lable at ScienceDirect

Tetrahedron 70 (2014) 3466e3470

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Synthesis of oxindole-3-acetates through iron-catalyzed oxidativearylalkoxycarbonylation of activated alkenes

Gao Wang, Shan Wang, Jian Wang, Shan-Yong Chen *, Xiao-Qi Yu *

Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, PR China

a r t i c l e i n f o

Article history:Received 21 January 2014Received in revised form 10 March 2014Accepted 19 March 2014Available online 29 March 2014

Keywords:CarbazatesAlkene difunctionalizationAlkoxycarbonylation/cyclization

Sc

* Corresponding authors. Tel./fax: þ86 28 8541588scu.edu.cn (S.-Y. Chen), xqyu@scu.edu.cn (X.-Q. Yu).

0040-4020/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2014.03.062

a b s t r a c t

An iron-catalyzed alkoxycarbonylation/cyclization reaction of N-arylacrylamides with carbazates hasbeen developed. This new alkene difunctionalization reaction provides an efficient and straightforwardmethod to obtain various ester-containing oxindoles.

� 2014 Elsevier Ltd. All rights reserved.

The direct difunctionalization of alkenes has become an at-tractive strategy for the assembly of functionalized organic com-pounds. A number of difunctionalization reactions for alkenes havebeen developed, such as arylalkylation,1 carboamination,2 diami-nation3 and dioxygenation.4 However, examples of alkox-ycarbonylative alkene difunctionalization reactions are rare.

Carboxylic esters are valuable commodity chemicals and usefulsynthetic building blocks.5 The addition of alkoxycarbonyl radicals

heme 1. The introduction of an alk

6; e-mail addresses: chensy@

All rights reserved.

tomultiple bonds is an efficient way to prepare esters. However, thegeneration of an alkoxycarbonyl radical often requires the use oftoxic reagents and special equipment.6 Using carbazates as theprecursors of alkoxycarbonyl radicals, Taniguchi et al. found thatalkoxycarbonyl groups could be easily introduced into a-methyl-styrenes under mild conditions (Scheme 1, equation a).7 Thesereadily available and environmentally friendly materials makealkoxycarbonyl radicals a useful tool for alkoxycarbonylation re-

oxycarbonyl group into alkenes.

actions.8 Very recent progress on the difunctionalization of N-ary-lacrylamides1,9 prompted us to envision the addition of analkoxycarbonyl radical to N-phenylacrylamide to generate a newradical that would be trapped by the benzene ring, thus providing

G. Wang et al. / Tetrahedron 70 (2014) 3466e3470 3467

oxindole-3-acetates (Scheme 1, equation b).10 Oxindole-3-acetateshave shown important biological activities and are versatile start-ing materials for the synthesis of a broad range of polycyclic com-pounds. For example, the substitution of oxindole-3-acetates caneasily produce the acetylcholinesterase inhibitor, (�)-physovenine(Scheme 2).11

Scheme 2. The utilization of oxindole-3-acetate derivatives.

We initiated our study on the reaction of N-methyl-N-phenyl-methacrylamide (1a) with methyl carbazate (2a) in ethyl acetate at80 �C to optimise the conditions (Table 1). In the presence of FeCl3and TBHP (tert-butyl hydroperoxide 70 wt % in water), the desiredproduct, methyl 1,3-dimethyl-oxindole-3-acetate (3a), was isolatedin low yield (entry 3). Subsequently, we were delighted to discoverthat the addition of 2a over 30 min could significantly increase theyield (entry 4 vs entry 3). After screening other catalysts, we foundthat n-Bu4NI or Co(OAc)2$4H2O were less effective, whereasFeCl2$4H2Owas as effective as FeCl3. Due to the ease of its handling,FeCl2$4H2O was chosen as the catalyst (entries 5e7). Only a traceamount of the product was detected in the absence of a catalyst(entry 2). K2S2O8 is an alternative oxidant; other oxidants are notsuitable for this transformation (entries 8e12). We discovered thatligands could remarkably influence the yields of this trans-formation. Among the tested ligands, 4-cyanopyridine was the bestchoice, providing the product in 80% yield (entry 20 vs entries13e19).12 The influence of air, water and solvents was also in-vestigated. The results demonstrated that this reaction was not

Table 1Optimisation of reaction conditionsa

Entry Catalyst Oxidant

1 FeCl3 d

2 d TBHP3 FeCl3 TBHP4 FeCl3 TBHP5 n-Bu4NI TBHP6 Co(OAc)2$4H2O TBHP7 FeCl2$4H2O TBHP8 FeCl2$4H2O DTBP9 FeCl2$4H2O O2

10 FeCl2$4H2O H2O2

11 FeCl2$4H2O PhI(OAc)212 FeCl2$4H2O K2S2O8

13 FeCl2$4H2O TBHP14 FeCl2$4H2O TBHP15 FeCl2$4H2O TBHP16 FeCl2$4H2O TBHP17 Fe(pc) TBHP18 FeCl2$4H2O TBHP19 FeCl2$4H2O TBHP20 FeCl2$4H2O TBHP

a Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), ligand (20 mol %), oxidant (1.0in portions over 20 min, and the reaction was exposed to air for 4 h at the same temper

b 2a was fed in one batch before the reaction. Cyclen¼1,4,7,10-tetraazacyclododecane

sensitive to air or a small amount of water and that ethyl acetatewas the best solvent.

With the optimal reaction conditions in hand, we examined thereaction of 1a with various carbazates (Table 2). The reactions ofmethyl, ethyl and propyl carbazates with 1a gave the correspondingproducts 3aec in good yields (entries 1e3). Phenyl carbazates were

also good substrates (entry 4). It should be noted that trace amountsof alkylarylation products 4 were often observed. In particular,when tert-butyl carbazatewas subjected to this reaction, no product3 was observed. Instead, 10% of alkylarylation product 4a was iso-lated (entry 5). This result shows that the tert-butyloxycarbonylradical readily undergoes decarboxylation to produce alkylradicals.13

Next, the scope of N-arylacrylamides was investigated, as shownin Table 3. First, the effects of substituents on the benzene ring werestudied. N-Arylacrylamides bearing an electron-withdrawing orelectron-donating group at the para-position of the benzene ringalways afforded the desired products in good to excellent yields(3ee3m). Notably, halides, esters, nitro and cyano groups weretolerated and furnished the corresponding products. N-Arylacry-lamides bearing meta-substituents showed good reactivity butpoor regioselectivity (3n). An ortho-substituent had a negative in-fluence on this transformation. For example, ortho-fluoro-N-phe-nylacrylamide and ortho-phenyl-N-phenylacrylamide providedproducts 3o and 3p in 40% and 43% yield, respectively. The effects of

Ligand Yield (%)

d 0d Traced 10b

d 45d 32d 17d 45d 0d 0d Traced Traced 3518-Crown-6 56Cyclen 40TMEDA TracePyridine 65d TracePhen 682,20-Bipyridine 404-Cyanopyridine 80

mmol) in ethyl acetate (2 mL). After stirring well at 80 �C, 2a (0.8 mmol) was addedature., TMEDA¼tetramethylethyl-enediamine, phen¼1,10-phenanthroline.

Table 3The scope of N-arylacrylamidesa

3a 80% 3e 66% 3f 82% 3g 78%

3h 72% 3i 73% 3j 61% 3k 66%

3l 58% 3m 54% 3n + 3n’ 65% (3:2)

3o 40% 3p 43% 3q 53% 3r 55%

3s 48% 3t 0% 3u 60% 3v 0%

3w 0% 3x 77% 3y 90%a Reaction conditions: 1 (0.2 mmol), FeCl2 ·4H2O (10 mol %), 4-cyanopyridine (20 mol %), TBHP

(1.0 mmol) in ethyl acetate (2 mL). After stirring well at 80 °C, 2a (0.8 mmol) was added in portions,

and the reaction was exposed to the air for 4 h at the same temperature.

Table 2Scope of carbazates estera

Entry R Product/yield (%)

3 4

1 Me (3a)80 Trace2 Et (3b)76 Trace3 n-Pr (3c)66 Trace4 Ph (3d)62 05 t-Bu 0 (4a)106 Bn 0 Trace

a Reaction conditions: 1a (0.2 mmol), FeCl2$4H2O (10 mol %), 4-cyanopyridine (20 mol %), TBHP (1.0 mmol) in ethyl acetate (2 mL). After stirring well at 80 �C, 2 (0.8 mmol)was added in portions, and the reaction was exposed to air for 4 h at the same temperature.

G. Wang et al. / Tetrahedron 70 (2014) 3466e34703468

G. Wang et al. / Tetrahedron 70 (2014) 3466e3470 3469

substituents on nitrogen were then investigated. Alkylated N-phenylacrylamides gave the corresponding product in moderate togood yields (3qe3s). However, N-phenylacrylamides with a freeNeH did not undergo this transformation (3t). Finally, substrateswith various alkenes were examined. N-Arylacrylamides withouta substituent at the alkene did not produce the desired product(3v). Substrates with an acetoxymethyl or Phth-protected amino-methyl group generated the corresponding products in excellentyields (3x and 3y); this tolerance would be useful for the con-struction of complicated compounds with multiple functionalgroups. In contrast, a substrate with a free hydroxymethyl did notgive the product (3w), which may be a result of its instability underoxidative conditions.

To elucidate the mechanism, this reaction was conducted inthe presence of a radical inhibitor (Scheme 3, a). In the pres-ence of 5 equiv of TEMPO, this reaction did not afford oxin-doles, but gave trapped product 5, suggesting that analkoxycarbonyl radical was generated in this reaction. An in-termolecular kinetic isotope experiment was also performed(Scheme 3, b). No kinetic isotope effect (kH/kD¼1.0) was ob-served, demonstrating that the cleavage of the aromatic CeHbond was not the rate-limiting step. Simultaneously, controlled

Scheme 3. Control

Scheme 4. Plausible re

experiments support that Fe (III) directly oxidizes and disinte-grates carbazates to give alkoxycarbonyl radicals. Meanwhile,TBHP can oxidize Fe (II) to Fe (III) and make cycle smoothlyproceed (Scheme 3, c and d).

In terms of these experimental results and the previous reports,a plausible mechanism for this reaction is shown in Scheme 4.Carbazate 2 is oxidised to diazene A, which further undergoesoxidisation to give radical intermediate B. The release of molecularnitrogen from B gives alkoxycarbonyl radical C, which adds to thecarbonecarbon double bond of N-arylacrylamide to produce radi-cal intermediate D. Alkoxycarbonyl radical C may undergo de-carboxylation to produce an alkyl radical. The intramolecularcyclization of intermediate D with its aryl ring generates radicalintermediate E. Finally, the radical E gives an electron to TBHP andthen loses a proton to product 3 via a proton-coupled electrontransfer (PCET) process.

In summary, we have developed a new arylalkoxycarbonylationof alkenes in which an alkoxycarbonyl radical attacks carbon-ecarbon bonds in N-arylacrylamide, which is followed by intra-molecular cyclization of the generated intermediates with the arylrings. This reaction affords various oxindole-3-acetates in goodyields from simple substrates. Asymmetric arylalkoxycarbonylation

experiments.

action mechanism.

G. Wang et al. / Tetrahedron 70 (2014) 3466e34703470

and applications for this reaction in organic synthesis are currentlybeing investigated in our laboratory.

Acknowledgements

This work was supported financially by the National Program onKey Basic Research Project of China (973 Program, 2013CB328900)and the National Natural Science Foundation of China (Grant No.21202107, 21321061, J1310008 and J1103315); we also thank theAnalytical & Testing Center at Sichuan University for performingNMR analyses.

References and notes

1. (a)Wu, T.; Mu, X.; Liu, G. S. Angew. Chem., Int. Ed. 2011, 50, 12578; (b) Zhou, M.-B.;Wang, C.-Y.; Song, R.-J.; Liu, Y.;Wei,W.-T.; Li, J.-H. Chem. Commun. 2013, 10817; (c)Meng, Y.; Guo, L.-N.;Wang, H.; Duan, X.-H. Chem. Commun. 2013, 7540; (d) Xie, J.;Xu, P.; Li, H.; Xue, Q.; Jin, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2013, 5672.

2. (a) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc.2009, 131, 9488; (b) Hopkins, B. A.; Wolfe, J. P. Angew. Chem., Int. Ed. 2012, 51,9886; (c) Babij, N. R.; Wolfe, J. P. Angew. Chem., Int. Ed. 2013, 52, 9247.

3. (a) So, S.M.;Mui, L.; Kim,H.; Chin, J.Acc. Chem. Res.2012, 45,1345; (b) Cardona, F.;Goti, A. Nat. Chem. 2009, 1, 269; (c) de Figueiredo, R. M. Angew. Chem., Int. Ed.2009, 48, 1190; (d) Ch�avez, P.; Kirsch, J.; H€ovelmann, C. H.; Streuff, J.; Martínez-Belmonte,M.; Escudero-Ad�an, E. C.; Martin, E.; Mu~niz, K. Chem. Sci. 2012, 3, 2375.

4. (a) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc. 2011, 133, 3658; (b) Schmidt, V. A.;Alexanian, E. J. Angew. Chem., Int. Ed. 2010, 49, 4491; (c) Li, Y.; Song, D.; Dong, V.M. J. Am. Chem. Soc. 2008, 130, 2962.

5. (a) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. 1996, 35, 1050; (b) Ryu, I. Chem. Soc.Rev. 2001, 30, 16; (c) Brennf€uhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int.Ed. 2009, 48, 4114.

6. (a) Saicic, R. N.; Zard, S. Z. Chem. Commun. 1996, 1631; (b) Takahashi, S.; Nakata,T. J. Org. Chem. 2002, 67, 5739; (c) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem.Soc. 2008, 130, 16424.

7. Taniguchi, T.; Sugiura, Y.; Zaimoku, H.; Ishibashi, H. Angew. Chem., Int. Ed. 2010,49, 10154.

8. Su, Y.-H.; Wu, Z.; Tian, S.-K. Chem. Commun. 2013, 6528.9. For selected examples, see: (a) Ayitou, A. J.-L.; Sivaguru, J. Chem. Commun. 2011,

2568; (b) Fabry, D. C.; Stodulski, M.; Hoerner, S.; Gulder, T. Chem.dEur. J. 2012,18, 10834; (c) Mu, X.; Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc.2012, 134, 878; (d) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.;Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 3638; (e) Egami, H.;Shimizu, R.; Kawamura, S.; Sodeoka, M. Angew. Chem., Int. Ed. 2013, 52, 4000; (f)Matcha, K.; Narayan, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 7985;(g) Zhou, S.-L.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem.dEur. J. 2013, 19, 12970;(h) Wei, X.-H.; Li, Y.-M.; Zhou, A.-X.; Yang, T.-T.; Yang, S.-D. Org. Lett. 2013, 15,4158; (i) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254; (j) Li, X.; Xu,X.; Hu, P.; Xiao, X.; Zhou, C. J. Org. Chem. 2013, 78, 7343; (k) Fu, W.; Xu, F.; Fu, Y.;Zhu, M.; Yu, J.; Xu, C.; Zou, D. J. Org. Chem. 2013, 78, 12202.

10. One case of carboalkoxycarbonylation of alkene with large dosage of ethylformate under high temperature sees: Zhou, M.-B.; Song, R.-J.; Ouyang, X.-H.;Liu, Y.; Wei, W.-T.; Deng, G.-B.; Li, J.-H. Chem. Sci. 2013, 4, 2690.

11. (a) Luo, Y.-L.; Yu, Q.-S.; Chrisey, L.; Brossi, A. Heterocycles 1990, 31, 283; (b) Jaton,J.-C.; Roulin, K.; Rose, K.; Sirotnak, F. M.; Lewenstein, A.; Brunner, G.; Fank-hauser, C. P.; Burger, U. J. Nat. Prod. 1997, 60, 356.

12. During the preparation of this manuscript, a similar work by Li group hadpublished Xu, X.; Tang, Y.; Li, X.; Hong, G.; Fang, M.; Du, X. J. Org. Chem. 2014, 79,446 We found this reaction independently, and we can’t repeat Li’s excellentyields (without ligands and methyl carbazate was fed in one batch) in ourlaboratory.

13. For kinetic studies of alkoxycarbonyl radicals, see: (a) Simakov, P. A.; Martinez,F. N.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1998, 63, 1226; (b) Coote, M. L.;Easton, C. J.; Zard, S. Z. J. Org. Chem. 2006, 71, 4996.