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Keto reduction with sodium borohydride in water; Dihydrobenzpthalide

SyntheticPage 930
Submitted Jul 02, 2020, published Jul 13, 2020
Ramesha Ramakrishna (
A contribution from ramesha

			Reaction Scheme: Keto reduction with sodium borohydride in water

Chemicals Used

1. Benzpthalide, commercial, min. 99% (one can also buy from Aldrich)

2. Sodium borohydride (Aldrich).

3. Toluene, commercial, 99%

4. Sodium hydroxide - commercial, min. 99%

5. Hydrochloric acid - commercial, about 35%



To a stirred solution of sodium hydroxide (42 g, 1.05 mole) in water (1.1 Lt), benzpthalide (222 g, 1 mole) was added all at once and heated to about 95-98°C. After stirring for 30-35 min, benzpthalide is completely soluble in water. The aqueous solution was cooled to about 30°C. Sodium borohydride (11 g, 0.28 mole) was added in small portions keeping the reaction temperature below 35°C over a period of 4 hours. After complete addition of NaBH4, the reaction mixture was heated and stirred at 40-42°C for 2 h and at 50-55°C for additional 2h, then ooled to room temperature. The aqueous layer thus obtained is added to 200 mL of conc. HCl (200 mL). This mass is heated for 1 h at about 60-65°C for the lactone formation. Cooled and extracted with toluene (750 mL x 2 ). The toluene layer thus obtained is washed with water twice and filtered. This toluene layer concentrated under vacuum to get an oily mass (about 210-220 g). This is the required product and is almost pure by NMR. If required, this product can be crystalized from hexane to get nice crystals with melting point of 55-57°C (crystallization only gives about 70% (~ 155 g) pure product). The product thus obtained is practically pure by NMR. (Yield: 210 g, 94%).

Author's Comments

1. Practically all the hydrogen of NaBH4 is used in the reduction. It is essential to maintain the pH of the reaction medium above 9.

2. During the addition of NaBH4, temperature of the reaction medium should be below 40°C. If the temperature increases, NaBH4 decomposes with loss of hydrogen. The result would be incomplete reduction.



1H NMR (200 MHz, CDCl3): δ 7.85-7.15 (3 m, 9H), 5.69(t, 1H), 3.31-3.26 (dd, 1H), 3.18-3.13 (dd, 1H)

13C NMR (50 MHz, CDCl3): δ 170.23, 149.08, 134.97, 133.69, 129.68, 129.17, 128.52, 127.14, 126.22, 125.58, 122.27, 81.19, 40.84.


Lead Reference

Shashikant V. Dighe, US patent No 3518300, 1970

Other References


Supplementary Information

NMR Data.doc

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Get structure file (.cdx, .sk2, .mol)

Keywords: aromatics/arenes, Benzpthalide, carboxylic acids, esters, NaBH4, reduction, reduction in water

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