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Extramural Research

Final Report: Opportunities Offered by Indium-Promoted Carbon-Carbon Bond-Forming Reactions in Water

EPA Grant Number: R824725
Title: Opportunities Offered by Indium-Promoted Carbon-Carbon Bond-Forming Reactions in Water
Investigators: Paquette, Leo A.
Institution: Ohio State University - Main Campus
EPA Project Officer: Karn, Barbara
Project Period: October 1, 1995 through September 30, 1997
Project Amount: $300,000
RFA: Technology for a Sustainable Environment (1995)
Research Category: Pollution Prevention/Sustainable Development

Description:

Objective:

The objective of this project was to generalize on the serviceability of free hydroxyl groups for promoting stereochemical control in organic reactions performed in aqueous environments under catalysis by indium metal.

Summary/Accomplishments (Outputs/Outcomes):

The first phase of the present research project focused on bringing ketones into carbon-carbon bond-forming reactions with indium reagents. This class of compounds, traditionally considered to be unreactive under these circumstances, is indeed adequately reactive under the proper conditions. In fact, a-hydroxy ketones undergo condensation smoothly and efficiently in water and do so with exceptionally high levels of chelation control (Paquette and Lobben, 1996). Compounds 1-3 constitute representative examples.

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The behavior of 4 is particularly noteworthy. In the classical organic solvent tetrahydrofuran, non-chelation control operates to the extent of 37 percent. This finding contrasts strikingly with the fact that chelation control is the exclusive pathway under environmentally friendly aqueous conditions. More remains to be explored in this arena, but the results acquired so far are exciting.

To us, stereochemical issues are of prime importance because they are of immediate concern to synthetic chemists worldwide. For this reason, we have pursued the quest for higher level

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diastereoselection in water-based processes. Our results so far have proven to be dramatically impressive (Isaac and Paquette, 1997). The critical factor here is the inability of the allylic indium reagent to undergo rapid E/Z equilibration. In simple systems of the crotyl and -bromoallyl type, we have discovered that the stereochemical interconversioin of geometric isomers occurs readily (Paquette and Mitzel, 1996). This is not the case with bromides such as 5, which couples with high stereoselectivity to set three contiguous stereogenic centers under aqueous conditions. Work in this area is continuing in a purposeful effort to define existing limitations.

Two other facets of the present investigation have not proven to be as useful. We have proposed to examine other halide types. Prior to our intended study of propargylic halides, a Canadian group published their results that were sufficiently allied to our plans that we did not go forward. We also had intended to examine the possibility of involving l-halo alkynes as reaction partners. However, this class of reagents does not behave properly and holds no value as agents amenable to coupling with carbonyl compounds in aqueous environments. We also had hoped to be able to engage properly substituted imines in comparable reactions as a means for synthesizing amines efficiently in water. However, we have discovered that a large variety of substituted imines undergo hydrolysis more rapidly than carbon-carbon condensation. This phenomenon operates presumably because the indium-water system develops acidity as it progresses. When proper buffering was implemented, a complete lack of reactivity was seen.

Far more productive were our studies designed to expand on selected issues of far-reaching stereochemical importance. The stereochemistry of the indium-promoted reaction of allyl bromide with -thia (PhS- and MeS-), disubstituted -amino (Bn2N-, Me2N, isoindolyl), and protected a-amino aldehydes (Ac and Boc) in water has been evaluated (Paquette et al., 1997). The reactions involving the sulfur derivatives are minimally diastereoselective, indicating that

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the allylindium reagent is not thiophilic. Chelation is not observed and -facial discrimination is achieved via Felkin-Ahn transition states under the steric control of the substituents. The Garner aldehyde also is anti-diastereoselective. Interestingly, N-acetyl mannosamine is appreciably responsive to chelation control and is capable of generating 90 percent of the syn -amino alcohol when reacted in 0.5 M NH&I solution. While the a-dibenzylamino substituent is too bulky to enter into complexation, the -dimethylamino group is not and can lead to high levels (99%) of syn diastereomer. The size of other neighboring substituents does have an impact on -facial discrimination in these systems and can erode the stereoselectivity accordingly.

Factors influencing 1,4-asymmetric induction during the indium-promoted coupling of oxygen-substituted allylic bromides to aldehydes in aqueous solution also has been investigated in detail. As shown below, the (tert-butyldimethylsilyl)oxy derivatives are the most diastereoselective of

image 4

this group of reagents, giving rise to levels of syn-1,4-asymmetric induction in the range of 87-99 percent. Interestingly, syn stereoselectivity is eroded and reactions proceed more rapidly when the steric bulk of the oxygen substituent is reduced as in the hydroxy and methoxy derivatives. This dropoff in -facial differentiation with kinetic acceleration is attributed to the operation of chelation effects during oxidative addition of the metal into the carbon-bromine bond, but not during the coupling stage. Once the aldehyde enters into the coordination sphere of the indium, internal chelation to the proximal oxygen is disrupted and conformational restrictions are released. These effects, in combination with the absence of a powerful steric control element in the latter examples, permit competitive passage via syn and anti transition states.

image 5.

In a companion effort, the treatment of enantiopure -hydroxy- -lactones with allyl bromide and indium powder in dilute aqueous hydrochloric acid (pH 3) was found to result in selective replacement of the hydroxyl substituent with an 8x0 allyl group (73-93 percent yield) (Bernardelli and Paquette, 1997). The predominant formation of 8x0 diastereomers is consistent with addition of the allylindium species to the aldehydo acid tautomers under chelation control by the neighboring carboxyl substituent. Ring closure delivers the observed products. The high level of

image 6

stereochemical guidance that can be provided to C-C bond formation by a COOH group can be offset to some degree by an alcoholic OH in comparably close proximity to the reaction center. Notwithstanding, the carboxylic functionality appears to be the more effective chelator to the allylindium reagent.

image 7

The level of effective 1,4-asymmetric C-C/C-O stereoinduction in indium-promoted couplings of aldehydes to protected and unprotected [l -(bromomethyl)vinyl] alkanols has proven very rewarding (Paquette et al., 1998). The examples involving the O-silylated derivatives exhibit moderate anti stereoselectivity. In contrast, rather high (most often in excess of 80:20) syn diastereofacial bias is observed when hydroxy bromides are involved. Consequently, stereocontrolled 1,4-asymmetric induction under aqueous conditions can be realized in either direction on demand. These results are considered to reflect the fact that the siloxy systems enter into C-C bond formation via conventional Felkin-Anh transition state arrangements. The crossover observed for the unprotected analogs is believed to be a consequence of the preferred adoption of chelated transition states. The latter interactions are fundamental to aqueous organometallic chemistry and are likely to have a significant influence on future development of the field.

Finally, the stereodifferentiation attending the coupling of geometrically stable allylindium reagents to a 2,3-azetidinedione has been assessed and found to operate at a synthetically useful level in most cases (Paquette and Isaac, in press).


Journal Articles on this Report : 11 Displayed | Download in RIS Format

Other project views: All 13 publications 11 publications in selected types All 11 journal articles

Type Citation Project Document Sources
Journal Article Bernardelli P, Paquette LA. Stereoselective indium-promoted allylation of γ-hydroxy-γ-lactones under aqueous conditions. The neighboring carboxyl effect. Journal of Organic Chemistry 1997;62(24):8284-8285 (letter).
abstract available   full text available
R824725 (Final)
  • Abstract: ACS-Citation
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  • Journal Article Isaac MB, Paquette LA. Experimental test of setting three contiguous stereogenic centers in water. Diastereoselective coupling of geometrically biased allylic bromides to α-oxy aldehydes with indium. Journal of Organic Chemistry 1997;62(16):5333-5338.
    abstract available   full text available
    R824725 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Karangu NT, Rezac ME, Beckham HW. Synthesis and properties of processable polyimides containing diacetylene groups. Chemistry of Materials 1998;10(2):567-573.
    abstract available  
    R824725 (Final)
    R824727 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Paquette LA, Mitzel TM. Comparative diastereoselectivity analysis of crotylindium and 3-bromoallylindium additions to α-oxy aldehydes in aqueous and nonaqueous solvent systems. Journal of Organic Chemistry 1996;61(25):8799-8804.
    abstract available   full text available
    R824725 (Final)
  • Abstract from PubMed
  • Abstract: ACS-Abstract
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  • Journal Article Paquette LA, Lobben PC. π-Facial diastereoselection in the 1,2-addition of allylmetal reagents to 2-methoxycyclohexanone and tetrahydrofuranspiro-(2-cyclohexanone). Journal of the American Chemical Society 1996;118(8):1917-1930.
    abstract available   full text available
    R824725 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Paquette LA, Mitzel TM, Isaac MB, Crasto CF, Schomer WW. Diastereoselection during 1,2-addition of the allylindium reagent to α-thia and α-amino aldehydes in aqueous and organic solvents. Journal of Organic Chemistry 1997;62(13):4293-4301.
    abstract available   full text available
    R824725 (Final)
  • Abstract from PubMed
  • Abstract: ACS-Abstract
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  • Journal Article Paquette LA, Isaac MB. Diastereoselective indium-promoted addition of functionalized allyl bromides to N-benzyl-2,3-azetidinedione under aqueous conditions. Heterocycles 1998;47(1):107-110.
    abstract available   full text available
    R824725 (Final)
  • Abstract: Heterocycles-Abstract
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  • Journal Article Paquette LA, Bennett GD, Isaac MB, Chhatriwalla A. Effective 1,4-asymmetric C-C/C-O stereoinduction in indium-promoted coupling reactions of aldehydes to protected and unprotected [1-(bromomethyl)vinyl] alkanols. The status of intramolecular chelation within functionalized allylindium reagents. Journal of Organic Chemistry 1998;63(6):1836-1845.
    abstract available   full text available
    R824725 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Paquette LA, Mitzel TM. Addition of allylindium reagents to aldehydes substituted at Cα or Cβ with heteroatomic functional groups. Analysis of the modulation in diastereoselectivity attainable in aqueous, organic, and mixed solvent systems. Journal of the American Chemical Society 1996;118(8):1931-1937.
    abstract available   full text available
    R824725 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Rezac ME, Sorensen ET, Beckham HW. Transport properties of crosslinkable polyimide blends. Journal of Membrane Science 1997;136(1-2):249-259.
    abstract available   full text available
    R824725 (Final)
    R824727 (Final)
  • Full-text: ScienceDirect-Full Text PDF
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Rezac ME, Schoberl B. Transport and thermal properties of poly(ether imide)/acetylene-terminated monomer blends. Journal of Membrane Science 1999;156(2):211-222.
    abstract available   full text available
    R824725 (Final)
    R824727 (Final)
  • Full-text: ScienceDirect-Full Text HTML
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  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
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  • Supplemental Keywords:

    green chemistry, carbon-carbon bonding, aqueous and organic solvents, diastereoselection, 1,2 allylindium reagents, thia and a-amino aldehydes in indium-promoted coupling, allelic bromides., RFA, Scientific Discipline, Sustainable Industry/Business, Chemical Engineering, cleaner production/pollution prevention, Environmental Chemistry, Sustainable Environment, Technology for Sustainable Environment, Economics and Business, aldehydes, cleaner production, indium-promoted carbon bond forming, waste minimization, waste reduction, environmentally benign solvents, carbon bond formation, carbon-carbon binding, alternative materials, allylic halides, innovative technology, hydroxyl radicals, pollution prevention, source reduction, catalysis, green chemistry

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    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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