Research Summary Prabhu Mohapatra 1999 2007 Center for

Research Summary Prabhu Mohapatra 1999 -2007 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611 -7200 1

Problem: Low yields of 1, 3, 4 -oxadiazoles with unsaturated or nucleophilic substituent [06 TL 4827] Solution: N-acylbenzotriazoles are activated derivatives of carboxylic acids 2

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

Synthesis of ortho-Sulfamidotriazobenzenes from 1, 1’-Sulfonylbis(benzotriazole) [07 JOC 5805] Problem: Sulfuryl chloride is a toxic liquid, corrosive, and acts as a lachrymator Solution: Stable benzotriazole derivative of sulfuryl chloride ORTEP diagram of Bt 2 SO 2 ORTEP diagram of ring opened product ortho-Sulfamidotriazobenzenes of type 10 were unknown; however, closely related orthosulfonamidotriazobenzenes are known and have been used as color formers. [11 CB 2694] 4

Synthesis of ortho-Sulfamidotriazobenzenes from 1, 1’-Sulfonylbis(benzotriazole) [07 JOC 5805] 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. [06 Pharmazie 511] 5

Synthesis of ortho-Sulfamidotriazobenzenes from 1, 1’-Sulfonylbis(benzotriazole) [07 JOC 5805] Possible mechanism for the ring opening Literature synthesis of ortho-sulfonamidotriazobenzenes [11 CB 2694] 6

Synthesis of unsymmetrical sulfamides from N-sulfonylbenzotriazoles [07 JOC 5805] Sulfamides are of interest as (i) components stable to enzymatic hydrolysis in peptidomimetics, [00 T 9781] (ii) active components in epinephrine analogues, [81 JMC 1300] (iii) agonists of the 5 -HT 1 D receptor (regulating serotonin levels), [94 JMC 3023] and (iv) HIV protease inhibitors. [97 JMC 898] 7

1 -Benzotriazol-1 -yl-3, 3, 3 -trifluoro-2 -methoxy-2 -phenyl-propan-1 -one: Mosher-Bt [07 JOC 4268] 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, 19 a, showing one enantiomer 8

1 -Benzotriazol-1 -yl-3, 3, 3 -trifluoro-2 -methoxy-2 -phenyl-propan-1 -one: Mosher-Bt [07 JOC 4268] Reactions of Mosher-Bt reagents with aminoacids and peptides, products 20 b-f are single diastereomers as proved by chiral HPLC analysis (using Chirobactic T column, detection at 254 nm, 9 flow rate 0. 1 m. L/min, solvent Me. OH)

1 -Benzotriazol-1 -yl-3, 3, 3 -trifluoro-2 -methoxy-2 -phenyl-propan-1 -one: Mosher-Bt [07 JOC 4268] assignment of absolute configuration MTPA amides of (R)-Phenylalanine. Chemical shift (d) values in the 1 H, 13 C and 19 F NMR of MTPA amides of (R)-Phenylalanine entry product. Mosher amide abs. config. d-values (1 H NMR) d-values (13 C NMR) d-values (19 F NMR) methylene methine CF 3 1 (R, R)-2 a (R, R) 3. 28, 3. 14 4. 93 37. 6 55. 4, 55. 3 -69. 37 2 (S, R)-2 a (S, R) 3. 24, 3. 06 5. 03 37. 4 55. 0, 55. 0 -69. 31 0. 04, 0. 08 0. 1 0. 2 0. 4, 0. 3 0. 06 difference 10

1 -Benzotriazol-1 -yl-3, 3, 3 -trifluoro-2 -methoxy-2 -phenyl-propan-1 -one: Mosher-Bt [07 JOC 4268] 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 1 Hbenzotriazole (100 g, $25) and are thus more cost-effective as compared to commercially available MTPA chloride (250 mg, $100). 11

Problem: Reaction of acid chlorides with Grignard reagents gives low yields of ketones due to many side reactions including formation of undesired tertiary alcohols [05 OL 5593] Solution: N-acylbenzotriazoles are stable alternatives of acid chlorides 12

Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06 JOC 9861] 13

Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06 JOC 9861] 14

Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06 JOC 9861] No racemization proved by chiral HPLC analysis No racemization 15

Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by acylation of Organometallic Reagents [07 S 3141] 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. R 1 COBt = N-acylbenzotriazoles 1 a-d R 2 M = Grignard reagents 2 A-C and heteroaryllithium reagents 3 D-F 16

Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07 S 3141] 17

Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07 S 3141] 18

Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07 S 3141] 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 19

Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07 S 3141] 20 Lit. Bremner, J. B. ; Samosorn, S. ; Ambrus, J. I. Synthesis 2004, 2653. (DCC/DMAP mediated coupling of indoles with carboxylic acids)

Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07 S 3141] 21

Benzotriazole-Based Thioacylation Reagents [05 JOC 7866] Thioamides and Thiolesters from Thiocarbonylbenzotriazole (RCSBt) Thioureas, Thioamides, Thiocarbamates and Dithiocarbamates from Thiocarbamoylbenzotriazoles (RNHCSBt) 22

Benzotriazole-Based Thioacylation Reagents [05 JOC 7866] Alkyl/Aryloxythiocarbonylbenzotriazoles (ROCSBt) and Alkyl/Arylthiocarbonylbenzotriazoles (RSCSBt) Thionesters and Thiocarbamates from ROCSBt 23

New Synthesis of N-Functionalized Dithiocarbamates [05 ARK 63] 24

Synthesis of -Amino Amides [05 JSCS 319] Synthesis of -Benzotriazolyl Ketones [04 ARK 22] 25

Synthesis of Hexagonal Terpyridine-Ruthenium and -Iron Macrocycles by Step-wise or Self-assembly procedures [02 CEJ 2946] 26

Comparison of HNMR spectra of the monomer and hexamer [02 CEJ 2946] Monomer Hexamer 27

Synthesis of a family of hetero-metallomacrocycles by step-wise procedure [04 CEJ 1493] = Fe = Ru = Os 28

Synthesis of phenyl acetylene dendrons for antenna macrocycles [unpublished] 2 -Methyl-3 -butynol Pd(dba)2, Cu. I, NEt 3, PPh 3 KOH, Toluene Me 3 Si. Cl Et. Mg. Br, THF CF 3 SO 2)2 O 2 -Methyl-3 -butynol Pd(dba)2, Cu. I, NEt 3, PPh 3 KOH, Toluene Pyr A 2 eqiv. K 2 CO 3, Me. OH Pd(dba)2, Cu. I, NEt 3, PPh 3 B 29

Synthesis of antenna dendron substituted bis-terpyridine by Sonagashira coupling [unpublished] 30

Synthesis of Antenna G 1 homo-metallomacrocycles [unpublished] = Ru Possible use in photonics (light harvesting and storage applications) 31

Synthesis of Antenna G 2 homo-metallomacrocycles [unpublished] = Ru Possible use in photonics (light harvesting and storage applications) 32

Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06 Science 1782] 33

Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06 Science 1782] 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). 34

Synthesis of next generation non-nutritive sweetener Neotame C-7 [NS] Synthesis of 2, 6, 7 -trimethyl-5 -nitrosopyrrolo[1, 2 -b]pyridazine [L] 35

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) 36

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) 37

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] 38

Synthesis of 2, 3 -dimethyl-1 -nitroindolizine [L] Not separable by column chromatography Synthesis of 5 -nitrosopyrrolo[1, 2 -c]pyrimidine [L] 39

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-2 H-[2, 6]naphthyridin-1 -one [R] 40

Synthesis of 3 -fluoroadamantanylmethylamine hydrochloride [R] DAST Synthesis of 3 -fluoroadamantane-1 -carboxylic acid [R] Synthesis of novel 3 -noradamantylmethylamine BH 3 salt [R] 41

Synthesis of novel 5 -amino-isochromen-1 -one [R] Synthesis of novel 6 -bromo-5 -nitro-isochromen-1 -one [R] Regioisomers difficult to separate by column chromatography Regioisomers are separable by recrystallization 42