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Synlett 2010(17): 2607-2610  
DOI: 10.1055/s-0030-1258584
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Ag2O-Mediated Intramolecular Oxidative Coupling of Acetoacetanilides for the Synthesis of 3-Acetyloxindoles

Zhengsen Yu, Lijuan Ma, Wei Yu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. of China
Fax: +86(931)8915557; e-Mail: yuwei@lzu.edu.cn;

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Publication History

Received 7 July 2010
Publication Date:
23 September 2010 (online)

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Abstract

The intramolecular oxidative Csp²-Csp³ coupling of N-substituted acetoacetanilides was achieved by using Ag2O as the oxidant. The reaction constitutes a convenient approach toward 3-acetyloxindoles from unfunctionalized acetoacetanilides.

Key words

3-acetyloxindoles - acetoacetanilides - Ag2O - oxidative coupling

3-Acyloxindoles are of synthetic interest due to their existence in many pharmaceutically interesting compounds as well as their usefulness in the synthesis of other heterocyclic compounds. [¹] Several methods are available for the synthesis of 3-acyloxindoles, two of which employ the transitional-metal-catalyzed intramolecular C-C coupling of the β-keto anilide derivatives. [¹] [²] One is the rhodium-catalyzed aromatic C-H insertion of α-diazo anilides. [²] A relevant but different strategy is to transform β-keto 2-iodoanilides to 3-acyloxindoles via the CuI/l-proline-catalyzed α-arylation. [¹]

Scheme 1

Scheme 2

Recently, the synthetic strategy of forming C-C bond via the coupling of unfunctionalized carbon atoms (oxidative coupling) has gained prominence due to its high atom economy. [³] Efforts have been made to achieve the coupling of Csp³-H carbon with aryl Csp²-H carbon. [4] The α-arylation of carbonyl compounds is of great synthetic importance, [5] and it is highly desirable to develop means to realize the process via the direct Csp³-Csp² coupling (Scheme  [¹] ). [6] [7] One strategy to address this issue is to employ the alkyl-free radical addition to arenes or heteroar­enes. The free-radical addition to aromatic rings has been known for a long time and has found application in organic synthesis. [8] Generally, the alkyl radicals have to be generated by homolytic cleavage of C-X bonds. But when the alkyl radical center is at the α-position of the carbonyl compounds, they can be generated directly from carbonyl compounds by the action of one-electron oxidants. Recently, Kündig et al. reported a novel synthesis of 3-alkyl-3-aryl-oxindoles from N-methyl-N-phenyl-2-phenylpropanamide and its derivatives via the intramolecular oxidative Csp²-Csp³ coupling. [9] The reaction proved to be a free-radical process, which involved the addition of α-carbonylalkyl radicals to the phenyl ring. The α-carbonyl­alkyl radicals were generated by the CuCl2-mediated oxidation of the corresponding enolate precursors. Independently Taylor et al. reported a very similar process for the synthesis of 3,3-disubstituted-oxindoles and 3-alkyl substituted-oxindoles. [¹0] This synthetic design was similar to that of Nair et al. who tried to prepare 3-acetyloxindole directly from acetoacetanilide. [¹¹] In the work of Nair et al., the one-electron oxidant cerium(IV) ammonium nitrate (CAN) was employed to generate the α-keto radical. However, the desired reaction failed to take place, and instead, the oxamate product was obtained when the reaction was performed in the presence of O2 (Scheme  [²] ). With these aforementioned works in mind, we were interested to see whether 3-acyloxindoles could be synthesized from β-keto anilides via the free-radical-mediated intramolecular Csp³-Csp² coupling. Herein we wish to report our preliminary results.

The study was initiated by employing copper salts to promote the oxidation of N-methyl acetoacetanilide. However, the expected reaction did not took place when CuCl2, Cu(OAc)2, and Cu(OTf)2 were used as the oxidant. As copper salts failed to effect the reaction, we turned to other oxidants. CAN [¹²] and Mn(OAc)3 [¹³] are the most commonly used one-electron oxidants to generate free radicals from 1,3-dicarbonyl compounds. As mentioned above, the reaction of CAN and acetoacetanilide in MeOH was investigated before, but no oxindole product was obtained [¹¹] (Scheme  [²] ). We chose N-methyl acetoacetanilide as the substrate and reinvestigated the effect of CAN. However, no reaction was found to take place in MeOH. When MeCN was used as solvent, only a small amount of high polar products was formed, with the majority of starting material remained. Using Mn(OAc)3˙2H2O as oxidant also failed to deliver the desired results. After some more exploration of the reaction conditions, we found that when Ag2O [¹4] was used as oxidant in combination with base, the desired 3-acetyloxindole could be generated. The reaction conditions were optimized by varying the base, solvent, and reaction temperature (Table  [¹] ). The best result was obtained when the reaction was performed in DMF at 50 ˚C in the presence of 2.0 equivalents of Cs2CO3, with 1.1 equivalents of Ag2O as oxidant, and N-methyl 3-acetyloxindole was obtained in 63% isolated yield (Table  [¹] , entry 3). The reaction could take place at room temperature too, but it took several days for the reaction to complete. The effects of several silver salts were also examined. 3-Acetyloxindole was generated when Ag2CO3 was used, but the yield was low. AgBF4 and AgNO3 did not effect the reaction at all. These results are also summarized in Table  [¹] .

Table 1 Screening of the Reaction Conditionsa

Entry Oxidant Solvent Base Yield (%)b
 1 Ag2O DMF K2CO3 57
 2 Ag2O DMF Na2CO3 -c
 3 Ag2O DMF Cs2CO3 63
 4 Ag2O DMF K3PO4˙7H2O 35
 5 Ag2O DMF CsOAc -c
 6 Ag2O DMF NaOt-Bu 38
 7 Ag2O DMF KOt-Bu 25
 8 Ag2O DMF DBU -c
 9 Ag2O DMF none -c
10 Ag2O MeCN Cs2CO3 39
11 Ag2O DCE Cs2CO3 n.r.d
12 Ag2O toluene Cs2CO3 -c
13 Ag2O 1,4-dioxane Cs2CO3 -c
14 Ag2O DMSO Cs2CO3 54
15 Ag2O DMA Cs2CO3 57
16 Ag2CO3 DMF Cs2CO3 27
17 AgBF4 DMF Cs2CO3 n.r.d
18 AgNO3 DMF Cs2CO3 complex mixture
a Reaction conditions: 50 ˚C, argon atmosphere, Ag2O (1.1 equiv), base (2.0 equiv), 7 h.
b Isolated yield.
c Starting material decomposed.
d No reaction took place.

The optimized reaction conditions were then applied to a variety of substituted acetoacetanilides 1, and the results are outlined in Table  [²] . After reaction, the starting materials were consumed completely, and 3-acetyloxindoles 2 were generated in moderate to good yields for the chosen substrates except 1r, which was decomposed under the reactions conditions (entry 18, Table  [²] ). Apart from compounds 2, no other products could be obtained. The lost mass balance was apparently due to the decomposition of 1 and/or the reaction intermediates. The yields for the ortho-substituted substrates were generally lower than those for their para- and meta-substituted counterparts, probably due to the steric reasons. Compound 1j was converted to two regional isomers, with the less sterically hindered 2j-1 being the major product (entry 10). For substrates containing Cl and Br at the phenyl ring, dehalogenation product 2a was formed, and reactions were not complete in 7 hours. Longer reaction time would lead to the deceasing of the yields. Similar dehalogenation was also observed by Kündig et al. [9] Considering the free-radical nature of the process, the loss of Cl and Br was not surprising. Raising the reaction temperature to 80 ˚C could make the reaction complete in 4 hours for these substrates, and the dehalogenation was mitigated. For example, only trace amount of 2a was detected for 1d and 1o if the reaction was carried out at 80 ˚C (entries 4 and 15). In the case of 1s, however, the reaction afforded 2a as the single isolated product irrespective of the reaction temperature (entry 19).

Table 2 Ag2O-Mediated Oxidative Coupling of Acetoacetanilides 1 a

Entry Substrate R¹ R² Reaction time (h) Product, yield (%)c
 1 1a H Me 7 2a 63
 2 1b 4-Me Me 7 2b 65
 3 1c 4-EtO Me 7 2c 57
 4 1d 4-Cl Me 4b 2d 53
 5 1e 4-Br Me 4b 2e 39, 2a 27
 6 1f 2-Me Me 7 2f 50
 7 1g 2-MeO Me 7 2g 35
 8 1h 2-Cl Me 4b 2h 12, 2a 15
 9 1i 2-Br Me 4b 2i 14, 2a 11
10 1j 3-Me Me 7 2j-1 48, 2j-2 26d
11 1k H Bn 7 2k 71
12 1l 4-Me Bn 7 2l 63
13 1m 4-EtO Bn 7 2m 66
14 1n 4-F Bn 7 2n 48
15 1o 4-Cl Bn 4b 2o 33
16 1p 2-Me Bn 7 2p 43
17 1q 2-MeO Bn 4b 2q 33
18 1r 2-Br Bn 4b dec.
19 1s 3-Cl Bn 4b 2a 63
a The reaction was carried out on 0.5 mmol scale. The reaction temperature was 50 ˚C unless otherwise specified. [¹5]
b The reaction temperature was 80 ˚C.
c Isolated yield.

This protocol could be extended to compounds 3, which were transformed to the corresponding 3,3-disusbtituted oxindoles 4 in reasonable yields (Table  [³] ). On the other hand, when substrate 5 was subjected to the reaction conditions, the reaction failed to take place (Scheme  [³] ). The substrate sensitiveness of the reaction reflected the difficulty in realizing the direct intramolecular Csp²-Csp³ coupling of anilides. Beside the sensitiveness to substrate variations, the properties of the oxidant played a critical role. As aforementioned, while several oxidants are capable of generating α-keto radicals, only Ag2O was effective for the transformations of acetoacetanilides to 3-acetyloxindoles. In light of the synthetic usefulness of 3-acyloxindoles, it is much desirable to find more effective oxidation conditions which would have a broader substrate scope.

Table 3 Synthesis of Oxindoles 4 [¹6]

Entry 3 R 4 Yield (%)
1 3a H 4a 51
2 3b 4-Me 4b 70
3 3c 4-EtO 4c 74
4 3d 2-Me 4d 46
a The reaction temperature was 80 ˚C for 3a.

Scheme 3

In summary, the synthesis of 3-acetyloxindoles from acetoacetanilides via the direct intramolecular coupling of the Csp²-H and Csp³-H centers was realized by using Ag2O as the oxidant. This method is advantageous in that there is no need for the prefunctionalization such as prehalogenation at the substrates. Further work is being done in our laboratory to develop a general procedure which could be applied to diversely functionalized substrates in high efficiency.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

The authors thank the National Natural Science Foundation of China (No. 20772053) for financial support.

15

General Procedure for the Reactions of 1 To a solution of 1 (0.5 mmol) in DMF (5 mL) was added Cs2CO3 (1.0 mmol) and Ag2O (0.55 mmol). The mixture was stirred under argon at 50 ˚C for 7 h (or at 80 ˚C for 4 h). After the reaction was complete, the mixture was filtered though Celite and washed with EtOAc. The filtrate was added into sat. NH4Cl solution and extracted with EtOAc for three times. The combined organic phase was washed with brine and dried with anhyd MgSO4. The solvent was then removed under reduced pressure, and the residual was subjected to silica gel chromatography to give the product 2.

16

General Procedure for the Reactions of 3 To a solution of 3 (0.5 mmol) in DMF (10 mL) was added Cs2CO3 (1.0 mmol) and Ag2O (0.55 mmol). The mixture was stirred under argon at 50 ˚C for 7 h (for 3a, the reaction temperature was 80 ˚C). After the reaction was complete, the mixture was filtered though Celite and washed with EtOAc. The filtrate was added into sat. NH4Cl solution and extracted with EtOAc for three times. The combined organic phase was washed with brine and dried with anhyd MgSO4. The solvent was then removed under reduced pressure, and the residual was subjected to silica gel chromatography to give the product 4.

15

General Procedure for the Reactions of 1 To a solution of 1 (0.5 mmol) in DMF (5 mL) was added Cs2CO3 (1.0 mmol) and Ag2O (0.55 mmol). The mixture was stirred under argon at 50 ˚C for 7 h (or at 80 ˚C for 4 h). After the reaction was complete, the mixture was filtered though Celite and washed with EtOAc. The filtrate was added into sat. NH4Cl solution and extracted with EtOAc for three times. The combined organic phase was washed with brine and dried with anhyd MgSO4. The solvent was then removed under reduced pressure, and the residual was subjected to silica gel chromatography to give the product 2.

16

General Procedure for the Reactions of 3 To a solution of 3 (0.5 mmol) in DMF (10 mL) was added Cs2CO3 (1.0 mmol) and Ag2O (0.55 mmol). The mixture was stirred under argon at 50 ˚C for 7 h (for 3a, the reaction temperature was 80 ˚C). After the reaction was complete, the mixture was filtered though Celite and washed with EtOAc. The filtrate was added into sat. NH4Cl solution and extracted with EtOAc for three times. The combined organic phase was washed with brine and dried with anhyd MgSO4. The solvent was then removed under reduced pressure, and the residual was subjected to silica gel chromatography to give the product 4.

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Scheme 1

Scheme 2

Scheme 3