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Research Summary. Prabhu Mohapatra 1999-2007 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200. Problem: Low yields of 1,3,4-oxadiazoles with unsaturated or nucleophilic substituent [06TL4827].

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Research summary

Research Summary

Prabhu Mohapatra

1999-2007

Center for Heterocyclic Compounds, Department of Chemistry,

University of Florida, Gainesville, FL 32611-7200


Problem low yields of 1 3 4 oxadiazoles with unsaturated or nucleophilic substituent 06tl4827
Problem: Low yields of 1,3,4-oxadiazoles with unsaturated or nucleophilic substituent [06TL4827]

Solution: N-acylbenzotriazoles are activated derivatives of carboxylic acids


Efficient One Pot Synthesis of 1,3,4-Oxadiazoles from N-acylbenzotriazoles and Acyl Hydrazides [in progress]


Synthesis of N-acylbenzotriazoles and Acyl Hydrazides ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]Problem: Sulfuryl chloride is a toxic liquid, corrosive, and acts as a lachrymatorSolution: Stable benzotriazole derivative of sulfuryl chloride

ORTEP diagram of Bt2SO2

ORTEP diagram of

ring opened product

ortho-Sulfamidotriazobenzenes of type 10 wereunknown; however, closely related ortho-sulfonamidotriazobenzenes are known and have been used as color formers. [11CB2694]


Synthesis of ortho sulfamidotriazobenzenes from 1 1 sulfonylbis benzotriazole 07joc5805
Synthesis of N-acylbenzotriazoles and Acyl Hydrazides ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole)[07JOC5805]

No ring opening

In case of

alkyl-aryl

or diaryl amines

Thermodynamically

controlled

ring opening

In case of

dialkyl amines

Kinetically

controlled

ortho-Sulfamidotriazobenzenes 10 combine both the features of a triazine and a sulfamide group. Many triazines are known to display potent antitumor activity. [06Pharmazie511]


Synthesis of ortho sulfamidotriazobenzenes from 1 1 sulfonylbis benzotriazole 07joc58051
Synthesis of N-acylbenzotriazoles and Acyl Hydrazides ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole)[07JOC5805]

Possible mechanism for the ring opening

Literature synthesis of ortho-sulfonamidotriazobenzenes [11CB2694]


Synthesis of unsymmetrical sulfamides from n sulfonylbenzotriazoles 07joc5805
Synthesis of unsymmetrical sulfamides from N-acylbenzotriazoles and Acyl Hydrazides N-sulfonylbenzotriazoles[07JOC5805]

Sulfamides are of interest as (i) components stable to enzymatic hydrolysis in peptidomimetics, [00T9781](ii) active components in epinephrine analogues, [81JMC1300](iii) agonists of the 5-HT1D receptor (regulating serotonin levels), [94JMC3023] and(iv) HIV protease inhibitors. [97JMC898]


1 benzotriazol 1 yl 3 3 3 trifluoro 2 methoxy 2 phenyl propan 1 one mosher bt 07joc4268
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt[07JOC4268]

a-Methoxy-a-Trifluoromethyl Phenyl Acetic acid chloride (MTPA acid chloride): Mosher’s reagent

chiral derivatizing agents for determining both ee and absolute configuration of chiral alcohols and amines

ORTEP diagram of (rac)-MTPA Bt, 19a,

showing one enantiomer


1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]

Reactions of Mosher-Bt reagents with aminoacids and peptides, products 20b-f are single diastereomers

as proved by chiral HPLC analysis (using Chirobactic T column, detection at 254 nm,

flow rate 0.1 mL/min, solvent MeOH)


1 benzotriazol 1 yl 3 3 3 trifluoro 2 methoxy 2 phenyl propan 1 one mosher bt 07joc42681
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]

assignment of

absolute configuration

MTPA amides of (R)-Phenylalanine.

Chemical shift (d) values in the 1H, 13C and 19F NMR of MTPA amides of (R)-Phenylalanine


1 benzotriazol 1 yl 3 3 3 trifluoro 2 methoxy 2 phenyl propan 1 one mosher bt 07joc42682
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]

  • Compared to the corresponding acid chlorides of Mosher-Bt reagents have the following advantages:

  • they are non-corrosive, stable to moisture and heat, and can be stored at room temperature indefinitely; and thus easy to handle as compared to corrosive and moisture sensitive MTPA chloride,

  • the carboxyl groups of the aminoacids, di and tripeptides need no protection prior to making their MTPA amides,

  • high yields of corresponding Mosher’s amides are obtained,

  • their reactions can be carried out in aqueous conditions,

  • unlike MTPA chloride the absolute configuration of the Mosher-Bt reagent and the Mosher’s ester or amide are the same simplifying assignment of absolute configuration and

  • they are easily prepared in quantitative yield from the corresponding MTPA (250 mg, $36) using 1H-benzotriazole (100 g, $25) and are thus more cost-effective as compared to commercially available MTPA chloride (250 mg, $100).


Problem: Mosher-Bt Reaction of acid chlorides with Grignard reagents gives low yields of ketones due to many side reactions including formation of undesired tertiary alcohols [05OL5593]Solution: N-acylbenzotriazoles are stable alternatives of acid chlorides


Alkyl, Unsaturated, (Hetero)aryl and Mosher-Bt N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]


Alkyl, Unsaturated, (Hetero)aryl and Mosher-Bt N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]


Alkyl, Unsaturated, (Hetero)aryl and Mosher-Bt N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]

No racemization

proved by

chiral HPLC analysis

No racemization

No racemization

No racemization


R Mosher-Bt 1COBt =

N-acylbenzotriazoles 1a-d

R2M =

Grignard reagents 2A-C and heteroaryllithium reagents 3D-F

Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by acylation of Organometallic Reagents [07S3141]

Problem: Conventional Friedel-Crafts acylation of phenols and naphthols with acyl chlorides in the presence of Lewis acid catalysts and Fries type rearrangement of suitable aryl esters are frequently used for the preparation of hydroxyaryl ketones. However, these reactions often suffer a lack of selectivity. Usually both ortho- and para-acylation of phenols and naphthols takes place to give a mixture.


Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]


Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]


Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents[07S3141]

Possible mechanism of ketone synthesis

  • Stable alternatives of acid chlorides

  • Yields – high

  • Selectivity - Ketone vs. tertiary alcohols

  • Reactivity - Li reagents are more reactive (better nucleophiles) than Grignard reagents

  • Convenience – No need to protect the OH group

  • single product vs. mixture (ortho + para) in case of Friedal Craft acylation and Fries rearrangement to obtain hydroxyaryl ketones


Efficient n aroylation of substituted indoles with n aroylbenzotriazoles 07s3141
Efficient N-Aroylation of Substituted Indoles with -(Hetero)aryl Ketones by Acylation of Organometallic ReagentsN-Aroylbenzotriazoles[07S3141]

Lit. Bremner, J. B.; Samosorn, S.; Ambrus, J. I. Synthesis2004, 2653. (DCC/DMAP mediated coupling of indoles with carboxylic acids)


Efficient n aroylation of substituted indoles with n aroylbenzotriazoles 07s31411
Efficient N-Aroylation of Substituted Indoles with -(Hetero)aryl Ketones by Acylation of Organometallic ReagentsN-Aroylbenzotriazoles[07S3141]


Benzotriazole-Based Thioacylation Reagents -(Hetero)aryl Ketones by Acylation of Organometallic Reagents[05JOC7866]

Thioamides and Thiolesters from Thiocarbonylbenzotriazole (RCSBt)

Thioureas, Thioamides, Thiocarbamates and Dithiocarbamates from Thiocarbamoylbenzotriazoles (RNHCSBt)


Benzotriazole-Based Thioacylation Reagents -(Hetero)aryl Ketones by Acylation of Organometallic Reagents[05JOC7866]

Alkyl/Aryloxythiocarbonylbenzotriazoles (ROCSBt) and Alkyl/Arylthiothiocarbonylbenzotriazoles (RSCSBt)

Thionesters and Thiocarbamates from ROCSBt


New synthesis of n functionalized dithiocarbamates 05ark63
New Synthesis of N-Functionalized Dithiocarbamates -(Hetero)aryl Ketones by Acylation of Organometallic Reagents[05ARK63]


Synthesis of a amino amides 05jscs319
Synthesis of -(Hetero)aryl Ketones by Acylation of Organometallic Reagentsa-Amino Amides [05JSCS319]

Synthesis of a-Benzotriazolyl Ketones [04ARK22]


Synthesis of Hexagonal Terpyridine-Ruthenium and -Iron Macrocycles by Step-wise or Self-assembly procedures [02CEJ2946]


Comparison of HNMR spectra of the monomer and hexamer Macrocycles by Step-wise or Self-assembly procedures [02CEJ2946]

Monomer

Hexamer


Synthesis of a family of hetero-metallomacrocycles by step-wise procedure [04CEJ1493]

= Fe

= Ru

= Os


Synthesis of phenyl acetylene dendrons for antenna macrocycles [unpublished]

2-Methyl-3-butynol

Pd(dba)2, CuI,

NEt3, PPh3

KOH,

Toluene

Me3SiCl

EtMgBr,

THF

2-Methyl-3-butynol

Pd(dba)2, CuI,

NEt3, PPh3

KOH,

Toluene

CF3SO2)2O

Pyr

A

2 eqiv.

K2CO3,

MeOH

Pd(dba)2, CuI,

NEt3, PPh3

B



Synthesis of antenna g1 homo metallomacrocycles unpublished

= Ru Sonagashira coupling

Synthesis of Antenna G1 homo-metallomacrocycles [unpublished]

Possible use in photonics (light harvesting and storage applications)


= Ru Sonagashira coupling

Synthesis of Antenna G2 homo-metallomacrocycles [unpublished]

Possible use in photonics (light harvesting and storage applications)


Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06Science1782]


Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06Science1782]

Images of gasket 6. (A) AFM images at 1.12 x 1.12 µm and 100 x 100 nm. (B) TEM pictures with 50- and 20-nm scale bars for the lower- and higher-resolution images, respectively (all images were obtained unstained). (C) UHV-STM images (100 x 100 nm) on a Au(111) surface at 6 K, revealing a line of gaskets settled on a ridge on the gold surface and a color-enhanced and magnified image of a single molecule (scale bar, 3 nm).


Synthesis of next generation non nutritive sweetener neotame c 7 ns
Synthesis of next generation non-nutritive sweetener Neotame C-7 [NS]

Synthesis of 2,6,7-trimethyl-5-nitrosopyrrolo[1,2-b]pyridazine [L]


Synthesis of 4-(2,6-dimethylpyrrolo[1,2- C-7 b]pyridazin-7-ylazo)benzenesulfonic acid [L]

Synthesis of 2-methyl-1-nitrosoindolizine-3-carboxylic acid methyl ester [L]

Synthesis of 2-methylamino-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]

1-(methylamino)-1-(methylthio)-2-nitroethene is commercially available (Aldrich)


Synthesis of 2-methanesulfonyl-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]

Not separable by column chromatography

Synthesis of 7-dimethylamino-2-methylsulfanyl-1-nitroso-indolizine-3-carboxylic acid ethyl ester [L]

Nitroketene dithioacetal is commercially available (Aldrich)


Synthesis of (6,7-dimethyl-5-nitrosopyrrolo[1,2- 2-methanesulfonyl-1-nitrosoindolizine-3-carboxylic acid ethyl ester b]pyridazin-2-yl)diethylamine [L]

Not separable by column chromatography

Synthesis of 2-methyl-1-nitroindolizine [L]


Synthesis of 2,3-dimethyl-1-nitroindolizine 2-methanesulfonyl-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]

Not separable by column chromatography

Synthesis of 5-nitrosopyrrolo[1,2-c]pyrimidine [L]


Synthesis of 7-substituted-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile [R]

Synthesis of 6-benzyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-1-one [R]


Synthesis of 3-fluoroadamantanylmethylamine hydrochloride 7-substituted-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile [R]

DAST

Synthesis of 3-fluoroadamantane-1-carboxylic acid [R]

Synthesis of novel 3-noradamantylmethylamine BH3 salt [R]


Synthesis of novel 5-amino-isochromen-1-one 7-substituted-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile [R]

Synthesis of novel 6-bromo-5-nitro-isochromen-1-one [R]

Regioisomers are separable by recrystallization

Regioisomers difficult to separate by column chromatography


Synthesis of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, a key synthon of Repaglinide [R]

Preparation of Repaglinide [R]


Synthesis of Chiral Metabolites of Pioglitazone key synthon of Repaglinide [R]

Boekel-heide rearrangement


Preparation of midazolam maleate key synthon of Repaglinide [R]


Thanks
Thanks key synthon of Repaglinide


Thank you. key synthon of Repaglinide


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