Synthesis of N-Arylisoindolin-1-ones via Pd-Catalyzed Intramolecular Decarbonylative Coupling of N-(2-Bromobenzyl)oxanilic Acid Phenyl Esters

Abstract

Ethyl and phenyl oxanilates were readily prepared from N-(2-bromobenzyl)anilines and oxalyl chloride monoethyl and monophenyl esters, respectively. It was found that the ethyl oxanilate survived in the presence of K₂CO₃ in DMA at 120 ˚C and underwent an intramolecular direct arylation using Pd(OAc)₂-dppf, furnishing the 5,6-dihydrophenanthridine derivative. In contrast, the corresponding phenyl oxanilates decomposed upon exposure to K₂CO₃ in DMA at 120 ˚C and were transformed into N-arylisoindolin-1-ones via Pd(OAc)₂-dppf-catalyzed intramolecular decarbonylative coupling. Except for the 4-methoxy-substituted oxanilic acid phenyl ester, other phenyl oxanilates possessing electron-withdrawing (NO₂, Cl) and weak electron-donating (Me) substituents provided the N-arylisoindolin-1-ones in 43-80% yields.

decarbonylative coupling - direct arylation - isoindolin-1-ones - oxanilates - palladium

References and Notes

1 Baudoin O. Angew. Chem. Int. Ed.  2007,  46:  1373 

For selected examples of Heck reaction using aryl carboxylic acids, see:

2a Myers AG. Tanaka D. Mannion MR. J. Am. Chem. Soc.  2002,  124:  11250 

2b Tanaka D. Myers AG. Org. Lett.  2004,  6:  433 

2c Tanaka D. Romeril SP. Myers AG. J. Am. Chem. Soc.  2005,  127:  10323 

2d Hu P. Kan J. Su W. Hong M. Org. Lett.  2009,  11:  2341 

For selected examples of biaryl coupling reaction using aryl carboxylic acids, see:

3a Gooβen LJ. Deng G. Levy LM. Science  2006,  313:  662 

3b Forgione P. Brochu M.-C. St-Onge M. Thesen KH. Bailey MD. Bilodeau F. J. Am. Chem. Soc.  2006,  128:  11350 

3c Goossen LJ. Rodriguez N. Melzer B. Linder C. Deng G. Levy LM. J. Am. Chem. Soc.  2007,  129:  4824 

3d Becht J.-M. Catala C. Le Drian C. Wagner A. Org. Lett.  2007,  9:  1781 

3e Gooβen LJ. Zimmermann B. Keauber T. Angew. Chem. Int. Ed.  2008,  47:  7103 

3f Becht J.-M. Le Drian C. Org. Lett.  2008,  10:  3161 

3g Shang R. Fu Y. Wang Y. Xu Q. Yu H.-Z. Liu L. Angew. Chem. Int. Ed.  2009,  48:  9250 

3h Wang Z. Ding Q. He X. Wu J. Tetrahedron  2009,  65:  4635 

3i Moon J. Jang M. Lee S. J. Org. Chem.  2009,  74:  1403 

See also:

3j Duan Z. Ranjit S. Zhang P. Liu X. Chem. Eur. J.  2009,  15:  3666 

3k Dicktein JS. Mulrooney CA. O’Brien EM. Morgan BJ. Kozlowski MC. Org. Lett.  2007,  9:  2441 

4 Gooβen LJ. Rudolphi F. Oppel C. Rodríguez N. Angew. Chem. Int. Ed.  2008,  47:  3043 ; see also ref. 3e

5 Merkul E. Oeser T. Müller TJJ. Chem. Eur. J.  2009,  15:  5006 

6 Shang R. Fu Y. Li J.-B. Zhang S.-L. Guo Q.-X. Liu L. J. Am. Chem. Soc.  2009,  131:  5738 

For Cu-catalyzed reaction of zirconacyclopentenes with oxalyl chloride, see:

7a Chen C. Xi C. Jiang Y. Hong X. J. Am. Chem. Soc.  2005,  127:  8024 

7b Chen C. Liu Y. Xi C. Tetrahedron Lett.  2009,  50:  5434 

For selected recent examples, see:

8a Lee S. Shinji C. Ogura K. Shimizu M. Maeda S. Sato M. Yoshida M. Hashimoto Y. Miyachi H. Bioorg. Med. Chem. Lett.  2007,  17:  4895 

8b Hughes TV. Emanuel SL. O’Grady HR. Connolly PJ. Rugg C. Fuentes-Pesquera AR. Karnachi P. Alexander R. Middleton SA. Bioorg. Med. Chem. Lett.  2008,  18:  5130 

8c Lawson EC. Luci DK. Ghosh S. Kinney WA. Reynolds CH. Qi J. Smith CE. Wang Y. Minor LK. Haertlein BJ. Parry TJ. Damiano BP. Maryanoff BE. J. Med. Chem.  2009,  52:  7432 

9 Couture A. Deniau E. Lamblin M. Lorion M. Grandclaudon P. Synthesis  2007,  1434 

For examples of palladium-catalyzed carbonylative heteroannulation, see:

10a Mori M. Chiba K. Ban Y.
J. Org. Chem.  1978,  43:  1684 

10b Shim SC. Jiang LH. Lee DY. Cho CS. Bull. Korean Chem. Soc.  1995,  16:  1064 

10c Cho CS. Shim HS. Choi H.-J. Kim T.-J. Shim SC. Synth. Commun.  2002,  32:  1821 

10d Grigg R. Zhang L. Collard S. Keep A. Tetrahedron Lett.  2003,  44:  6979 

10e Grigg R. Gai X. Khamnaen T. Rajviroongit S. Sridharan V. Zhang L. Collard S. Keep A. Can. J. Chem.  2005,  83:  990 

10f G rigg R. Sridharan V. Shah M. Mutton S. Kilner C. MacPherson D. Milner P.
J. Org. Chem.  2008,  73:  8352 

10g Orito K. Miyazawa M. Nakamura T. Horibata A. Ushito H. Nagasaki H. Yuguchi M. Yamashita S. Yamazaki T. Tokuda M.
J. Org. Chem.  2006,  71:  5951 

10h Cao H. McNamee L. Alper H. Org. Lett.  2008,  10:  5281 

11 For addition of MeLi with imines, see: Strekowski L. Wydra RL. Cegla MT. Czarny A. Patterson S. J. Org. Chem.  1989,  54:  6120 

12a Abdel-Magid AF. Carson KG. Harris BD. Maryanoff CA. Shah RD. J. Org. Chem.  1996,  61:  3849 

12b Feng G. Wu J. Dai W.-M. Tetrahedron  2006,  62:  4635 

12c Wu J. Nie L. Luo J. Dai W.-M. Synlett  2007,  2728 

13 Mao CH. Wang QM. Huang RQ. Bi FC. Chen L. Liu YX. Shang J. J. Agric. Food Chem.  2004,  52:  6737 

14

Representative Procedure for Synthesis of Oxanilates 15 To a solution of phenol (235.0 mg, 2.0 mmol) and pyridine (0.31 mL, 3.0 mmol) in dry CH₂Cl₂ (5 mL) cooled in an ice-water bath was added oxalyl chloride (0.33 mL, 3.0 mmol) followed by stirring at r.t. for 30 min. The reaction mixture was evaporated, and hexane was added to the residue. The pyridinium salt was removed by quick filtration with washing by hexane. The combined filtrate was condensed under reduced pressure in a nitrogen atmosphere, and the crude oxalyl chloride monophenyl ester was used for next step without purification.^¹³
To a separate dry flask was added NaH (60.0 mg, 1.5 mmol) and dry THF (5 mL). To the resultant suspension cooled in an ice-water bath was added a solution of 14e (276.0 mg, 1.0 mmol) in dry THF (5 mL). After stirring at the same temperature for 1 h, a solution of oxalyl chloride monophenyl ester prepared above in dry THF (5 mL) was added. After stirring at r.t. for 1 h, the reaction was quenched by H₂O. The reaction mixture was extracted with EtOAc (3 × 15 mL), and the combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel with elution by 10% EtOAc in PE (60-90 ˚C) to give the phenyl oxanilate 15e (367.0 mg, 87%). The results are listed in Table  [¹] .
Characterization Data for Compound 15e White crystalline solid; mp 92-93 ˚C (CH₂Cl₂-hexane); R _f  = 0.59 (20% EtOAc in PE). IR (KBr): 1763, 1668, 1511, 1403, 1163 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.31-7.25 (m, 3 H), 7.21-7.12 (m, 6 H), 6.67 (d, J = 7.6 Hz, 2 H), 5.16 (s, 2 H), 2.35 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.4, 160.8, 149.4, 139.1, 136.5, 134.8, 132.9, 130.1 (3¥), 129.4 (2¥), 129.3, 127.8, 127.6 (2¥), 126.4, 123.8, 120.9 (2¥), 51.7, 21.1. MS (ESI⁺): m/z (%) = 448 (75) [M + 2 + Na⁺], 446 (100) [M + Na⁺]. Anal. Calcd for C₂₂H₁₈BrNO₃: C, 62.28; H, 4.28; N, 3.30. Found: C, 62.31; H, 4.31; N, 3.37.

15

We used N,N-dimethylacetamide (DMA) as received from commercial supplies. The anhydrous grade has 99.8% purity with <0.005% water content. In all of our experiments described in this work, water was not added. Upon heating phenyl oxanilate 15a in DMA at 120 ˚C in the presence of K₂CO₃, all materials in the reaction mixture remained on the base line of the TLC plate while ethyl oxanilate 15j could be developed up on the TLC plate.

16

Representative Procedure for Formation of 16 and 17 A 10 mL flask was charged with Pd(OAc)₂ (13.5 mg, 6.0¥10^-² mmol), dppf (33.0 mg, 6.0¥10^-² mmol), and K₂CO₃ (166.0 mg, 1.2 mmol). The loaded flask was evacuated and backfilled with N₂ (repeated for three times). To the degassed flask was added a solution of phenyl oxanilate 15e (255.0 mg, 0.6 mmol) in degassed DMA (3 mL). The resultant mixture was heated at 120 ˚C for 2 h under a nitrogen atmosphere. After cooling to r.t., the reaction was quenched by adding CH₂Cl₂ (20 mL), and the resultant mixture was washing with H₂O (3 × 10 mL) to remove DMA. The organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel with elution by 20% EtOAc in PE (60-90 ˚C) to give N-(p-tolyl)isoindolin-1-one (17e, 61.0 mg, 46%). The results are given in Scheme  [³] and Table  [³] .
Compound 16 was prepared in 71% yield from 15j (Scheme  [³] ) under the same conditions as described above for 17e. The sample of 16 contains two atropisomers along with a minor inseparable debromination byproduct in the ratio of 75:15:10. The result was confirmed by independent synthesis as found in Supporting Information.
Characterization Data for Compound 16 Pale yellow oil; R _f  = 0.27 (20% EtOAc in PE). IR (film): 2928, 1742, 1667, 1185 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.43-7.19 (m, 6 H), 4.95 (s, 2 H), 4.16 (q, J = 6.8 Hz, 2 H), 1.12 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 162.5, 160.4, 135.6, 133.2, 131.1, 129.0, 128.4, 128.4, 128.1, 127.3, 126.4, 124.7, 123.5, 121.8, 62.1, 44.5, 13.6. MS (ESI⁺): m/z (%) = 304 (100) [M + Na⁺]. HRMS (ESI⁺): m/z calcd for C₁₇H₁₅NO₃Na [M + Na⁺]: 304.0944; found: 304.0953.
Characterization Data for Compound 17e White crystalline solid; mp 126-128 ˚C (CH₂Cl₂-hexane). R _f  = 0.38 (20% EtOAc in PE). IR (KBr): 2921, 1683, 1513, 1447, 1390, 1305, 1159 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.92 (d, J = 7.2 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.60-7.48 (m, 3 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.83 (s, 2 H), 2.35 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.3, 140.1, 136.9, 134.2, 133.3, 131.9, 129.7 (2¥), 128.3, 124.1, 122.5, 119.6 (2¥), 50.8, 20.8. MS (ESI⁺): m/z (%) = 246 (35) [M + Na⁺], 224 (100) [M + H⁺]. Anal. Calcd for C₁₅H₁₃NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.56; H, 5.79; N, 6.28.

17 Pd(OAc)₂-BINAP were used for catalyzing intramolecular amidation to form 2-oxindoles, see: Xing X. Wu J. Luo J. Dai W.-M. Synlett  2006,  2099 

For Pd-Aphos-catalyzed Suzuki-Miyaura coupling, see:

18a Dai W.-M. Li Y. Zhang Y. Lai KW. Wu J. Tetrahedron Lett.  2004,  45:  1999 

18b Dai W.-M. Zhang Y. Tetrahedron Lett.  2005,  46:  1377 

18c Jin J. Chen Y. Li Y. Wu J. Dai W.-M. Org. Lett.  2007,  9:  2585 

18d Dai W.-M. Li Y. Zhang Y. Yue C. Wu J. Chem. Eur. J.  2008,  14:  5538 

19

Representative Procedure for Suzuki-Miyaura Coupling of Aryl Chlorides 17b,c A 10 mL flask was charged with the aryl chloride 17b (24.4 mg, 0.1 mmol), phenyl boronic acid (19.0 mg, 0.15 mmol), and K₃PO₄˙3H₂O (80.0 mg, 0.3 mmol). The loaded flask was evacuated and backfilled with N₂ (repeated for three times). To the degassed flask was added degassed H₂O (0.1 mL) and a stock THF (1 mL) solution containing Pd(OAc)₂ (0.23 mg, 1.0¥10^-³ mmol) and Aphos (0.80 mg, 2.0¥10^-³ mmol). The resultant mixture was heated at 60 ˚C for 24 h under a nitrogen atmosphere. After cooling to r.t., the reaction was quenched by H₂O, and the resultant mixture was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel with elution by 15% EtOAc in PE (60-90 ˚C) to give the coupling product 18a (27.0 mg, 95%). The results are found in Scheme  [4] .
Characterization Data for Compound 18a White crystalline solid; mp 126-128 ˚C (CH₂Cl₂-hexane). R _f  = 0.38 (20% EtOAc in PE). IR (KBr): 1691, 1600, 1483, 1429, 1376 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.13 (dd, J = 2.0, 2.0 Hz, 1 H), 7.93 (d, J = 7.2 Hz, 1 H), 7.85 (dd, J = 8.4, 2.0 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.60 (ddd, J = 6.4, 6.4, 1.2 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.48-7.35 (m, 4 H), 4.90 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 142.2, 140.8, 140.0, 139.9, 133.1, 132.1, 129.5, 128.7 (2¥), 128.4, 127.5, 127.2 (2¥), 124.1, 123.2, 122.6, 118.2, 118.2, 50.8. MS (ESI⁺): m/z (%) = 308 (95) [M + Na⁺], 286 (100) [M + H⁺]. Anal. Calcd for C₂₀H₁₅NO: C, 84.19; H, 5.30; N, 4.91. Found: C, 84.22; H, 5.32; N, 4.96.

For Pd- and Ni-catalyzed oxidative cleavage of aryl esters, see:

20a Gooβen LJ. Paetzold J. Angew. Chem. Int. Ed.  2002,  41:  1237 

20b Li Z. Zhang S.-L. Fu Y. Guo Q.-X. Liu L. J. Am. Chem. Soc.  2009,  131:  8815