One-Pot Synthesis of Highly Functionalized Oxindoles under Swern Oxidation Conditions

Abstract

The reaction of indole derivatives bearing a 3- or 4-hydroxyalkyl chain with dimethyl sulfoxide and oxalyl chloride under Swern conditions led to a one-pot process involving three different synthetic transformations, namely oxidation of indole to oxindole, introduction of a chlorine substituent at the oxindole C-3 position, and substitution of the hydroxyl group in the side chain by chlorine. In spite of its mechanistic complexity, this synthetically useful process proceeded in good to excellent overall yield.

indoles - Swern reaction - oxindole synthesis - halogenation - oxidation

References and Notes

1 Tokunaga T. Hume WE. Nagamine J. Kawamura T. Taiji M. Nagata R. Bioorg. Med. Chem. Lett.  2005,  15:  1789 

2a Smith CD. Zilfou JT. Stratmann K. Patterson GML. Moore RE. Mol. Pharmacol.  1995,  47:  241 

2b Zhang X. Smith CD. Mol. Pharmacol.  1996,  49:  288 

3 Zaveri NT. Jiang F. Olsen CM. Deschamps JR. Parrish D. Polgar W. Toll L. J. Med. Chem.  2004,  47:  2973 

4 Alcaraz M. Atkinson S. Cornwall P. Foster AC. Gill DM. Humphries LA. Keegan PS. Kemp R. Merifield E. Nixon RA. Noble AJ. O’Beirne D. Patel ZM. Perkins J. Rowa P. Sadler P. Singleton JT. Tornos J. Watts AJ. Woodland IA. Org. Process Res. Dev.  2005,  9:  555 

5 Kikuchi C. Hiranuma T. Koyama M. Bioorg. Med. Chem. Lett.  2002,  12:  2549 

6 Gallagher G. Lavanchi PG. Wilson JW. Hieble JP. DeMarinis RM. J. Med. Chem.  1985,  28:  1533 

For early surveys of oxindole alkaloids, see:

7a Cordell GA. An Introduction to Alkaloids: A Biogenetic Approach   Wiley-Interscience; New York: 1981. 

7b Bindra JS. Oxindole Alkaloids, In The Alkaloids - Chemistry and Physiology   Vol. 14:  Manske RHF. Academic Press; New York: 1973.  p.83 

8 Abourriche A. Abboud Y. Maoufoud S. Mohou H. Seffaj T. Charrouf M. Chaib N. Benamara A. Bontemps N. Francisco C. Farmaco  2003,  58:  1351 

9a Isolation: Cui CB. Kakeya H. Okada G. Onose R. Osada H. J. Antibiot.  1996,  49:  527 

9b Structure: Cui C. Kakeya H. Osada H. Tetrahedron  1996,  52:  12651 

Total syntheses:

9c Edmonson S. Danishefsky SJ. Angew. Chem. Int. Ed.  1998,  37:  1138 

9d Wang H. Ganesan A. J. Org. Chem.  2000,  65:  4685 

9e Sebahar PR. Williams RM. J. Am. Chem. Soc.  2000,  122:  5666 

9f Von Nussbaum F. Danishefsky SJ. Angew. Chem. Int. Ed.  2000,  39:  2175 

9g Cytotoxic activity: Edmondson SE. Danishefsky SJ. Sepp-Lorenzino L. Rosen N. J. Am. Chem. Soc.  1999,  121:  2147 

For reviews of the chemistry of the welwitindolinones, see:

10a Avendaño C. Menéndez JC. Curr. Org. Synth.  2004,  1:  65 

10b Menéndez JC. In Bioactive Heterocycles V, In Topics in Heterocyclic Chemistry   Vol. 11:  Springer; Berlin/Heidelberg: 2007.  p.63 

11a Szabo-Pusztay K. Szabo L. Synthesis  1979,  276 

11b Underwood R. Prasad K. Repic O. Hardtmann G. Synth. Commun.  1992,  22:  343 

11c Cushing TD. Sanz-Cervera JF. Williams RM. J. Am. Chem. Soc.  1993,  115:  9323 

12 For a review of the synthesis of 2-oxindoles, see: Karp GM. Org. Prep. Proced. Int.  1993,  25:  481 

13 Bailey PD. Cochrane PJ. Irvine F. Morgan KM. Pearson DPJ. Veal KT. Tetrahedron Lett.  1999,  40:  4593 

14 Some of these compounds are known in the literature. See: Harrington PE. Kerr MA. Synlett  1996,  1047 

15 Wuest FR. Kniess T. J. Labelled Compd. Radiopharm.  2005,  48:  31 

16

Representative Experimental Procedure
To a solution of oxalyl chloride (5 equiv) in anhyd CH₂Cl₂ (10 mL), at -78 °C under an argon atmophere, was added DMSO (7 equiv). The solution was stirred for ca. 10 min, until effervescence ceased. A solution of alcohol 6b (350 mg, 0.77 mmol) in anhyd CH₂Cl₂ (3 mL) was added dropwise via cannula, and the red solution was stirred for 10 min at -78 °C. Then, Et₃N (10 equiv) was added and the solution was left to warm to r.t. for 20 min, while stirred. The reaction mixture was diluted with CH₂Cl₂ (20 mL) and washed with sat. aq NH₄Cl (3 × 20 mL). The organic layer was dried (Na₂SO₄) and evaporated, and the residue was purified by rapid chromatography on silica gel, eluting with PE-EtOAc mixtures (gradient from 20:1 to 5:1), to yield compound 8b (357 mg, 90%). Slower chromatographic separation may lead to considerable amounts of decomposition products, specially from hydrolysis of the terminal chloromethylene moiety.

17

Data for Representative Compounds 8
Compound 8b: IR (film on NaCl): 1731.6 (C=O), 1112.9 (C-O) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.73-7.67 (m, 4 H, H-2′′,6′′), 7.50-7.35 (m, 8 H, H-5,6,3′′,4′′,5′′), 6.77 (d, 1 H, J = 7.6 Hz, H-7), 5.07 (d, 1 H, J = 14.2 Hz, CH₂O), 4.90 (d, 1 H, J = 14.2 Hz, CH₂O), 3.31-3.13 (m, 2 H, H-3′), 3.21 (s, 3 H, NCH₃), 2.40-2.17 (m, 2 H, H-1′), 1.43-1.28 (m, 2 H, H-2′), 1.12 [s, 9 H, C(CH₃)₃]. ¹³C NMR (62.9 MHz, CDCl₃): δ = 173.2 (C-2), 142.4 (C-7a), 139.1 (C-4), 135.5 (C-2′′,6′′), 133.0 (C-1′′), 130.5 (C-6), 129.9 (C-4′′), 127.8 (C-3′′,5′′), 123.2 (C-3a), 121.6 (C-5), 107.4 (C-7), 64.4 (C-3), 60.9 (CH₂O), 43.6 (C-3′), 35.6 (C-1′), 27.7 (C-2′), 26.85 (NCH₃), 26.75 [C(CH₃)₃], 19.3 [C(CH₃)₃]. Anal. Calcd for C₂₉H₃₃Cl₂NO₂Si: C, 66.15; H, 6.32; N, 2.66. Found: C, 65.97; H, 6.02; N, 2.36.
Compound 8d (major diastereomer, 8da; minor diastereomer, 8db): IR (film on NaCl): 1729.0 (C=O) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.35-7.25 (m, 2 H, H-4,6), 7.07 (t, 1 H, J = 7.6 Hz, H-5), 6.80 (d, 1 H, J = 7.8 Hz, H-7), 3.75-3.60 (m, 1 H, H-3′), 3.18 (m, 3 H, NCH₃), 2.70-2.10 (m, 2 H, H-1′), 1.80-1.35 (m, 4 H, H-2′, CH₂CH₃), 0.95-0.80 (m, 3 H, CH₂CH₃). ¹³C NMR (62.9 MHz, CDCl₃): δ = 174.1 (CO), 143.0 (C-7a, 8da), 142.9 (C-7a, 8db), 130.7 (C-4), 129.7 (C-3a, 8da), 129.5 (C-3a, 8db), 124.6 (C-6), 124.0 (C-5, 8db), 123.9 (C-5, 8da), 109.1 (C-7), 65.1 (C-3′, 8db), 64.9 (C-3′, 8da), 64.7 (C-3), 36.8 (C-1′, 8db), 36.3 (C-1′, 8da), 33.1 (C-2′, 8db), 32.7 (C-2′, 8da), 31.8 (CH₂, 8da), 31.5 (CH₂, 8db), 27.1 (NCH₃), 11.3 (CH₂CH₃). Anal. Calcd for C₁₄H₁₇Cl₂NO: C, 58.75; H, 5.99; N, 4.89. Found: C, 58.80; H, 5.91; N, 4.99.
Compound 8g (major diastereomer, 8ga; minor diastereomer, 8gb): IR (film on NaCl): 3296.0 (NH), 1718.7 (C=O) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.96 (s, 1 H, NH, 8ga), 8.90 (s, 1 H, NH, 8gb), 6.96 (d, 1 H, J = 2.4 Hz, H-4), 6.88 (d, 1 H, J = 8.5 Hz, H-6), 6.82 (dd, 1 H, J = 8.5, 2.4 Hz, H-7), 4.05-3.85 (m, 1 H, H-3′), 3.81 (s, 3 H, OCH₃), 2.60-2.40 (m, 2 H, H-1′), 2.40-2.20 (m, 2 H, H-2′), 1.48 (d, 3 H, J = 6.5 Hz, CH₃, 8ga), 1.46 (d, 3 H, J = 6.3 Hz, CH₃, 8gb). ¹³C NMR (62.9 MHz, CDCl₃): δ = 177.1 (CO), 156.3 (C-5), 141.1 (C-7a), 134.1 (C-3a, 8gb), 133.8 (C-3a, 8ga), 115.7 (C-7, 8gb), 115.5 (C-7, 8ga), 111.8 (C-4, 8ga), 111.5 (C-4, 8gb), 111.3 (C-6), 68.0 (C-3), 58.2 (C-3′, 8gb), 58.0 (C-3′, 8ga), 56.2 (OCH₃), 36.9 (C-1′, 8gb), 36.5 (C-1′, 8ga), 35.1 (C-2′, 8gb), 34.8 (C-2′, 8ga), 25.7 (CH₃, 8gb), 25.5 (CH₃, 8ga). Anal. Calcd for C₁₃H₁₅Cl₂NO₂: C, 54.18; H, 5.25; N, 4.86. Found: C, 53.95; H, 5.12; N, 4.75.

Compound 8a has been previously obtained in 7% yield by treatment of alcohol 6a with NCS in CH₂Cl₂ followed by addition of aq NH₄Cl. See:

18a Hino T. Miura H. Nakagawa T. Murata R. Nakagawa M. Heterocycles  1975,  3:  805 

18b Hino T. Miura H. Murata R. Nakagawa M. Chem. Pharm. Bull.  1978,  26:  3695 

19

Data for 3-Chloro-1-methyl-3-(3-oxobutyl)oxindole
IR (film on NaCl): 1728.2, 1717.0 (C=O) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.39 (d, 1 H, J = 7.6 Hz, H-4), 7.37 (t, 1 H, J = 7.6 Hz, H-6), 7.15 (t, 1 H, J = 7.6 Hz, H-5), 6.87 (d, 1 H, J = 7.6 Hz, H-7), 3.25 (s, 3 H, NCH₃), 2.65-2.40 (m, 4 H, H-1′,2′), 2.11 (s, 3 H, COCH₃). ¹³C NMR (62.9 MHz, CDCl₃): δ = 206.9 (C-3′), 173.9 (C-2), 142.7 (C-7a), 130.8 (C-4), 129.8 (C-3a), 124.5 (C-6), 123.9 (C-5), 109.2 (C-7), 64.4 (C-3), 38.4 (C-2′), 33.2 (C-1′), 30.4 (COCH₃), 27.0 (NCH₃). MS: m/z = 251 [M⁺]. Anal. Calcd for C₁₃H₁₄ClNO₂: C, 62.03; H, 5.61; N, 5.56. Found: C, 62.35; H, 5.81; N, 5.62.

A related spirocyclization was observed after exposure of two N-acyltryptophan derivatives to DMSO-Ms₂O at-20 °C for 5 h, which gave the corresponding five-membered spirolactones in yields of around 65% as mixtures of diastereomers. See:

20a Büchi G. DeShong PR. Katsumura S. Sagimura Y. J. Am. Chem. Soc.  1979,  101:  5084 

For a similar reaction using a mixture of DMSO and tert-butyl bromide, see:

20b Palla G. Marchelli R. Casnati G. Dossena A. Gazz. Chim. Ital.  1982,  112:  535 

20c Labroo RB. Labroo VM. King MM. Cohen LA. J. Org. Chem.  1991,  56:  3637 

21

Indeed, compounds 8 were not obtained when oxalyl chloride was replaced by TFAA.

22 Nozoye T. Shibanuma Y. Nakai T. Hatori H. Chem. Pharm. Bull.  1988,  36:  4980 

23 McComas CC. Perales JB. Van Vranken DL. Org. Lett.  2002,  3:  2337