Synthesis of thyroid hormone analogues. Part 3. Iodonium salt approaches to SK&amp;F L-94901

Hickey, Deirdre M. B.; Leeson, Paul D.; Novelli, Riccardo; Shah, Virendra P.; Burpitt, B. E.; Crawford, L. P.; Davies, B. J.; Mitchell, Michael B.; Pancholi, K. D.; Tuddenham, David; Lewis, N. J.; O'farrell, C.

doi:10.1039/p19880003103

Cited by 27 publications

(11 citation statements)

References 7 publications

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“…Thus the effects of ring substitution are not strictly additive and consequently compound 16 is an outlier in eq 11 and 12 (Table IV). If the 4-pyridyl 13 and meta pyridone 17 analogues are excluded, overall substituent hydrophilicity ( ) in eq 12 can be replaced by Q-p, the specific partial charge on the aryl para substituent: log S = -3.33Q-p -0.618D-o,m + 0.859 (13) = 18, r = 0.882, s = 0.337, F = 26.2 íQ.p = 5.04 (p < 0.001); tD.0,m = 4.31 (p < 0.001) Inclusion of the 4-pyridyl 13 and meta pyridone 17 analogues results in a significantly poorer equation [r = 0.710, s = 0.511, F = 8.62 (p = 0.0026)] with these compounds being outliers. The Q-p term for pyridine 13 refers to the partial negative charge on the nitrogen atom (-0.25, Table IV), and consequently eq 13 predicts that this compound will be selective.…”

Section: '-(Arylmethyl)-35-diiodo-l-thyroninesmentioning

confidence: 99%

“…The D enantiomer 26 was prepared from a D-tyrosine precursor by the same method as described for 15,11 and the 3,5dichloro compound 33 was synthesized by the route developed for SK&F L-94901 (32). 13 Preparation of the 3,5-dimethyl analogue 23 required arylation of 2,6-dimethyl-4-formylphenol (52, Scheme IV). This was achieved either by Ullmann coupling with the iodide 53 [obtained as the byproduct in reactions of 50 (Scheme III)] or by coupling of the potassium salt of 52 with iodonium salt 50 in the presence of 18-crown-6.…”

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Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Leeson¹,

Emmett²,

Shah³

et al. 1989

J. Med. Chem.

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Introduction of specific arylmethyl groups at the 3'-position of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3), and its known hormonally active derivatives, gives liver-selective, cardiac-sparing thyromimetics, with potential utility as plasma cholesterol lowering agents. Selectivity-conferring 3'-substituents include substituted benzyl, e.g. p-hydroxybenzyl, and heterocyclic methyl, e.g. 2-oxo-1,2-dihydropyrid-5-ylmethyl and 6-oxo-1,6-dihydropyridazin-3-ylmethyl. Correlations between in vivo and in vitro receptor binding affinities show that liver/heart selectivity does not depend on receptor recognition but on penetration or access to receptors in vivo. QSAR studies of the binding data of a series of 20 3'-arylmethyl T3 analogues show that electronegative groups at the para position increase both receptor binding and selectivity in vivo. However, increasing 3'-arylmethyl hydrophobicity increases receptor binding but reduces selectivity. Substitution at ortho and meta positions reduces both binding and selectivity. Replacement of the 3,5-iodo groups by halogen or methyl maintains selectivity, with 3,5-dibromo analogues in particular having increased potency combined with oral bioavailability. Diphenyl thioether derivatives also have improved potency but are less orally active. At the 1-position, the D enantiomer retains selectivity, but removal of the alpha-amino group to give a propionic acid results in loss of selective thyromimetic activity.

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Section: '-(Arylmethyl)-35-diiodo-l-thyroninesmentioning

confidence: 99%

mentioning

confidence: 99%

Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Leeson¹,

Emmett²,

Shah³

et al. 1989

J. Med. Chem.

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“…To furthere xpand the applications of monoaryl-l 3iodanes as arylating agents, we considered that the develop-ment of efficient synthetic methodso fm onoaryl-l 3 -iodanes containing multiple functional groupsi sc rucial.Direct introduction of the -I III L 2 fragment to aromatic rings using iodine tricarboxylates [14] has been described in af ew reports (Scheme1c). [14][15][16][17][18] As early as 1974, Maletina and co-workers reported electrophilic aromatic substitution using iodine tris(trifluoroacetate) (ITT, 1a), [15] followed by areport by Kurosawa and co-workers on the reactions between aryl ketones and ITT 1a. [16] Recently,W irth and co-workers reported that I(OAc) 3 1b or ITT 1a reacts with several aromatic compounds to give (dicarboxyiodo)arenes.…”

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confidence: 99%

“…In all cases, the product was converted to the corresponding iodonium ylide 7 for isolation and characterization. Iodoniumy lides of this type were not only stable and easy to isolate, but also served as efficient precursors for 18 Fp ositron emission tomography probes. [6] p-Substituted arylgermanes underwent as elective ipso-substitution reaction to provide 7a-7f regardless of the electronic properties and orientation toward electrophilica romatic substitution of the substituent (3a-3f).…”

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Synthesis of Functionalized Monoaryl‐λ³‐iodanes through Chemo‐ and Site‐Selective ipso‐Substitution Reactions

Komami

Matsuoka

Nakano

et al. 2018

Chemistry A European J

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Monoaryl-l 3 -iodanesa re potentially attractive arylating agents. They are generally synthesized from aryl iodidesv ia oxidation, which can cause functional group incompatibility,e specially when polyfunctionalized derivatives are desired. This work describes the directs ynthesis of monoaryl-l 3 -iodanes through ac hemoselective ipsosubstitution reaction of arylgermanes and arylstannanes with iodine tris(trifluoroacetate). The generated iodanes were convertedt oi odoniumy lides or used for further transformations in one pot. The presented method enables the preparation of polyfunctionalized monoaryl-l 3 -iodanes.Hypervalent iodine compounds are widely studied in organic chemistry due to their unique reactivity and low toxicity. [1] Amongt he variousI III/V/VII compounds reported,m onoaryl-l 3iodane (ArIL 2 )isone of the most popularclasses of hypervalent iodine compounds in terms of its versatile applications in oxidation reactions. Although thesec ompounds are mainly used for oxidative transformations in which the aryl group is not involved in the products, some recent studies focusedo nt heir potentiala sa rylating agents. [2][3][4][5][6][7] An interesting feature of most arylation reactions using am onoaryl-l 3 -iodane is that the CÀI bond of the reagent is not cleaved, and a2 -iodoaryl group is introduced through sigmatropicr earrangement( Scheme 1a, left side). [2, 3] Furthermore, monoaryl-l 3 -iodanes are easily converted to iodonium ylides, which also serve as arylating agents (Scheme 1a,r ight side). [5,6] The typical synthesis of monoaryll 3 -iodanes involves the introduction of I I to an aromatic ring and oxidation to I III (Scheme 1b). [1,[8][9][10][11][12][13] The oxidation step can cause functional group incompatibility and limit the accessible structures. To furthere xpand the applications of monoaryl-l 3iodanes as arylating agents, we considered that the develop-ment of efficient synthetic methodso fm onoaryl-l 3 -iodanes containing multiple functional groupsi sc rucial.Direct introduction of the -I III L 2 fragment to aromatic rings using iodine tricarboxylates [14] has been described in af ew reports (Scheme1c). [14][15][16][17][18] As early as 1974, Maletina and co-workers reported electrophilic aromatic substitution using iodine tris(trifluoroacetate) (ITT, 1a), [15] followed by areport by Kurosawa and co-workers on the reactions between aryl ketones and ITT 1a. [16] Recently,W irth and co-workers reported that I(OAc) 3 1b or ITT 1a reacts with several aromatic compounds to give (dicarboxyiodo)arenes. [17] The scope of theser eactions, however,i sl imited to rather simple substrates, and the functional groupc ompatibility was not well elucidated.M oreover,t he site selectivity of these electrophilic substitution reactionsd epends on the electronic nature of the substrates, and the introduction of the -I III L 2 moiety at the less electron-rich positioni sd ifficult in principle.Here, we report the directs ynthesis of monoaryl-l 3 -iodanes by chemo-and site-selective ipso-substitution reacti...

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2000

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Synthesis of thyroid hormone analogues. Part 3. Iodonium salt approaches to SK&F L-94901

Cited by 27 publications

References 7 publications

Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Synthesis of Functionalized Monoaryl‐λ³‐iodanes through Chemo‐ and Site‐Selective ipso‐Substitution Reactions

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Synthesis of thyroid hormone analogues. Part 3. Iodonium salt approaches to SK&F L-94901

Cited by 27 publications

References 7 publications

Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-arylmethyl substituents

Synthesis of Functionalized Monoaryl‐λ3‐iodanes through Chemo‐ and Site‐Selective ipso‐Substitution Reactions

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Synthesis of Functionalized Monoaryl‐λ³‐iodanes through Chemo‐ and Site‐Selective ipso‐Substitution Reactions