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Claude Lecomte - One of the best experts on this subject based on the ideXlab platform.
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anharmonicity and isomorphic phase transition a multi temperature x ray single crystal and powder diffraction study of 1 2 aminophenyl 2 methyl 4 Nitroimidazole
IUCrJ, 2014Co-Authors: Agnieszka Poulain, Maciej Kubicki, Pierrick Durand, Emmanuel Wenger, Katarzyna N Jarzembska, Radoslaw Kaminski, Pierre Fertey, Claude LecomteAbstract:The harmonic model of atomic nuclear motions is usually enough for multipole modelling of high-resolution X-ray diffraction data; however, in some molecular crystals, such as 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole [Paul, Kubicki, Jelsch et al. (2011). Acta Cryst. B67, 365-378], it may not be sufficient for a correct description of the charge-density distribution. Multipole refinement using harmonic atom vibrations does not lead to the best electron density model in this case and the so-called `shashlik-like' pattern of positive and negative residual electron density peaks is observed in the vicinity of some atoms. This slight disorder, which cannot be modelled by split atoms, was solved using third-order anharmonic nuclear motion (ANM) parameters. Multipole refinement of the experimental high-resolution X-ray diffraction data of 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole at three different temperatures (10, 35 and 70 K) and a series of powder diffraction experiments (20 <= T <= 300 K) were performed to relate this anharmonicity observed for several light atoms (N atoms of amino and nitro groups, and O atoms of nitro groups) to an isomorphic phase transition reflected by a change in the b cell parameter around 65 K. The observed disorder may result from the coexistence of domains of two phases over a large temperature range, as shown by low-temperature powder diffraction.
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r free factor and experimental charge density analysis of 1 2 aminophenyl 2 methyl 4 Nitroimidazole a crystal structure with z 2
Acta Crystallographica Section B-structural Science, 2011Co-Authors: Agnieszka Paul, Maciej Kubicki, Christian Jelsch, Pierrick Durand, Claude LecomteAbstract:The experimental charge-density distribution was determined for 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole crystals. An anharmonic model was applied to the N atoms of both amino groups and to one nitro group in order to account for high residual peaks after harmonic multipole refinement and to obtain a better charge-density model. Free R-factor calculations [Brunger (1992). Nature, 355, 472-475] with restrained models implemented in MoPro were used to determine the degree of similarity of the two symmetry-independent molecules in the unit cell. The results are compared with 1-phenyl-4-Nitroimidazole in order to analyze the influence of the amine and methyl functional groups. The asymmetric unit contains two symmetry-independent molecules giving rise to a dimer connected via strong N-H...N hydrogen bonds; these dimers are the building blocks of the crystal. In the crystal structure there are also weaker interactions and many short directional contacts (C-H...O, C-H...N and C-H...[pi]), for which the Koch-Popelier topological criteria were applied. This analysis revealed that the C-H...[pi] interactions lie at the border between weak hydrogen bonds and van der Waals interactions. Special attention was also paid to stabilizing H...H interactions. It turned out that the electron density, Laplacian and density energies at the critical points show an exponential dependence on the contact distance, similar to the relation found for other interactions.
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experimental electron density of 1 phenyl 4 Nitroimidazole and topological analysis of c h o and c h n hydrogen bonds
Journal of Physical Chemistry B, 2002Co-Authors: Maciej Kubicki, Teresa Borowiak, Grzegorz Dutkiewicz, Mohamed Souhassou, Christian Jelsch, Claude LecomteAbstract:The electron density of 1-phenyl-4-Nitroimidazole was analyzed by X-ray diffraction at 0.55 A resolution. The topology of the bonding scheme within the molecule as well as of the weak intermolecular C-H...O and C-H...N hydrogen bonds has been investigated. The topological analysis and the deformation density peak heights on the covalent bonds of the imidazole ring are consistent with the usual chemical knowledge. The nitro group has an electron-withdrawing effect, as it is globally negatively charged and the electrostatic potential around it is slightly negative. This potential is significantly weaker than that generated by other oxygen-containing chemical entities, which is related to the hydrophobicity of the nitro group. The nitro group forms three weak C-H...O hydrogen bonds, and the unsubstituted imidazole nitrogen is also hydrogen-bonded to a C-H group, as confirmed by the presence of critical points in the topological analysis.
Maciej Kubicki - One of the best experts on this subject based on the ideXlab platform.
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Research Online
2016Co-Authors: Maciej Kubicki, Pawel Wagner, Maciej Kubickia, Paweø WagnerbAbstract:Two different modes of halogen bonding in two 4-Nitroimidazole derivative
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anharmonicity and isomorphic phase transition a multi temperature x ray single crystal and powder diffraction study of 1 2 aminophenyl 2 methyl 4 Nitroimidazole
IUCrJ, 2014Co-Authors: Agnieszka Poulain, Maciej Kubicki, Pierrick Durand, Emmanuel Wenger, Katarzyna N Jarzembska, Radoslaw Kaminski, Pierre Fertey, Claude LecomteAbstract:The harmonic model of atomic nuclear motions is usually enough for multipole modelling of high-resolution X-ray diffraction data; however, in some molecular crystals, such as 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole [Paul, Kubicki, Jelsch et al. (2011). Acta Cryst. B67, 365-378], it may not be sufficient for a correct description of the charge-density distribution. Multipole refinement using harmonic atom vibrations does not lead to the best electron density model in this case and the so-called `shashlik-like' pattern of positive and negative residual electron density peaks is observed in the vicinity of some atoms. This slight disorder, which cannot be modelled by split atoms, was solved using third-order anharmonic nuclear motion (ANM) parameters. Multipole refinement of the experimental high-resolution X-ray diffraction data of 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole at three different temperatures (10, 35 and 70 K) and a series of powder diffraction experiments (20 <= T <= 300 K) were performed to relate this anharmonicity observed for several light atoms (N atoms of amino and nitro groups, and O atoms of nitro groups) to an isomorphic phase transition reflected by a change in the b cell parameter around 65 K. The observed disorder may result from the coexistence of domains of two phases over a large temperature range, as shown by low-temperature powder diffraction.
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r free factor and experimental charge density analysis of 1 2 aminophenyl 2 methyl 4 Nitroimidazole a crystal structure with z 2
Acta Crystallographica Section B-structural Science, 2011Co-Authors: Agnieszka Paul, Maciej Kubicki, Christian Jelsch, Pierrick Durand, Claude LecomteAbstract:The experimental charge-density distribution was determined for 1-(2'-aminophenyl)-2-methyl-4-nitro-1H-imidazole crystals. An anharmonic model was applied to the N atoms of both amino groups and to one nitro group in order to account for high residual peaks after harmonic multipole refinement and to obtain a better charge-density model. Free R-factor calculations [Brunger (1992). Nature, 355, 472-475] with restrained models implemented in MoPro were used to determine the degree of similarity of the two symmetry-independent molecules in the unit cell. The results are compared with 1-phenyl-4-Nitroimidazole in order to analyze the influence of the amine and methyl functional groups. The asymmetric unit contains two symmetry-independent molecules giving rise to a dimer connected via strong N-H...N hydrogen bonds; these dimers are the building blocks of the crystal. In the crystal structure there are also weaker interactions and many short directional contacts (C-H...O, C-H...N and C-H...[pi]), for which the Koch-Popelier topological criteria were applied. This analysis revealed that the C-H...[pi] interactions lie at the border between weak hydrogen bonds and van der Waals interactions. Special attention was also paid to stabilizing H...H interactions. It turned out that the electron density, Laplacian and density energies at the critical points show an exponential dependence on the contact distance, similar to the relation found for other interactions.
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1 2 aminophenyl and 1 2 hydroxyphenyl 2 methyl 4 Nitroimidazole crystallizing with two molecules in the asymmetric unit
Journal of Molecular Structure, 2008Co-Authors: Maciej Kubicki, Pawel WagnerAbstract:Abstract Two similar 4-Nitroimidazole derivatives, 1-(2′-aminophenyl)-2-methyl-4-Nitroimidazole, C 10 H 9 N 3 O 3 , and 1-(2′-hydroxyphenyl)-2-methyl-4-Nitroimidazole, C 10 H 10 N 4 O 2 , crystallize with two molecules in the asymmetric unit ( Z ′ = 2). Packing conflicts may result from tendency towards closing hydrogen-bonded rings (dimer for amino-, and tetramer for hydroxy-derivative) and molecular stacking. These conflicts are solved in different ways in both compounds, due to the different nature of 2′-substituents, but in both cases the crystal structure involves multiple molecules in the asymmetry unit. The geometrical features of symmetry-independent molecules are similar. The nitro group is almost coplanar with the imidazole plane in amino derivative while it is significantly twisted in hydroxy-one.
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two different modes of halogen bonding in two 4 Nitroimidazole derivatives
Acta Crystallographica Section C-crystal Structure Communications, 2007Co-Authors: Maciej Kubicki, Pawel WagnerAbstract:In the crystal structures of the two imidazole derivatives 5-chloro-1,2-dimethyl-4-nitro-1H-imidazole, C5H6ClN3O2, (I), and 2-chloro-1-methyl-4-nitro-1H-imidazole, C4H4ClN3O2, (II), C—Cl⋯O halogen bonds are the principal specific interactions responsible for the crystal packing. Two different halogen-bond modes are observed: in (I), there is one very short and directional C—Cl⋯O contact [Cl⋯O = 2.899 (1) A], while in (II), the C—Cl group approaches two different O atoms from two different molecules, and the contacts are longer [3.285 (2) and 3.498 (2) A] and less directional. In (I), relatively short C—H⋯O hydrogen bonds provide the secondary interactions for building the crystal structure; in (II), the C—H⋯O contacts are longer but there is a relatively short π–π contact between molecules related by a centre of symmetry. The molecule of (I) is almost planar, the plane of the nitro group making a dihedral angle of 6.97 (7)° with the mean plane of the imidazole ring. The molecule of (II) has crystallographically imposed mirror symmetry and the nitro group lies in the mirror plane.
Andrew M Thompson - One of the best experts on this subject based on the ideXlab platform.
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repositioning antitubercular 6 nitro 2 3 dihydroimidazo 2 1 b 1 3 oxazoles for neglected tropical diseases structure activity studies on a preclinical candidate for visceral leishmaniasis
Journal of Medicinal Chemistry, 2016Co-Authors: Andrew M Thompson, Adrian Blaser, Scott G Franzblau, Delphine Launay, Denis Martin, Patrick D Oconnor, Vanessa Yardley, Louis Maes, Suman Gupta, Baojie WanAbstract:6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-Nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
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Repositioning Antitubercular 6‑Nitro-2,3-dihydroimidazo[2,1‑b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis
2016Co-Authors: Andrew M Thompson, Adrian Blaser, Scott G Franzblau, Delphine Launay, Denis Martin, Vanessa Yardley, Louis Maes, Suman Gupta, Patrick D. O’connor, Baojie WanAbstract:6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-Nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead
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synthesis reduction potentials and antitubercular activity of ring a b analogues of the bioreductive drug 6s 2 nitro 6 4 trifluoromethoxy benzyl oxy 6 7 dihydro 5h imidazo 2 1 b 1 3 oxazine pa 824
Journal of Medicinal Chemistry, 2009Co-Authors: Andrew M Thompson, Adrian Blaser, Robert F Anderson, Sujata S Shinde, Scott G Franzblau, William A Denny, Brian D PalmerAbstract:The nitroimidazooxazine S-1 (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron reduction potentials E(1) (from −570 to −338 mV, compared with −534 mV for S-1). The observed E(1) values closely correlated with the σm values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compounds spanned a range of E(1) values around that of S-1, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this reduction pathway, which is determined by the nature of the substituent at the 2-position of the 4-Nitroimidazole ring.
John M. Essigmann - One of the best experts on this subject based on the ideXlab platform.
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in vivo bypass efficiencies and mutational signatures of the guanine oxidation products 2 aminoimidazolone and 5 guanidino 4 Nitroimidazole
Journal of Biological Chemistry, 2004Co-Authors: William L Neeley, James C Delaney, Paul T Henderson, John M. EssigmannAbstract:Abstract The in vivo mutagenic properties of 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole, two products of peroxynitrite oxidation of guanine, are reported. Two oligodeoxynucleotides of identical sequence, but containing either 2-aminoimidazolone or 5-guanidino-4-Nitroimidazole at a specific site, were ligated into single-stranded M13mp7L2 bacteriophage genomes. Wild-type AB1157 Escherichia coli cells were transformed with the site-specific 2-aminoimidazolone- and 5-guanidino-4-Nitroimidazole-containing genomes, and analysis of the resulting progeny phage allowed determination of the in vivo bypass efficiencies and mutational signatures of the DNA lesions. 2-Aminoimidazolone was efficiently bypassed and 91% mutagenic, producing almost exclusively G to C transversion mutations. In contrast, 5-guanidino-4-Nitroimidazole was a strong block to replication and 50% mutagenic, generating G to A, G to T, and to a lesser extent, G to C mutations. The G to A mutation elicited by 5-guanidino-4-Nitroimidazole implicates this lesion as a novel source of peroxynitrite-induced transition mutations in vivo. For comparison, the error-prone bypass DNA polymerases were overexpressed in the cells by irradiation with UV light (SOS induction) prior to transformation. SOS induction caused little change in the efficiency of DNA polymerase bypass of 2-aminoimidazolone; however, bypass of 5-guanidino-4-Nitroimidazole increased nearly 10-fold. Importantly, the mutation frequencies of both lesions decreased during replication in SOS-induced cells. These data suggest that 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole in DNA are substrates for one or more of the SOS-induced Y-family DNA polymerases and demonstrate that 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole are potent sources of mutations in vivo.
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in vivo bypass efficiencies and mutational signatures of the guanine oxidation products 2 aminoimidazolone and 5 guanidino 4 Nitroimidazole
Journal of Biological Chemistry, 2004Co-Authors: William L Neeley, James C Delaney, Paul T Henderson, John M. EssigmannAbstract:Abstract The in vivo mutagenic properties of 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole, two products of peroxynitrite oxidation of guanine, are reported. Two oligodeoxynucleotides of identical sequence, but containing either 2-aminoimidazolone or 5-guanidino-4-Nitroimidazole at a specific site, were ligated into single-stranded M13mp7L2 bacteriophage genomes. Wild-type AB1157 Escherichia coli cells were transformed with the site-specific 2-aminoimidazolone- and 5-guanidino-4-Nitroimidazole-containing genomes, and analysis of the resulting progeny phage allowed determination of the in vivo bypass efficiencies and mutational signatures of the DNA lesions. 2-Aminoimidazolone was efficiently bypassed and 91% mutagenic, producing almost exclusively G to C transversion mutations. In contrast, 5-guanidino-4-Nitroimidazole was a strong block to replication and 50% mutagenic, generating G to A, G to T, and to a lesser extent, G to C mutations. The G to A mutation elicited by 5-guanidino-4-Nitroimidazole implicates this lesion as a novel source of peroxynitrite-induced transition mutations in vivo. For comparison, the error-prone bypass DNA polymerases were overexpressed in the cells by irradiation with UV light (SOS induction) prior to transformation. SOS induction caused little change in the efficiency of DNA polymerase bypass of 2-aminoimidazolone; however, bypass of 5-guanidino-4-Nitroimidazole increased nearly 10-fold. Importantly, the mutation frequencies of both lesions decreased during replication in SOS-induced cells. These data suggest that 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole in DNA are substrates for one or more of the SOS-induced Y-family DNA polymerases and demonstrate that 2-aminoimidazolone and 5-guanidino-4-Nitroimidazole are potent sources of mutations in vivo.
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efficient synthesis of dna containing the guanine oxidation nitration product 5 guanidino 4 Nitroimidazole generation by a postsynthetic substitution reaction
Organic Letters, 2004Co-Authors: William L Neeley, Paul T Henderson, John M. EssigmannAbstract:[reaction: see text] A convertible nucleoside was synthesized and used to prepare the 2'-deoxynucleoside of 5-guanidino-4-Nitroimidazole, a putative in vivo product of the reaction of peroxynitrite with guanine. The convertible nucleoside was incorporated into an oligodeoxynucleotide by the phosphoramidite method and converted postsynthetically to yield an oligodeoxynucleotide containing 5-guanidino-4-Nitroimidazole at a specific site. The oligodeoxynucleotide was inserted into a viral genome. Melting temperature analysis revealed that duplexes containing 5-guanidino-4-Nitroimidazole were greatly destabilized relative to unmodified duplexes.
Denis Martin - One of the best experts on this subject based on the ideXlab platform.
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repositioning antitubercular 6 nitro 2 3 dihydroimidazo 2 1 b 1 3 oxazoles for neglected tropical diseases structure activity studies on a preclinical candidate for visceral leishmaniasis
Journal of Medicinal Chemistry, 2016Co-Authors: Andrew M Thompson, Adrian Blaser, Scott G Franzblau, Delphine Launay, Denis Martin, Patrick D Oconnor, Vanessa Yardley, Louis Maes, Suman Gupta, Baojie WanAbstract:6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-Nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
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Repositioning Antitubercular 6‑Nitro-2,3-dihydroimidazo[2,1‑b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis
2016Co-Authors: Andrew M Thompson, Adrian Blaser, Scott G Franzblau, Delphine Launay, Denis Martin, Vanessa Yardley, Louis Maes, Suman Gupta, Patrick D. O’connor, Baojie WanAbstract:6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-Nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead
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an improved kilogram scale synthesis of 2 bromo 4 nitro 1h imidazole a key building block of Nitroimidazole drugs
Organic Process Research & Development, 2013Co-Authors: Srinivasa Rao Pedada, Vijay Satam, Pawan J Tambade, Srinivas A Kandadai, Rama Mohan Hindupur, Hari N Pati, Delphine Launay, Denis MartinAbstract:An efficient two-step method for the synthesis of 2-bromo-4-Nitroimidazole, 6, a key building block for Nitroimidazole drugs, has been developed. The synthesis involves dibromination of 4-Nitroimidazole 10 followed by selective debromination using in situ reductive deiodination strategy. The reactions are facile, safe, and easy to scale up. The large-scale applicability of this improved method was tested by conducting the reactions on kilogram scale to produce the desired product in high yield and quality.
