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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

slide3
Efficient One Pot Synthesis of 1,3,4-Oxadiazoles from N-acylbenzotriazoles and Acyl Hydrazides [in progress]
slide4

Synthesis of 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 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 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-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

slide9

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).
slide12

Problem: 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

slide13
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]
slide14
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]
slide15
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]

No racemization

proved by

chiral HPLC analysis

No racemization

No racemization

No racemization

slide16

R1COBt =

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.

slide17
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]
slide18
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]
slide19
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 N-Aroylbenzotriazoles[07S3141]

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

slide22

Benzotriazole-Based Thioacylation Reagents [05JOC7866]

Thioamides and Thiolesters from Thiocarbonylbenzotriazole (RCSBt)

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

slide23

Benzotriazole-Based Thioacylation Reagents [05JOC7866]

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

Thionesters and Thiocarbamates from ROCSBt

synthesis of a amino amides 05jscs319
Synthesis of a-Amino Amides [05JSCS319]

Synthesis of a-Benzotriazolyl Ketones [04ARK22]

slide26
Synthesis of Hexagonal Terpyridine-Ruthenium and -Iron Macrocycles by Step-wise or Self-assembly procedures [02CEJ2946]
slide28

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

= Fe

= Ru

= Os

slide29

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

Synthesis of Antenna G1 homo-metallomacrocycles [unpublished]

Possible use in photonics (light harvesting and storage applications)

slide32

= Ru

Synthesis of Antenna G2 homo-metallomacrocycles [unpublished]

Possible use in photonics (light harvesting and storage applications)

slide33

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

slide34

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]

slide36

Synthesis of 4-(2,6-dimethylpyrrolo[1,2-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)

slide37

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)

slide38

Synthesis of (6,7-dimethyl-5-nitrosopyrrolo[1,2-b]pyridazin-2-yl)diethylamine [L]

Not separable by column chromatography

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

slide39

Synthesis of 2,3-dimethyl-1-nitroindolizine [L]

Not separable by column chromatography

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

slide40

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]

slide41

Synthesis of 3-fluoroadamantanylmethylamine hydrochloride [R]

DAST

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

Synthesis of novel 3-noradamantylmethylamine BH3 salt [R]

slide42

Synthesis of novel 5-amino-isochromen-1-one [R]

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

Regioisomers are separable by recrystallization

Regioisomers difficult to separate by column chromatography

slide43

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

Preparation of Repaglinide [R]

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