Iron-Catalyzed Chemoselective Cross-Coupling of Primary and Secondary Alkyl Halides with Arylzinc Reagents

Abstract

Functional-group-compatible cross-coupling reaction of alkyl halides with arylzinc reagents takes place under iron catalysis in the presence of TMEDA, producing a variety of aromatic ­compounds in good to excellent yield. The pronounced effect of a magnesium salt was found to be the key to the promotion of the iron-catalyzed coupling reaction.

Key words

iron catalyst - zinc reagents - alkyl halides - cross-coupling - substitution

References

• 1a Littke AF. Fu GC. Angew. Chem. Int. Ed.  2002,  41:  4176 
• 1b Cross-Coupling Reactions. A Practical Guide, Topics in Current Chemistry   Vol. 219:  Miyaura N. Springer; Berlin: 2002. 
• 1c Metal-Catalyzed Cross-Coupling Reactions   2nd Ed.:  Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
• 2a Bolm C. Legros J. Paih JL. Zani L. Chem. Rev.  2004,  104:  6217 
• 2b Fürstner A. Martin R. Chem. Lett.  2005,  34:  624 
• 2c Nagano T. Hayashi T. Org. Lett.  2005,  7:  491 
• 2d Sapountzis I. Lin W. Kofink CC. Despotopoulou C. Knochel P. Angew. Chem. Int. Ed.  2005,  44:  1654 
• 2e Duplais C. Bures F. Sapountzis I. Korn TJ. Cahiez G. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  2968 
• 2f Scheiper B. Bonnekessel M. Krause H. Fürstner A. J. Org. Chem.  2004,  69:  3943 
• 2g Shinokubo H. Oshima K. Eur. J. Org. Chem.  2004,  2081 
• 2h Fürstner A. Leitner A. Méndez M. Krause H. J. Am. Chem. Soc.  2002,  124:  13856 
• 2i Dohle W. Kopp F. Cahiez G. Knochel P. Synlett  2001,  1901 ; and references cited therein
• 3a Nakamura M. Matsuo K. Ito S. Nakamura E. J. Am. Chem. Soc.  2004,  126:  3686 
• 3b See also: Nakamura M. Hirai A. Nakamura E. J. Am. Chem. Soc.  2000,  122:  978 
• 3c Nakamura M. Matsuo K. Inoue T. Nakamura E. Org. Lett.  2003,  5:  1373 
• 4a Martin R. Fürstner A. Angew. Chem. Int. Ed.  2004,  43:  3955 
• 4b Nagano T. Hayashi T. Org. Lett.  2004,  6:  1297 
• 4c Bedford RB. Bruce DW. Frost RM. Goodby JW. Hird M. Chem. Commun.  2004,  2822 
• 5a Frisch AC. Beller M. Angew. Chem. Int. Ed.  2005,  44:  674 
• 5b Powell DA. Fu GC. J. Am. Chem. Soc.  2004,  126:  7788 
• 5c Zhou J. Fu GC. J. Am. Chem. Soc.  2004,  126:  1340 
• 5d Zhou J. Fu GC. J. Am. Chem. Soc.  2003,  125:  14726 
• 5e Tsuji T. Yorimitsu H. Oshima K. Angew. Chem. Int. Ed.  2002,  41:  4137 
• For overviews of the difficulty for cross-coupling of alkyl halides:
• 6a Cardenas DJ. Angew. Chem. Int. Ed.  2003,  42:  384 
• 6b Luh T.-Y. Leung M.-K. Wong K.-T. Chem. Rev.  2000,  100:  3187 
• 8 Boudier A. Bromm LO. Lots M. Knochel P. Angew. Chem. Int. Ed.  2000,  39:  4414 
• 9 Berger S. Langer F. Lutz C. Knochel P. Mobley TA. Reddy CK. Angew. Chem. Int. Ed. Engl.  1997,  36:  1496 
• 10 Isobe M. Kondo S. Nagasawa N. Goto T. Chem. Lett.  1977,  679 
• 13 Wakabayashi K. Yorimitsu H. Oshima K. J. Am. Chem. Soc.  2001,  123:  5374 

7

An organomanganate and an organozincate have been used in the iron-catalyzed cross-coupling of aryl electrophiles; see ref. 2h.

11

Typical Experimental Procedure A (Table 2); 5-Phenyl-1-(trimethylsilyl)pent-1-yne: In a dry reaction vessel, a mixture of ZnCl₂·TMEDA (379 mg, 1.5 mmol) and PhMgBr (0.93 M solution in THF, 3.22 mL, 3.0 mmol) was stirred for 1 h. To the resulting suspension was added 5-iodo-1-(trimethylsilyl)pent-1-yne (266 mg, 1.0 mmol), and then FeCl₃ (0.1 M solution in THF, 0.5 mL, 0.05 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 0.5 h. After quenching with a saturated aqueous solution of NH₄Cl, the mixture was filtered through a pad of Florisil^®, and concentrated in vacuo. Purification by silica gel chromatography afforded 5-phenyl-1-(trimethylsilyl)pent-1-yne (201 mg, 93%); FTIR (neat): 2958 (w), 2902 (w), 2175 (w), 1478 (w), 1451 (s), 1395 (w), 1366 (s), 1268 (w), 1167 (w), 997 (s) cm^-1; ¹H NMR (500 MHz, CDCl₃): δ = 7.31-7.25 (m, 3 H), 7.21-7.17 (m, 2 H), 2.72 (t, J = 7.6 Hz, 2 H), 2.24 (t, J = 7.1 Hz, 2 H), 1.84 (tt, J = 7.6, 7.1 Hz, 2 H), 0.16 (s, 9 H); ¹³C NMR (125 MHz, CDCl₃): δ = 141.3, 128.2 (2 C), 128.0 (2 C), 125.5, 106.8, 87.4, 34.5, 30.0, 19.1, 0.0 (3 C); HRMS (EI, 70 eV): m/z calcd for C₁₄H₂₀Si [M]⁺, 216.1334; found, 216.1305; Anal. Calcd for C₁₄H₂₀Si: C, 77.71; H, 9.32. Found: C, 77.53; H, 9.13.

12

Typical Experimental Procedure B (Table 3); 4-(4-Cyanophenyl)- N -(benzyloxycarbonyl)piperidine: In a dry reaction vessel, a mixture of ArZnBr (0.48 M solution in THF, 4.2 mL, 2.0 mmol) and Me₃SiCH₂MgCl (1.1 M solution in Et₂O, 1.8 mL, 2.0 mmol) was stirred at 0 °C for 1 h. To the resulting solution was added TMEDA (0.30 mL, 2.0 mmol), 4-bromo-N-(benzyloxycarbonyl)piperidine (298 mg, 1.0 mmol), and then FeCl₃ (0.1 M solution in THF, 0.5 mL, 0.05 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 6 h. After quenching with a saturated aqueous solution of NH₄Cl, the mixture was filtered through a pad of Florisil^®, and concentrated in vacuo. Purification by silica gel chromatography afforded 4-(4-cyanophenyl)-N-(benzyloxycarbonyl)piperidine (253 mg, 79%); FTIR (neat): 3014 (w), 2943 (w), 2923 (w), 2856 (w), 2227 (m), 1688 (s), 1466 (m), 1455 (m), 1436 (m), 1273 (w), 1218 (s), 1125 (m), 1057 (m), 1009 (m), 917 (w), 838 (m), 760 (s), 702 (s) cm^-1; ¹H NMR (500 MHz, CDCl₃): δ = 7.59 (d, J = 8.6 Hz, 2 H), 7.39-7.26 (m, 7 H), 5.16 (br s, 2 H), 4.35 (br s, 2 H), 2.89 (br s, 2 H), 1.90-1.78 (m, 2 H), 1.70-1.58 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 155.2, 150.8, 136.7, 132.4 (2 C), 128.5 (2 C), 128.0, 127.9 (2 C), 127.6 (2 C), 118.8, 110.3, 67.2, 44.3 (2 C), 42.7, 32.6 (2 C); Anal. Calcd for C₂₀H₂₀N₂O₂: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.80; H, 6.42; N, 8.54.