DMF mediated Henry reaction of isatins: an efficient synthesis of 3-hydroxy-2-oxindole

Figures & data

Figure 1.  Representative examples of natural products containing 3-hydroxy-2-oxindoles and 3-substituted 3-β amino-2-oxindoles structural motifs.

short-legendScheme 1. Optimization of reaction condition for the synthesis of 3 hydroxy-3-(nitroalkyl)-2-oxindole.

Table 1. Study towards the optimization of reaction condition for the synthesis of 3-hydroxy-3-(nitromethyl)-2-oxindole (3a).^a

Entry	Solvent	Conversion^b	Time	Yield (%)^c
1	Neat	–	24 h	–
2	DMSO^d	Trace	24 h	–
3	DMF^d	33	24 h	31
4	DMF^e	92	85 min	90
5	DMF	95	72 min	93
6	DMSO	34	24 h	32
7	CH3CN	38	24 h	36
8	THF	35	24 h	33
9	DCM	29	24 h	27
10	Ethanol	27	24 h	25
11	n-Butanol	22	24 h	20
12	CHCl3	24	24 h	21
13	Toluene	19	24 h	17
14	Dioxane	23	24 h	21
15	Diethyl ether	24	24 h	21
^aReactions condition: All reactions were performed using isatin 1a (1.0 mmol) and nitromethane 2a (2.0 mmol) in 3 ml freshly distilled dry solvent at room temperature.
^bConversion of isatin to 3-hydroxy oxindole was evaluated by ^1H NMR of crude reaction mixture.
^cIsolated yields of purified products.
^dReagent grade.
^eWith 10 mg activated 4 Å moleculra sieve.

short-legendScheme 2. Synthesis of 3-hydroxy-3-(nitroalkyl)-oxindole by DMF mediated Henry reaction of Isatin with nitoalkanes.

Figure 2.  Illustration for the possibility of formation of six member chair conformation by hydrogen bonding in threo configuration.

Table 2. Synthesis of 3-hydroxy-3-(nitroalkyl)-oxindole derivative by DMF mediated Henry reaction of isatins and nitroalkanes.^a

Entry	Isatin (1a–i)	Nitroalkane (2a,b)	Product	Time (min)	Yield^b (%)
1				72	93
2				75	91
3				90	90
4				85	91
5				72	93
6	1f			90	89
7	1g			86	94 (77:29)*
8				90	89 (67:33)*
9				86	90 (91:09)*
10				72	92 (67:37)*
11				90	89 (72:28)*
12				90	88 (88:12)*
^aReactions condition: All reactions were performed with isatins (1a–l) (1 mmol), nitroalkane (2a,b) (2 mmol) in 3 ml freshly distilled dry DMF at room temperature.
^bIsolated yields of purified products.
*Inseparable mixture of diasteromers, threo:erythro ratio written in parentheses.

short-legendScheme 3. Proposed mechanistic pathway for the DMF mediated Henry reaction of isatins.

INDEX

Title	Page No
General experimental section	29
Detail experimental procedure and spectral data for compound 3a-3l	29–31
^1H NMR and ^13C NMR Spectrum of compound 3a-3l	32–43