A Mild Copper-mediated Intramolecular Amination of Aryl Halides

Abstract

A unique combination of copper iodide and cesium acetate was found to mediate intramolecular amination of aryl halides under mild conditions. The reaction proceeds at room temperature with primary or N-benzyl amines and at moderately elevated temperatures with other amine derivatives. The reaction has been applied to the formation of 5-, 6-, and 7-membered rings. Remarkably, halogens at the meta-position were retained, providing a definitive advantage over palladium-catalyzed systems.

aryl amination - cyclization - copper - cesium acetate - nitrobenzenesulfonamides

References

For reviews, see:

1a Belfield AJ. Brown GR. Foubister AJ. Tetrahedron  1999,  55:  11399 

1b Yang BH. Buchwald SL. J. Organomet. Chem.  1999,  576:  125 

1c Wolfe JP. Wagaw S. Marcoux J.-F. Buchwald SL. Acc. Chem. Res.  1998,  31:  805 

1d Hartwig JF. Angew. Chem. Int. Ed.  1998,  37:  2046 

2a Ullmann F. Ber. Dtsch. Chem. Ges.  1903,  37:  2382 

2b Goldberg I. Ber. Dtsch. Chem. Ges.  1906,  39:  1691 

2c Goodbrand HB. Hu N.-X. J. Org. Chem.  1999,  64:  670 

2d Arterburn JB. Pannala M. Gonzalez AM. Tetrahedron Lett.  2001,  42:  1475 

2e Lang F. Zewge D. Houpis IN. Volante RP. Tetrahedron Lett.  2001,  42:  3251 

2f For a review, see: Lindley J. Tetrahedron  1984,  40:  1433 

3 Sorenson RJ. J. Org. Chem.  2000,  65:  7747 ; and references therein

4 Elliott GI. Konopelski JP. Org. Lett.  2000,  20:  3055 ; and references therein

5a Antilla JC. Buchwald SL. Org. Lett.  2001,  3:  2077 

5b Lam YSP. Vincent G. Clark CG. Deudon S. Jadhav PK. Tetrahedron Lett.  2001,  42:  3415 

6 Lam PYS. Deudon S. Averill KM. Li R. He MY. DeShong P. Clark CG. J. Am. Chem. Soc.  2000,  122:  7600 

7 Ma D. Zhang Y. Yao J. Wu S. Tao F. J. Am. Chem. Soc.  1998,  120:  12459 

8 Kiyomori A. Marcoux J.-F. Buchwald SL. Tetrahedron Lett.  1999,  40:  2657 

9 Sugahara M. Ukita T. Chem. Pharm. Bull.  1997,  45:  719 

10 Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc.  2001,  123:  7727 

11

The term amidation refers to coupling specifically with N-acyl amines. The term amination, in our case, includes coupling with N-free, N-alkyl, N-acyl, N-alkoxycarbonyl, and N-sulfonyl amines.

12 Yang BH. Buchwald SL. Org. Lett.  1999,  1:  35 

13

The reaction also proceeded in acetonitrile and DME, but did not proceed in toluene, methylene chloride, dioxane, THF or methanol. Addition of water as co-solvent retarded the reaction.

14

Buchwald indicated one example of room temperature amidation, although elevated temperature was generally needed (ref. [ 10] ).

15

Attempts at intermolecular amination with CuI/CsOAc system have not been successful.

16

Typical Procedure. A pyrex test tube was charged with CsOAc (213 mg, 1.11 mmol, 5 equiv), CuI (84 mg, 441 µmol, 2 equiv) and a small amount of dry benzene. The tube was evacuated and backfilled with argon. The substrate 1d (64 mg, 221 µmol, 1 equiv) in degassed DMSO (1.1 mL) was then added. The mixture was stirred magnetically under argon atmosphere (balloon) for 5 h. To the resulting solution were added ether and ammoniacal aq NaCl. The mixture was shaken vigorously to dissolve the precipitate. The aq layer was extracted three times with ether. The combined ether layer was dried over MgSO₄, filtered and concentrated in vacuo. Preparative TLC (5% EtOAc-hexanes) provided 40 mg (191 µmol, 87% yield) of 2d.

17a Fukuyama T. Jow C.-K. Cheung M. Tetrahedron Lett.  1995,  36:  6373 

17b Fukuyama T. Cheung M. Jow C.-K. Hidai Y. Kan T. Tetrahedron Lett.  1997,  38:  5831 

18

When 3e was treated at r.t. for 9 h, 4e was obtained in 39% yield with substantial recovery of the unreacted 3e.

19

CsOBz has an additional advantage of being significantly less hygroscopic than CsOAc, facilitating its handling. Also, use of cesium salicylate vastly improved the stability of the copper species, but the decreased reactivity rendered its use impractical.

20

A treatment of 5 with Pd₂(dba)₃ (20 mol%), (S)-BINAP (30 mol%), Cs₂CO₃ (1.4 equiv) in toluene at 100 °C gave multiple products from which a mixture of 6 and the deiodinated product was isolated in less than 3% yield.

21 Interestingly, a reported example of modified copper-mediated intramolecular amidation of aryl halide utilized sodium hydride as the base, which was heated in DMF at 80 °C for 12 h: Kametani T. Ohsawa T. Ihara M. Heterocycles  1980,  45:  277 

22

Initially, poor reproducibility was a problem, sometimes resulting in seemingly spontaneous decomposition of the soluble copper species into green precipitate.

23

When 1a was treated with 2 equiv of CuI and 20 equiv of CsOAc in non-degassed DMSO for 21 h, the desired product 1b was obtained in 79% yield.

24

No reaction was observed when triethylamine, DBU or EDTA was used as the base, resulting in the formation of deep-blue Cu-amine complex. For the use of diamine ligand in copper catalysis, see ref. [10] .

25

CuBr and (Thienyl)Cu were almost equally effective. No reaction was observed when Cu(II) species were used.

A catalytic cycle through alternation between Cu(I) and Cu(III) oxidation states has been proposed:

26a Barton DHR. Finet J.-P. Khamsi J. Tetrahedron Lett.  1987,  28:  887 

26b Barton DHR. Donnelly DMX. Finet J.-P. Guiry PJ. J. Chem. Soc., Perkin Trans. 1  1991,  2095 

26c

For a list of possible mechanisms in Cu(I)-mediated amination of aryl halides, see ref. [2f] .