Stereocontrol in the synthesis of acyclic systems: applications to natural product synthesis

Meso-ionic heterocycles (1976–1980)

A catheter (12) having a therapeutic agent chemically bonded to a substrate (16) on its exterior surface using a linker (18) which photolytically releases the agent upon exposure to light energy at an appropriate wavelength. The linker (18) is attached to the substrate (16) via a complementary chemical group, with the opposing end containing an aromatic ring with a nitro group in the ortho position relative to a methyl or ethyl group which is functionalized to accept a complementary bond to the therapeutic agent (20). The substrate (16) may include materials such as glass, polyamide, polyester, polyolefin, polypropylene, polyurethane, or latex. The therapeutic agent (20) may include peptides, proteins, steroids, carbohydrates, nucleotides, or other alipathic or heterocyclic products, and may be bonded to a molecular lattice or meshwork to accomodate a high molecular concentration per unit area and the inclusion of ancillary compounds such as markers or secondary emitters.

Catheter system for controllably releasing a therapeutic agent at a remote tissue site

Cycloaddition reactions have figured prominently in both synthetic and mechanistic organic chemistry.1,2 Current understanding of the underlying principles in this area has grown from a fruitful interplay between theory and experiment.3 The monumental work of Huisgen and coworkers in the early 1960s led to the general concept of 1,3-dipolar cycloaddition.4–7 Few reactions rival this process in the number of bonds that undergo transformation during the reaction, producing products considerably more complex than the reactants. Over the years this reaction has developed into a generally useful method of five-membered heterocyclic ring synthesis, since many 1,3-dipolar species are readily available and react with a wide variety of dipolarophiles. 1,3-Dipolar cycloadditions are bimolecular in nature and involve the addition of a 1,3-dipole (1) to a multiple π-bond system (2) leading to five-membered heterocycles (3; equation 1).

4.9 – Intermolecular 1,3-Dipolar Cycloadditions

Transformations of heterocycles into tetrazoles as well as conversions of the latter into other rings are reviewed. The literature is covered through early 1998 (material that has been surveyed by Van der Plas [1] and Benson [2] is resumed in abridged fashion). From the wide variety of interconversions accumulated in this overview a great many processes emerge that are of prime importance preparatively; moreover, quite a number of reactions will arouse interest in their mechanisms.

Ring Transformations in Tetrazole Chemistry

2, 2, 3-Triphenyl-2H-azirine (4a) in a matrix of 2, 2-dimethylbutane/pentane 8:3 (DMBP) at −185° gave rise on irradiation with light of 250–350 nm to a new UV.-maximum at 350 nm (Fig. 1). We assign the dipole benzonitrildiphenylmethylide (1a) to this new maximum. Irradiation with monochromatic light of 366 nm destroyed this maximum and the initial absorption curve reappeared (Fig. 2). When the azirine 4a was photolysed in DMBP at −185° in the presence of methyl trifluoracetate (TFEM), the maximum at 350 nm was obtained again. This maximum vanished upon increasing the temperature to −160°. Through gas chromatography we were able to show that 5-methoxy-5-trifluormethyl-2, 2, 4-triphenyl-3-oxazoline (6a) was produced. 6a was also obtained upon irradiation of 4a at room temperature in the presence of TFEM (scheme 1 and table 1). Modification of the previously described experiment, in which the maximum at 350 nm was extinguished in the matrix due to irradiation at 366 nm gave, after warm up, almost no dipole adduct 6a (table 1). From these experiments, an extinction coefficient of 17, 000 for the 350 nm maximum of 1a, was calculated. These experiments have shown that irradiation of triphenylazirine 4a leads to the dipole 1a, which can be reversed photochemically – but not tharmally – into azirine 4a. 1a reacts at less than −160° with TFEM to give adduct 6a. The results which were obtained with triphenylazirine 4a could be correspondingly obtained with 2, 3-diphenyl-2H-azirine 4b (Fig. 3, scheme 2 and table 2). The dipole 1b showed two UV.-maxima at 330 nm (e = 17, 500) and 343 nm (e = 21, 000). Later experiments established, that the two maxima belonged to a single dipole species.



The dipole 1c obtained upon irradiation of 2, 2-dimethyl-3-phenyl-2H-azirine (4c) in DMBP at −190°, appears to absorb in the same region as the azirine 4c. The presence of the dipole 1c was univocally established by low temperature trapping experiments with TFEM. The dipole 1a showed no ESR.-spectrum characteristic for a triplet state. We assume therefore, that 1a is in a singlet state. Photolysis of oxazolinone 7 at −190° in DMBP led to the dipole 1a with loss of CO2. 1a recombines apparently in considerable amount with the CO2 trapped in the matrix to give starting oxazolinone 7 because the 350 nm-maximum of 1a appeared with low extinction. Irradiation with light of 366 nm into this matrix produccd triphenylazirine 4a. Low temperature trapping experiments with TFEM led to small amounts of 5-methoxy-5-trifluormethyl-triphenyl-3-oxazolinc (6a).

Tieftemperaturbestrahlungen von 3‐Phenyl‐2H‐azirinen

The photochemical behaviour of several 3,4-disubstituted sydnones (cf. Scheme 5) in dioxane solution was investigated. The pure sydnones give, as was already reported [2-6], 2,4,5-trisubstituted 1,2,3-triazoles 2 (cf. Scheme 1) in 25-30% yield. In the presence of dipolarophiles (cf. Scheme 1) pyrazole derivatives 3 or 4 are formed which can be taken as a proof for the formation of nitril-imines 5 as primary products in sydnone photochemistry. Since irradiation of 2-[15N]-3,4-diphenyl- sydnone (2-[15N]-15) in dioxane leads to the formation of 1,3-[15N]-2,4,5-triphenyl-1,2,3-triazole (1,3-[15N]-22; cf. Scheme 10), nitril-imine formation must be induced by the creation of a bond between N(2) und C(4) in the excited sydnones (cf. Scheme 22). The irradiation of sydnones in dioxane solution in the presence of carboxylic acids yields N'-acylhydrazides in 50-70% (cf. Scheme 14), the formation of which can be explained by addition of the acids to the nitril-imines and rearrangement of the primarily formed anhydride monohydrazones (Scheme 15). By analogy, the formation of 1-benzoyl-2-(t-butyl)-4-phenyl-1,2-diazetidin-3-one (14; Scheme 4 ) during the photolysis of 3-(t-butyl)-4-phenylsydnone (12) in benzene solution (cf. [5b]) may also be explained: Sydnone 12 undergoes two different photoreactions leading by loss of carbon dioxide to the corresponding nitril-imine 5 (R = t-C4H9, R' = C6H5) and by loss of isobutylene to a 1,2,3-oxadiazolin-5-one of type 48 or 49 which isomerizes to yield diazophenylacetic acid (51; cf. Scheme 17). Reaction of both products (5 and 51) results in the formation of the N'-acylhydrazide 52 (Scheme 18) which may cyclize after loss of nitrogen to yield the diazeti- dinone 14 in a carbene type reaction. The triazoles 2 are formed photochemically from the corresponding 1,2-bisazo-ethylenes 64 (Scheme 26) which arise from a direct 'head-to-head' dimerization of the nitril-imines 5. This type of reaction seems to be common to all nitrilium betaines (Schema 30). The photolysis of the 2,4-disubstituted 1,3,4-oxadiazolines 76 does not lead to nitril-imines 5 (cf. [11]). On the contrary, loss of carbon monoxide induces the formation of azoketones 77 (cf. Scheme 31), which may be photo-reduced to yield hydrazides or may undergo cleavage of the N,acyl bond to form derivatives of 1,2-diketones (cf. Scheme 32).

Zum photochemischen Verhalten von Sydnonen und 1,3,4‐Oxadiazolin‐2‐onen. 56. Mitteilung über Photoreaktionen

On the Mechanism of the Cope Rearrangement



The rates of the Cope rearrangement of 2,5-dicyano-3-methyl-hexa-1, 5-diene (12), (E)- and (Z)-2, 5-dicyano-hepta-1,5-diene ((E)- and (Z)-14) as well as of 2, 5-dimethoxycarbonyl-3-methyl-hexa-1,5-diene (13) and (E)- and (Z)-2,5-dimethoxycarbonyl-hepta-1,5-diene ((E)- and (Z)-15) were measured in decane solution in the temperature range of 50 to 150° (see Tables 5 and 8 to 12). A detailed English summary of this work is given in [1 b].

Über den Mechanismus der Cope-Umlagerung

On the Photochemistry of 2, 1-Benzisoxazoles (Anthraniles) and on the Thermal and Photochemical Decomposition of 2-Azido-acylbenzenes in Strongly Acidic Solution



Anthranils 6(Scheme 3), when irradiated with a mercury high-pressure lamp, in 96% sulfuric acid yielded, after work-up, 2-amino-5-hydroxy-acylbenzenes 8 and as side products 2-amino-3-hydroxy-acylbenzenes 9(cf. Schemes 5–7 and Table 1). When C(5) of the anthranils 6 carries a methyl group a more complex reaction mixture is found after irradiation in 96% sulfuric acid (cf. Schemes 8 and 9): 3, 5-dimethyl-anthranil (6d) yielded (after irradiation and acetylation) 2-acetyl- amino-5-methyl-acetophenone (15), 2-acetylamino-5-acetoxymethyl-acetophenone (18d) and 2-acetylamino-5-acetoxy-6-methyl-acetophenone (12c). The latter product was also formed after irradiation of 3, 4-dimethylanthranil (6c) in 96% sulfuric acid. 3, 5, 7-Trimethyl-anthranil (6f) formed under the same conditions 2-acetylamino-3, 5-dimethyl-acetophenone (15f) and 2-acetylamino-5-acetoxymethyl-3-methyl-acetophenone (18f). Since qualitatively the same product patterns were observed when the corresponding 2-azido-acetophenones 7 were decomposed in 96% sulfuric acid it is concluded that anthranilium ions (cf.6b-H⊕, Scheme 11) on irradiation are transformed by cleavage of the N, O-bond into 2-acyl-phenylnitrenium ions (cf. 25b-H⊕) in the singlet ground state. The nitrenium ions are trapped directly by nucleophiles (HSO⊖4 in 96% sulfuric acid), thus, yielding the hydroxy-acetophenones 8 and 9(Scheme 11). If C(5) is blocked by a methyl group a [1, 2]-rearrangement of the methyl group may occur (cf. Scheme 13) or loss of sulfuric acid can lead to quinomethane iminium ions (cf. 32-H⊕, Scheme 13) which will react with HSO⊖4 ions to yield, after hydrolysis and acetylation, the 5-acetoxymethyl substituted acetophenones 18d and 18f. It is assumed that the reduction products (2-acetylamino-acetophenones 15) are formed from the corresponding nitrenium ions in the triplet ground state.

Zur Photochemie von 2, 1‐Benzisoxazolen (Anthranilen) und thermischen und photochemischen Umsetzungen von 2‐Azido‐acylbenzolen in stark saurer Lösung

The photochemical reactions of different allyl aryl ethers (Scheme 3) were investigated in hydrocarbons (Chap. 3.1) and in alcoholic solvents (Chap. 3.2). The composition of the photoproducts depended very much on the nature of the solvent. Irradiation (3-95 h) of different methyl substituted allyl aryl ethers (1, 3, 5, 7 and 11) with a low pressure mercury lamp (lambda(Emiss.) = 254nm; 6 or 15 Watt) under argon (quartz vessel) resulted in the formation of 2-, 3- and 4-substituted phenols, dienones and products of consecutive reactions (Tables 1-4 and 6). The results suggested that all products were formed by homolytic cleavage of the C-O bond in the singlet state of the ethers to intermediate radical-geminates (Scheme 5) followed by radical recombination of the two fragments. No products were formed by concerted processes (Table 5, Schemes 5 and 6). Upon irradiation of allyl aryl ethers lacking alkyl substituents at position 4 (1 and 5) in protic solvents, mainly 2- and 4-allylated phenols were obtained (Tables 1 and 4); 3-allylated phenols were formed only in small amounts (0.02%). However, in aromatic hydrocarbons or cyclohexane 3-allylated phenols were obtained from 1, 5 and 11 in significant amounts (3-11%; Tables 1, 4 and 6). E.g., upon irradiation of allyl-2,6-dimethylphenyl ether (5) in toluene, the main photoproduct was 6-allyl-2,6-dimethy1-2,4-cyclohexadien-1-one (6) besides 3- and 4-ally1-2,6-dimethylphenol (23 and 24). Irradiation of 5 in methanol afforded 23 and 6 only in traces, whereas 24 was the main product. Ethers alkylated at position 4 (3 and 7) yielded 3-allylated phenols after irradiation in hydrocarbons and in methanol (Tables 2 and 3). The time independent equilibration of deuterium labelling in the allyl chain of dienone d3-6 obtained upon irradiation of 2,6-dimethylphenyl-2’, 3’, 3’-trideuterioallyl ether (2’,3’, 3’-d3-5) (cf. Table 5) demonstrated that the photolysis of aromatic allyl ethers did not occur by a [1s,3s]-sigmatropic process (cf. Chap. 3.1.4.2). For the photochemical formation of 3-allylated phenols, the following two mechanisms may be envisaged: 1. According to CIDNP measurements [12] at least one portion of the 3-allylated phenols 14, 20 and 23 is produced via a direct recombination of the triplet-geminate, which is formed from the singlet-radical-geminate via intersystem crossing (Scheme 5, pathway d). 2. Formation of 4-allyl-2,5-cyclohexadien-1-ones (III, IV and 12) could occur via a singlet-geminate (Scheme 5, pathway c). These dienones undergo photochemical excitation and give bicyclic intermediates, which after further photoexcitation are finally transformed into the 3- allylated phenols 14, 20 and 23 (cf. Scheme 6, pathway g, h and i). This path allows the formation of significant amounts of 3-allylated phenols (3- 11%) during photo-Claisen-rearrangement of allyl phenyl ethers lacking a substituent at position 4. The lifetimes of the initially formed 4-monosubstituted dienones III and IV in hydrocarbons were long enough to permit photochemical isomerization to 3- allylated phenols. In protic solvents however, a fast enolization of 3 and IV to 4-allylated phenols is expected, so that the photochemical isomerization is interrupted. The presence of bases which catalyse this heterolytic enolization further suppress the photochemical isomerization (Table 1). The very small amount (0,01- 0,1%) of 3-allylphenols, which were still formed after the irradiation of allyl aryl ethers lacking a substituent at position 4 in protic solvents or under basic conditions, must be produced by direct radical recombination within the triplet-geminate (cf. Scheme 5, pathway m and n). Free phenoxy and allyl radicals were also formed from the triplet-geminate (cf. ESR. experiments, Chap. 5). The former yielded the observed phenols after hydrogen abstraction from the solvent. A crossover experiment with tritiated ether 3’-t-3 and ether 1 suggested that recombination of free phenoxy and allyl radicals during photolysis did occur only to a very small extent (2 - 0,1%; cf. Chap. 4). The photochemical transformation of ((E)- or (Z)-2’-buteny1-2,6-dimethylphenylether ((E)- and (Z)-11, respectively) to (E)- or (Z)-6-(2’-butenyl)-2,6-dimethyl-2,4-cyclohexadien-1-one ((E)- and (Z)-26, respectively) at 7° showed, that the configurational integrity of the allyl radical was maintained (90-95%) until the recombination had occurred (Table 6).

Hans-Jürgen Hansen

Papers

Tieftemperaturbestrahlungen von 3‐Phenyl‐2H‐azirinen

Zum photochemischen Verhalten von Sydnonen und 1,3,4‐Oxadiazolin‐2‐onen. 56. Mitteilung über Photoreaktionen

Über den Mechanismus der Cope-Umlagerung

Zur Photochemie von 2, 1‐Benzisoxazolen (Anthranilen) und thermischen und photochemischen Umsetzungen von 2‐Azido‐acylbenzolen in stark saurer Lösung

Zur Photochemie von Allylaryläthern. 55. Mitteilung über Photoreaktionen