Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking University, 202 Chengfu Road, 098#, Beijing 100871, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 200060, China

Transition-Metal-Free Coupling Reactions

https://chemistry.mdma.ch/hiveboard/rhodium/pdf/indole.synth.review.1994-99.pdf

Recent developments in indole ring synthesis—methodology and applications

/pdf/manganese-iii-based-oxidative-free-radical-cyclizations-50xxse872f.pdf

Manganese(III)-Based Oxidative Free-Radical Cyclizations

Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions

Organocatalysis has captured the imagination of a significant group of synthetic chemists. Much of the mechanistic understanding of these reactions has come from computational investigations or studies involving both experimental and complementary computational explorations. As much as any other area of chemistry, organocatalysis has advanced because of both empirical discoveries and computational insights. Quantum mechanical calculations, particularly with density functional theory (DFT), can now be applied to real chemical systems that are studied by experimentalists; this review describes the quantum mechanical studies of organocatalysis.

The dramatic growth of computational investigations on organocatalysis in the last decade reflects the great attention focused on this area of chemistry since the discoveries of List, Lerner, and Barbas of the proline-catalyzed intermolecular aldol reaction, and by MacMillan in the area of catalysis by chiral amino-acid derived amines. The number of reports on the successful applications of organocatalysts and related mechanistic investigations for understanding the origins of catalysis and selectivities keep growing at a breathtaking pace. Literature coverage in this review is until October 2009, except for very recent discoveries that alter significantly the conclusions based on older literature.

1.1 Computational methods for organocatalysis
Over the last two decades, DFT has become a method of choice for the cost-effective treatment of large chemical systems with high accuracy.1 Most of the studies reported in this review were carried out using the B3LYP functional with the 6-31G(d) basis set, which is a standard in quantum mechanical calculations. Nevertheless, DFT is experiencing continuing developments of new functionals and further improvements. The availability of many new functionals and, in particular, the rapidly evolving performance issues of B3LYP have stimulated extra efforts on benchmarking DFT methods for the prediction of key classes of organic reactions.2 The well-documented deficiencies of B3LYP include the failure to adequately describe medium-range correlation and photobranching effects,3,4 delocalization errors causing significant deviations in π→σ transformations,2b,5 and incorrect description of non-bonding and long-range interactions,6 which are likely to be key factors in determining stereoselectivities. Benchmark results also show that newer functionals considerably improve some of the underlying issues.2–7 Recent advances, especially in the treatment of dispersion effects, now offer more reliable models of the reaction profiles and stereoselectivities.

Most benchmarks focus on energetics rather than stereoselectivities. Systematic benchmarking for stereoselectivities requires more sophisticated techniques and averaging over conformations. To date, such benchmarking based upon stereoselectivity is available for only three reactions,8 and even there only various basis sets with B3LYP, as well as comparisons of results predicted using enthalpies and free energies. It is not possible to assign error bars for stereoselectivities for the majority of reports discussed in this review. Because stereoisomeric transition structures are very similar species, their relative energies are likely to be calculated accurately, as shown by the good agreement between calculated and experimental values.

More recently Harvey (Harvey, 2010, faraday discussions) has studied two typical organic reactions of polar species (Wittig and Morita-Baylis-Hillman reactions) at different levels of theory.2i He showed that many standard computational methods, involving B3LYP, are qualitatively useful, but the energetics may be misleading for larger reactive partners; the quantitative prediction of rate constants remains difficult. These studies suggest that although B3LYP provides valuable qualitative insight into the reaction mechanisms and selectivities, the energetics may require testing with higher accuracy methods for complex organic systems. On the other hand, Simon and Goodman found B3LYP to be “only slightly less accurate” than newer methods, and recommended its use for organic reaction mechanisms.9

/pdf/quantum-mechanical-investigations-of-organocatalysis-3nwyyq4bog.pdf

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

A most useful strategy has been devised for the synthesis of 3-substituted pyrroles on the basis of the kinetic electrophilic substitution of 1-(triisopropylsilyl) pyrrole (1) at the β position and subsequent fluoride ion induced desilylation. This now becomes the preferred route to 3-monosubstituted pyrroles

N-(Triisopropylsilyl)pyrrole. A progenitor "par excellence" of 3-substituted pyrroles

Addition of excess hydrogen peroxide (10 equiv) to a sonicated solution of FeSO 4 :7H 2 O (1 equiv) in DMSO containing the N-(ω-iodoalgyl)indoles 4, 5, 11, and 13 effected oxidative radical cyclization to 6, 7, 14, and 15, respectively. The (ω-iodoalkyl)pyrroles 21, 22, 27, 38, and 49 underwent analogous cyclization reactions to 23, 24, 28, 39, and 50, respectively. The regiochemistry of these radical cyclization reactions was correctly predicted by FMO calculations in all cases but one. For compound 38, FMO calculations indicated that radical attack should take place at both C-3 and C-5. Only the product of cyclization at C-5, i.e., 39, was observed. The enantiomerically pure bicyclic ketone 42, prepared by the above technique from the iodide 53, was converted into 55 which, on catalytic reduction (H 2 /Rh-Al 2 O 3 ), gave a mixture of (―)-monomorine (40) and three of its diastereoisomers 56-58

Oxidative Radical Cyclization of (.omega.-Iodoalkyl)indoles and Pyrroles. Synthesis of (-)-Monomorine and Three Diastereomers

Short, efficient, and convergent syntheses of ketorolac (1) based on the inter- or intramolecular oxidative addition of malonyl and substituted malonyl radicals to 2-benzoylpyrrole and derivatives ...

Radical-based syntheses of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (ketorolac)

The syntheses of several N-methyltropan-3-ylindoles, designed as conge- ners of ibogaine, are described. The synthetic approach to N-methyltro- pan-3-yl-2-indole revealed that the tropanyl 3'-center was quite sensi- tive to acid-catalyzed epimerization. The carbocyclic analog, N-methyl- 2-[bicyclo[3.2.1]-oct-3-yl]indole, also underwent this rearrangement. However, N-methyltropan-3-yl-3-indole was insensitive to acid or base, even under more vigorous conditions. This simple isomerization is quite rare for 2-substituted indoles, especially for cases where the center of reaction is not additionally activated, and normally only takes place under extreme reaction conditions. The mechanism of this reaction was investigated using ab initio molecular orbital calculations, NMR spec- troscopy, and deuterium labeling studies. The difference in reactivity is suggested to arise from a decrease in the relative energy of the exocyclic enamine tautomer due to the presence of increased strain in the endo bicyclic 2-substituent. The title compounds displayed modest pharmacological activity in a variety of biological assays

Abbreviated Ibogaine Congeners. Synthesis and Reactions of Tropan-3-yl-2- and -3-indoles. Investigation of an Unusual Isomerization of 2-Substituted Indoles Using Computational and Spectroscopic Techniques

Bicyclo[4.1.0]hept-1,6-ene has been generated by elimination of 1-chloro-2-(trimethysilyl)bicyclo[4.1.0]heptane in the gas phase over solid fluoride at 25 degrees C. The cyclopropene dimerizes by a rapid ene reaction forming two diastereomeric cyclopropenes. In tetrahydrofuran or chloroform the ene dimers couple to form a single crystalline triene tetramer, whereas a mixture of tricyclohexane tetramers is formed when the neat dimers are allowed to warm to room temperature. Oxidation by dimethyldioxirane or dioxygen gives carbonyl products. Quantum mechanical calculations yielded an increase in strain of approximately 17 kcal/mol over that for 1,2-dimethylcyclopropene. The potential enegy barrier to flexing (folding) along the fused double bond of bicyclo[4.1.0]hept-1,6-ene is only approximately 1 kcal/mol at the highest level of theory investigated.

Dean R. Artis

Papers

N-(Triisopropylsilyl)pyrrole. A progenitor "par excellence" of 3-substituted pyrroles

Oxidative Radical Cyclization of (.omega.-Iodoalkyl)indoles and Pyrroles. Synthesis of (-)-Monomorine and Three Diastereomers

Radical-based syntheses of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (ketorolac)

Abbreviated Ibogaine Congeners. Synthesis and Reactions of Tropan-3-yl-2- and -3-indoles. Investigation of an Unusual Isomerization of 2-Substituted Indoles Using Computational and Spectroscopic Techniques

Synthesis and Chemistry of Bicyclo[4.1.0]hept-1,6-ene.