Synthesis of 3,4-disubstituted isoquinolines via palladium-catalyzed cross-coupling of o-(1-alkynyl)benzaldimines and organic halides.

[reaction: see text] 3,4-Disubstituted isoquinolines have been prepared in good yields by the palladium-catalyzed cross-coupling of N-tert-butyl-o-(1-alkynyl)benzaldimines with aryl, allylic, and alkynyl halides.

Synthesis of isoquinolines and pyridines by the palladium-catalyzed iminoannulation of internal alkynes.

A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[f]isoquinoline, pyrindine, and pyridine heterocycles have been prepared in good to excellent yields via annulation of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst. The best results are obtained by employing 5 mol % of Pd(OAc)(2), an excess of the alkyne, 1 equiv of Na(2)CO(3) as a base, and 10 mol % of PPh(3) in DMF as the solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted alkynes. When electron-rich imines are employed, this chemistry can be extended to alkyl-substituted alkynes. Trimethylsilyl-substituted alkynes also undergo this annulation process to afford monosubstituted heterocyclic products absent the silyl group.

Synthesis of 9-alkylidene-9H-fluorenes by a novel, palladium-catalyzed cascade reaction of aryl halides and 1-aryl-1-alkynes.

In the presence of a palladium catalyst and NaOAc, aryl iodides react with 1-aryl-1-alkynes to afford 9-alkylidene-9H-fluorenes in good yields. The products from this reaction are highly dependent on the base employed. This process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) rearrangement of the resulting vinylic palladium intermediate to an arylpalladium species, and (4) aryl-aryl coupling with simultaneous regeneration of the Pd(0) catalyst. Consistent with this mechanism is the fact that 9-alkylidene-9H-fluorenes can also be prepared by the Pd-catalyzed rearrangement of 1,1-diaryl-2-iodo-1-alkenes.

Synthesis of isoquinolines and naphthyridines by electrophilic ring closure of iminoalkynes.

Substituted isoquinolines and naphthyridines have been prepared in good to excellent yields by the reaction of iminoalkynes with a variety of electrophiles under mild reaction conditions. Reaction: see text.

Synthesis of beta- and gamma-carbolines by the palladium-catalyzed iminoannulation of internal alkynes.

[reaction: see text] A variety of substituted beta- and gamma-carbolines have been prepared in good to excellent yields by the annulation of internal acetylenes by the tert-butylimines of N-substituted 3-iodoindole-2-carboxaldehydes and 2-haloindole-3-carboxaldehydes, respectively, in the presence of a palladium catalyst.

Synthesis of isoindolo[2,1-alpha]indoles by the palladium-catalyzed annulation of internal acetylenes.

A wide variety of substituted isoindolo[2,1-alpha]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles from readily available starting materials. The mechanism of this interesting annulation process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition of the resulting vinylic palladium intermediate to the C-N double bond of the imine, (4) either electrophilic palladation of the resulting sigma-palladium intermediate onto the adjacent aromatic ring derived from the internal alkyne or oxidative addition of the neighboring aryl carbon-hydrogen bond, and (5) reduction of the tetracyclic product and Pd(0). A variety of internal acetylenes have been employed in this annulation process in which the aromatic ring of the alkyne contains either a phenyl or a heterocyclic ring.

Synthesis of fluoren-9-ones via palladium-catalyzed cyclocarbonylation of o-halobiaryls.

The synthesis of various substituted fluoren-9-ones has been accomplished by a novel palladium-catalyzed cyclocarbonylation of o-halobiaryls. The cyclocarbonylation of 4'-substituted-2-iodobiphenyls produces very high yields of 2-substituted fluoren-9-ones bearing either electron-donating or electron-withdrawing substituents. 3'-Substituted 2-iodobiphenyls afford in excellent yields with good regioselectivity 3-substituted fluoren-9-ones. This chemistry has been successfully extended to polycyclic and heterocyclic fluorenones.

Palladium-catalyzed heteroannulation of 1,3-dienes to form alpha-alkylidene-gamma-butyrolactones.

alpha-Alkylidene-gamma-butyrolactones are readily prepared by the palladium-catalyzed heteroannulation of a variety of 1,3-dienes by alpha-iodo and alpha-bromo acrylic acids. The best results are obtained by employing a catalytic amount of the sterically hindered chelating alkyl phosphine D-t-BPF [(di-tert-butylphosphino)ferrocene]. In most cases, this process is highly regioselective. The reaction is believed to proceed via (1) oxidative addition of the vinylic halide to Pd(0), (2) organopalladium addition to the less hindered end of the 1,3-diene to form a pi-allylpalladium intermediate, and (3) nucleophilic displacement of the palladium by the carboxylate ion.

Heartworm (Dirofilaria immitis) disease and glomerulonephritis in a black-footed cat (Felis nigripes).

A 6-yr-old, 1.36-kg, intact female black-footed cat (Felis nigripes) was presented to the Veterinary Medical Teaching Hospital, University of Florida, with a history of depression, lethargy, and anorexia. Cardiac dysfunction and renal failure were diagnosed on the basis of antemortem and postmortem findings. At necropsy, heartworms (Dirofilaria immitis), glomerulonephritis, and endometritis were present. The glomerulonephritis could have been immune mediated and may have been associated with the heartworm infection or the chronic endometritis or both. Heartworm disease should be included in the list of differential diagnoses for any exotic cat housed outdoors in an endemic heartworm region that dies peracutely or has suggestive gastrointestinal or respiratory signs. Heartworm prophylaxis and annual serologic testing in exotic cats housed outdoors in heartworm endemic regions are recommended.

Neurologic examination of sea turtles.

OBJECTIVE: To determine whether neurologic examination techniques established for use on dogs and cats could be adapted for use on sea turtles. DESIGN: Prospective controlled observational study. ANIMALS: 4 healthy Green Turtles (Chelonia mydas), 1 healthy Kemp's ridley sea turtle (Lepidochelys kempi), and 6 Green Turtles suspected to have neurologic abnormalities. PROCEDURE: Neurologic examinations were performed while sea turtles were in and out of the water and in ventral and dorsal recumbency. Mentation, general activity, head and body posture, movement and coordination, thoracic and pelvic limb movement, strength and muscle tone, and tail movement were observed. Thoracic and pelvic limb flexor reflexes and nociception, righting response, cranial nerve reflexes, clasp and cloacal reflexes, and neck, dorsal scute, cloacal and tail nociception were tested. RESULTS: Results of neurologic evaluations were consistent for healthy sea turtles. Sea turtles suspected to have neurologic abnormalities had abnormal results. CLINICAL IMPLICATIONS: Many of the neurologic examination techniques used to evaluate dogs and cats can be adapted and used to evaluate sea turtles. A standardized neurologic examination should result in an accurate assessment of neurologic function in impaired sea turtles and should help in evaluating effects of rehabilitation efforts and suitability for return to their natural environment.

Immunohistochemical staining characteristics of canine gastrointestinal stromal tumors.

Sections from 35 formalin-fixed, paraffin-embedded, canine gastrointestinal stromal tumors consisting of 14 leiomyomas (five stomach, three small intestine, two colon, four rectum), 18 leiomyosarcomas (one stomach, five small intestine, nine cecum, three rectum), two undifferentiated sarcomas (two stomach), and one neurofibrosarcoma (small intestine) were examined for the expression of vimentin, S-100 protein, alpha-smooth muscle actin, and desmin via immunoperoxidase methodology using an avidin-biotin complex technique. The leiomyomas were 4/14 (29%) vimentin-positive, 3/14 (21%) S-100 protein-positive, 10/14 (71%) alpha-smooth muscle actin-positive and 13/14 (93%) desmin-positive. Leiomyosarcomas were 18/18 (100%) vimentin-positive, 11/18 (61%) S-100 protein-positive, 9/18 (50%) a-smooth muscle actin-positive, and 15/18 (83%) desmin-positive. The undifferentiated sarcomas were 2/2 (100%) vimentin-positive, 2/2 (100%) S-100 protein-positive, 1/2 (50%) alpha-smooth muscle actin-positive, and 0/2 (0%) desmin-positive. The neurofibrosarcoma was vimentin and S-100 protein-positive and alpha-smooth muscle actin- and desmin-negative. Thirty-one of thirty-five (89%) of all neoplasms demonstrated reactivity for either desmin and/or alpha-smooth muscle actin. S-100 protein reactivity occurred in 17/35 (49%) of all specimens. Lack of desmin and alpha-smooth muscle actin reactivity occurred in 4/35 (11%) of all specimens, all of which were vimentin-positive. The immunohistochemical results indicate that the majority of canine gastrointestinal stromal tumors (GIST) with light microscopic features of smooth muscle cells have immunohistochemical staining patterns supporting smooth muscle differentiation. Vimentin reactivity correlated with a light microscopic diagnosis of malignancy. The lack of smooth muscle cell markers in some tumors and the high percentage of cases positive for S-100 protein may suggest a more complex histogenesis or differentiation for subgroups of these tumors.

Acute myelogenous leukaemia in a mare.

A 5-year-old Thoroughbred mare presented with a 4 week history of weight loss, fever and leukopenia. Rectally, a large active foetus, thickened spleen and an abdominal mass were palpated. Leukopenia, mild anaemia, marked thrombocytopenia and hyperfibrinogenaemia were found. Cytology and cytochemical staining of a bone marrow aspirate supported a diagnosis of acute myelogenous leukaemia. The mare deteriorated despite medical therapy and was humanely euthanased.