products have been characterized by single-crystal X-ray crystallography. Interconversion of E and Z isomers of phosphono-chromenes is demonstrated by (31)P NMR spectroscopy. A novel P-C bond cleavage reaction of some of these chromenes leading to substituted enones is also reported. In a few cases, phenol addition products are also isolated. In order to probe the pathways in the latter reaction, allenylphosphonates have also been treated with activated phenols in the presence of base to selectively afford either allylic phosphonyl ethers or vinylic phosphonyl ethers depending on the substituents on the allenylphosphonate. Theoretical calculations were consistent with experimental results. Finally, utilization of allylic phosphonyl ether in the Horner-Wadsworth-Emmons reaction to afford substituted trans-1,3-butadiene in good yields is demonstrated.

Single diastereomers of unsymmetrical tris-spirocyclic cyclotriphosphazenes based on 1,1'-bi-2-naphthol--synthesis and structures.

Diastereoselective synthesis and characterization of chiral unsymmetrical tris-spirocyclic cyclotriphosphazenes based on chiral 1,1'-bi-2-naphthol (BINOL) are reported. Specifically, the chiral compounds (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)Cl(2) [(-)-4] and (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2)NMe)(2) [(-)-5] are prepared by starting with the chiral mono-spiro compound (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)]Cl(4) [(-)-3]. Synthesis of four other chiral spirocyclics, N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2) NMe)(O-2,2'C(6)H(4)-C(6)H(4)O)[(-)-6 and (+)-6], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](NMe(2))(4) [(-)-7], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)(NMeCH(2)CH(2)OH)(2) [(-)-8 and (+)-8], and N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)[NHCH(2)CH(2)CH(2)Si(OEt)(3)](2) (9) is also reported herein. Compounds 4-6 are obtained in the solid state diastereoselectively and their X-ray structures have been determined and discussed. The diastereoselectivity is also shown by structural characterization of two distinct isomers in the case of 6 [(-)-6 and (+)-6, respectively] by starting with precursor of 3 having (R) or (S)-BINOL residue. The (1)H NMR spectra of 7 and 8 exhibit doublets with virtual coupling for the methyl protons, consistent with the chiral nature of the binaphthoxy residue. The potential of 9, which hydrolyzes readily in CDCl(3) solution, as a useful precursor for chiral polymer applications is highlighted.

Further characterization of Mitsunobu-type intermediates in the reaction of dialkyl azodicarboxylates with P(III) compounds.

Structural characterization of compounds analogous to the proposed intermediates in the Mitsunobu esterification process is achieved by the combined use of NMR spectroscopy and X-ray diffractometric studies. The results show that compounds (t-BuNH)P(mu-N-t-Bu)(2)P[(N-t-Bu)(N-(CO(2)R)-N(H)(CO(2)R))] [R = Et (11), i-Pr (12)], obtained by treating [(t-Bu-NH)P-mu-N-t-Bu](2) (10) with diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD), respectively, have a structure with the NH proton residing between the two nitrogen atoms ((P)N(t-Bu) and (P)N-N(CO(2)Et)); this is the tautomeric form of the expected betaine (t-BuNH)P(mu-N-t-Bu)(2)P(+)[(NH-t-Bu)(N-(CO(2)R)-N(-)(CO(2)R)]. Treatment of ClP(mu-N-t-Bu)(2)P[(N-t-Bu){N-(CO(2)-i-Pr)-N(H)(CO(2)-i-Pr)] (6) with 2,6-dicholorophenol affords (2,6-Cl(2)-C(6)H(3)-O)P(mu-N-t-Bu)(2)P(+)[(NH-t-Bu){N[(CO(2)i-Pr)(HNCO(2)i-Pr)]}](Cl(-))(2,6-Cl(2)-C(6)H(3)-OH) (14) that has a structure similar to that of (CF(3)CH(2)O)P(mu-N-t-Bu)(2)P(+)[(NH-t-Bu){N[(CO(2)i-Pr)(HNCO(2)i-Pr)]}](Cl(-)) (13), but with an additional hydrogen bonded phenol. Both of these have the protonated betaine structure analogous to that of Ph(3)P(+)N(CO(2)R)NH(CO(2)R)(R'CO(2))(-) (2) proposed in the Mitsunobu esterification. Two other compounds, (ArO)P(mu-N-t-Bu)(2)P(+)(NH-t-Bu){N(CO(2)i-Pr)(HNCO(2)i-Pr)}(Cl(-)) [Ar = 2,6-Me(2)C(6)H(3)O- (15) and 2-Me-6-t-Bu-C(6)H(3)-O- (16)], are also prepared by the same route. Although NMR tube reactions of 11 or 12 with tetrachlorocatechol, catechol, 2,2'-biphenol, and phenol revealed significant changes in the (31)P NMR spectra, attempted isolation of these products was not successful. On the basis of (31)P NMR spectra, the phosphonium salt structure (t-BuNH)P(mu-N-t-Bu)(2)P(+)[(HN-t-Bu){N-(CO(2)R)-N(H)(CO(2)R)](ArO(-)) is proposed for these. The weakly acidic propan-2-ol or water did not react with 11 or 12. Treatment of 12 with carboxylic acids/ p-toluenesulfonic acid gave the products (t-BuNH)P(mu-N-t-Bu)(2)P(+)[(HN-t-Bu){N-(CO(2)-i-Pr)-N(H)(CO(2)-i-Pr)](ArCO(2)(-)) [Ar = Ph (18), 4-Cl-C(6)H(4)CH(2) (19), 4-Br-C(6)H(4) (20), 4-NO(2)-C(6)H(4) (21)] and (t-BuNH)P(mu-N-t-Bu)(2)P(+)[(HN-t-Bu){N-(CO(2)-i-Pr)-N(H)(CO(2)-i-Pr)](4-CH(3)-C(6)H(4)SO(3)(-)) (22) that have essentially the same structure as 2. Compound 18 has additional stabilization by hydrogen bonding, as revealed by X-ray structure determination. Finally it is shown that the in situ generated (t-BuNH)P(mu-N-t-Bu)(2)P(+)[(HN-t-Bu){N-(CO(2)Et)-N(H)(CO(2)Et)](4-NO(2)-C(6)H(4)CO(2)(-)) can also effect Mitsunobu esterification. A comparison of the Ph(3)P-DIAD system with the analogous synthetically useful Ph(3)P-dimethyl acetylenedicarboxylate (DMAD) system is made.