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Hajos-Parrish-Eder-Sauer-Wiechert Reaction

Published Online: 15 SEP 2010

DOI: 10.1002/9780470638859.conrr290

Comprehensive Organic Name Reactions and Reagents

Comprehensive Organic Name Reactions and Reagents

How to Cite

2010. Hajos-Parrish-Eder-Sauer-Wiechert Reaction. Comprehensive Organic Name Reactions and Reagents. 290:1305–1309.

Publication History

  1. Published Online: 15 SEP 2010

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Abstract

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

Hajos-Parrish-Eder-Sauer-Wiechert reaction is an enantioselective aldol reaction catalyzed by (S)-proline. This reaction has a wide application in synthetic organic chemistry and extensively explored in asymmetric aldol reaction, α-alkylation, Mannich reaction, Michael addition of carbonyl compounds. Hajos–Parrish reaction is the asymmetric version of the Robinson annulation catalyzed by (S)-proline. The cyclic aldol product from this reaction is known as Hajos–Parrish ketol and cyclic (S)-enedione—(7aS)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1(5,6H)-dione—is referred to as Hajos–Parrish ketone, Hajos-Parrish diketone, or Hajos–Wiechert ketone. This reaction is also presumed to involve in formation of a carbinolamine intermediate and nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide.

1 General Description of the Reaction

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

This reaction was independently reported by two groups in 1971: the group of Hajos and Parrish 1 and the group of Eder, Sauer, and Wiechert. 2 It is an enantioselective Aldol Reaction catalyzed by (S)-proline, one of the earliest enantioselectively catalyzed reactions of practical use in synthetic organic chemistry. Owing to its wide application in organic synthesis, it has been extensively explored and extended to asymmetric Aldol Reaction, 3 α-alkylation, 4 Mannich Reaction, 5 Michael Addition, 6 and α-amination 7 of carbonyl compounds. In the literature, this reaction has been referred to by different names: Hajos-Parrish-Eder-Sauer-Wiechert reaction, 8 Hajos-Eder-Sauer-Wiechert reaction, 9 Hajos-Wiechert reaction, 10 and Hajos-Parrish-Wiechert reaction. 11 The asymmetric version of the Robinson Annulation catalyzed by (S)-proline is known as the Hajos-Parrish reaction, 12 Hajos-Parrish-Robinson annulation, 13 or Hajos-Wiechert aldol reaction. 14 The resulting cyclic aldol product is called the Hajos-Parrish ketol. 15 In addition, the cyclic (S)-enedione—(7aS)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1(5,6H)-dione 16—is referred to as Hajos-Parrish ketone, 17 Hajos-Parrish diketone, 18 or Hajos-Wiechert ketone. 19 Initially, this reaction was assumed to “involve the formation of a carbinolamine intermediate followed by the displacement of the proline moiety by nucleophilic attack of the enol from ketone,” (8d, 20) but more experimental and theoretical evidence indicate that this reaction involves “nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide”. (8d)

3 Proposed Mechanisms

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

Illustrated here is the mechanism involved in the nucleophilic addition of the neutral enamine to carbonyl group. (8d)

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4 Modification

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

This reaction has been extended to other reactions, including α-alkylation, 4 Mannich Reaction, 5 Michael Addition, 6 and α-amination 7 of ketones.

5 Applications

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

This reaction has wide use in the synthesis of enantiomerically pure molecules involving ketones.

7 Cited Experimental Examples

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References
original image

Reference 5a.

A suspension of 40 mg (S)-proline (0.35 mmol), 135 mg p-anisidine (1.1 mmol), and 0.86 g isovaleraldehyde (1.0 mmol) in 10 mL acetone was stirred at room temperature for 48 h. The mixture was filtered to recover ∼ 35 mg (S)-proline. Concentration of the filtrate followed by column chromatography (15 % EtOAc in hexanes) gave 224 mg (R)-4-(4-methoxy-phenylamino)-6-methyl-heptan-2-one (0.9 mmol), in a yield of 90 % and 93 % e.e.

original image

Reference 10b.

Under an argon atmosphere, a mixture of 1.30 mL diisopropyl malonate (6.72 mmol), 0.50 mL 2-cycloheptenone (4.48 mmol), and 46 mg l-proline rubidium salt (0.22 mmol) in 5 mL chloroform was stirred for 59 h at 25°C. The reaction was quenched with 2 M HCl, and organic materials were extracted twice with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and flash chromatographed over silica gel to give 1.21 g diisopropyl (R)-(+)-(3-oxocycloheptyl)malonate, in a yield of 91 %, and 59 % e.e.

Other references related to the Hajos-Parrish-Eder-Sauer-Wiechert reaction are cited in the literature. 21

References

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References