Arvind Jaganathan

An Organocatalytic Asymmetric Chlorolactonization

A reagent controlled organocatalytic enantioselective chlorolactonization reaction has been developed. Several 4-aryl pentenoic acids were cyclized in the presence of 0.1 equiv of (DHQD)(2)PHAL, employing various N-chlorinated hydantoins as the terminal chlorenium source. Ten examples are presented with selectivities ranging from 43 to 90% ee. This work represents the first example of an enantioselective reagent-controlled chlorolactonization that approaches synthetically useful enantioselectivities.

A Catalytic Asymmetric Chlorocyclization of Unsaturated Amides

Stereodefined carbon–halogen bonds are ubiquitous in nature with several natural products exhibiting this motif. While the biogenetic origins of this unique chiral functionality has been a subject of several investigations in the past, attempts by organic chemists to forge the carbon–halogen bond stereoselectively have largely been unsuccessful. This problem has come into focus only recently. Several elegant reports of asymmetric halogenations of alkenes and alkynes followed by an intramolecular attack of a pendant nucleophile have appeared in the literature in the last decade. Kang et al. reported a cobalt–salen catalyzed iodoetherification reaction. An asymmetric fluorocyclization of allyl silanes mediated by a cinchona alkaloid dimer was reported by Gouverneur and co-workers. Tang and co-workers disclosed an asymmetric bromolactonization of enynes catalyzed by a cinchona alkaloid derived urea; other bromolactonizations have also appeared following the disclosure of their report. More recently, Veitch and Jacobsen reported an asymmetric iodolactonization reaction mediated by chiral thiourea catalysts. Polyene cyclizations induced by chiral halonium ions have also been realized as reported by the research groups of Ishihara and Snyder. However, given the fledgling nature of this research area, one may find it easy to highlight the many drawbacks and limitations even in the present state of the art—for example, the relatively large catalyst loadings (superstoichiometric quantities in some cases) to achieve meaningful levels of enantioselectivity or the lack of a robust catalytic system that can catalyze a number of diverse reactions rather than one specific reaction. Moreover, efficient asymmetric chlorocyclizations have remained underdeveloped. This situation is attributable, at least in part, to the highly reactive nature of chloronium ions, which are known to exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions, thus making the development of chlorocyclizations a formidable challenge. Our research group has recently reported the catalytic asymmetric chlorolactonization of alkenoic acids. Herein, we disclose the efficient halocyclization of unsaturated amides to furnish chiral heterocycles. Furthermore, these heterocycles have been transformed into useful chiral building blocks such as amino alcohols. Chiral heterocycles such as oxazolines and dihydrooxazines are commonly encountered motifs in natural products, molecules of pharmaceutical interest, and in several chiral ligands. Their syntheses, however, usually employ stoichiometric quantities of chiral amino alcohols. With only one precedented method to access these molecules in a catalytic asymmetric fashion, we were intrigued by the possibility of one-step access to these versatile chiral heterocycles by a catalytic asymmetric halocyclization of easily accessed unsaturated amides. We chose the conversion of benzamide 1 into oxazoline 2 as our initial test reaction. Among the several ligands screened for the test reaction, (DHQD)2PHAL emerged as the best candidate, thus affording the desired oxazoline 2 in 57% ee (Table 1, entry 1) with DCDMH as the terminal chlorine source. Reactions with other chlorenium sources

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (HalA) Scale

We introduce a previously unexplored parameter—halenium affinity (HalA)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a “free halenium ion”. Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

Solvent-dependent enantiodivergence in the chlorocyclization of unsaturated carbamates.

A remarkable solvent-controlled enantiodivergence is seen in the hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates. Eyring plot analyses of this previously unreported reaction are used to probe and compare the R- and S-selective pathways. In the CHCl3/hexanes solvent system, the pro-R process shows a surprising increase in selectivity with increasing temperature. These studies point to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways.

Chlorosulfonamide Salts Are Superior Electrophilic Chlorine Precursors for the Organocatalytic Asymmetric Chlorocyclization of Unsaturated Amides

Chloramine-T·3H(2)O and other chlorosulfonamide salts can serve as readily available, stable, and inexpensive precursors of electrophilic chlorine in the organocatalytic asymmetric chlorofunctionalization of olefins. In conjunction with commercially available organocatalysts, they can be utilized in the asymmetric chlorocyclization of unsaturated amides to yield products with unprecedented levels of stereoselectivity even at ambient temperatures and high concentrations.

Highly Stereoselective Intermolecular Haloetherification and Haloesterification of Allyl Amides

An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A variety of alkene substituents and substitution patterns are compatible with this chemistry. Notably, electronically unbiased alkene substrates exhibit exquisite regio- and diastereoselectivity for the title transformation. We also demonstrate that the same catalytic system can be used in both chlorination and bromination reactions of allyl amides with a variety of nucleophiles with little or no modification.

Aqueous Suzuki Coupling Reactions of Basic Nitrogen-Containing Substrates in the Absence of Added Base and Ligand: Observation of High Yields under Acidic Conditions.

A series of aqueous heterogeneous Suzuki coupling reactions of substrates containing basic nitrogen centers with phenylboronic acid in the absence of added base and ligand is presented. High yields of products were obtained by employing aryl bromides containing aliphatic 1°, 2°, and 3° amine substituents, and good to high yields were obtained by employing a variety of substituted bromopyridines. In the former series, the pH of the aqueous phase changed from basic to acidic during the course of the reaction, while in the latter series the aqueous phase was on the acidic side of the pH scale throughout the entire course of reaction. A mechanistic interpretation for these observations, which generally preserves the oxo palladium catalytic cycle widely accepted in the literature, is presented.

Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides

We report a highly regio-, diastereo- and enantioselective vicinal dihalogenation of allyl amides. E- and Z-alkenes with both aryl and alkyl substituents were compatible with this chemistry. This is the result of exquisite catalyst controlled regioselectivity enabling use of electronically unbiased substrates. The reaction employs commercially available catalysts and halenium sources along with cheap inorganic halide salts to affect this transformation. A preliminary effort to extend this chemistry to heterodihalogenation is also presented.

Absolute and relative facial selectivities in organocatalytic asymmetric chlorocyclization reactions

For four related 1,1-disubstituted olefins, (DHQD)2PHAL-catalyzed asymmetric chlorocyclization delivers Cl+ uniformly to one π face, but cyclizes with strong but differing net syn vs. anti addition.

Pd-Catalyzed Suzuki coupling reactions of aryl halides containing basic nitrogen centers with arylboronic acids in water in the absence of added base

The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXium®PtB) was used. In contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXium®PtB, produced high yields of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was attributed to the decomposition of the Pd–ligand complex due to the protonation of the ligand in the more acidic aqueous media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH 4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki catalytic cycle.