Download PDF
Synlett 2009(9): 1433-1436  
DOI: 10.1055/s-0029-1217169
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

LaCl3×2LiCl-Catalyzed Addition of Grignard Reagents to Ketones

Albrecht Metzger, Andrei Gavryushin, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany
Fax: +49(89)218077680; e-Mail: Paul.Knochel@cup.uni-muenchen.de;
Further Information

Publication History

Received 18 February 2009
Publication Date:
18 May 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

The addition of Grignard reagents to ketones using substoichiometric amounts of LaCl3˙2LiCl was studied. Catalytic amounts of LaCl3˙2LiCl (30 mol%) provide, in most cases, yields similar to those obtained using a stoichiometric amount.

Key words

1,2-addition - lanthanides - Grignard reagents - functionalized organometallics - lanthanum trichloride

    References and Notes

  • For recent reviews, see:
  • 1a Kobayashi S. Sugiura M. Kitagawa H. Lam WW.-L. Chem. Rev.  2002,  102:  2227 
    Google Scholar
  • 1b Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 
    Google Scholar
  • 2a Imamoto T. Sugiyura Y. Takiyama N. Tetrahedron Lett.  1984,  25:  4233 
    Google Scholar
  • 2b Imamoto T. Pure Appl. Chem.  1990,  62:  747 
    Google Scholar
  • 2c Martin CL. Overman LE. Rohde JM. J. Am. Chem. Soc.  2008,  130:  7568 
    Google Scholar
  • 2d Wang Q. Chen C. Org. Lett.  2008,  10:  1223 
    Google Scholar
  • 4 Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  497 
    CrossrefGoogle Scholar
  • 5 Nicolaou KC. Krasovskiy A. Trepanier VE. Chen DY.-K. Angew. Chem. Int. Ed.  2008,  47:  4217 
    CrossrefGoogle Scholar
  • 7a For the preparation of Grignard reagents via direct magnesium insertion into aromatic halides in the presence of LiCl, see: Piller FM. Appukkuttan P. Gavryushin A. Helm M. Knochel P. Angew. Chem. Int. Ed.  2008,  47:  6802 
    Google Scholar
  • 7b For the preparation of Grignard reagents via halogen-magnesium exchange reaction, see: Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 
    Google Scholar
3

LaCl3˙2LiCl solution in THF is commercially available from Chemetall GmbH, Frankfurt (Germany).

6

The addition of Grignard reagents to imines requires only
10 mol% of LaCl3˙2LiCl(6). An isolated example of the addition of PhMgBr to camphor using 10 mol% of LaCl3˙2LiCl has also been reported (ref. 4).

8

Typical Procedure 1 [30 mol% LaCl 3 ˙2LiCl (6)]; Preparation of 1-Phenyl-1-[2-(trifluoromethyl)-phenyl]ethanol (3f): In a flame-dried flask, flushed with argon, acetophenone (2e; 240 mg, 2.00 mmol) was added followed by LaCl3˙2LiCl (6; 1.15 mL, c = 0.52 M in THF, 30 mol%) and the mixture was stirred for 1 h. Then, THF (2.5 mL) was added. Into another flame-dried and argon-flushed flask 2-(trifluoromethyl)bromobenzene (495 mg, 2.20 mmol) was added followed by i-PrMgCl˙LiCl (1.32 mL, c = 1.64 M in THF, 2.16 mmol). After GC analysis of a hydrolyzed aliquot showed full conversion, the resulting aromatic Grignard reagent 1f was added to the ketone at 0 ˚C. The reaction mixture was stirred at this temperature until full conversion was achieved. Then, sat. NH4Cl solution (50 mL) was added and the layers were separated followed by extraction using Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography (pentane-Et2O = 7:1 + 1.0 vol% Et3N) furnished the alcohol 3f as a pale yellow liquid (381 mg, 72%). ¹H NMR (600 MHz, C4D10O): δ = 7.80 (d, J = 7.6 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 2 H), 7.11 (t, J = 7.4 Hz, 1 H), 4.31 (s, 1 H), 1.93 (s, 3 H). ¹³C NMR (150 MHz, C4D10O): δ = 149.9 (q, 5 J CF = 1.6 Hz), 148.4 (q, ³ J CF = 1.4 Hz), 131.6 (q, 4 J CF = 1.1 Hz), 129.9, 129.5 (q, ² J CF = 31.6 Hz), 128.8 (q, ³ J CF = 6.7 Hz), 128.4, 127.7, 127.1, 126.5 (q, 4 J CF = 0.8 Hz), 125.4, (q, ¹ J CF = 273.4 Hz), 76.7, 33.0 (q, 5 J CF = 1.7 Hz). MS (70 eV, EI): m/z (%) = 266 (2) [M+], 251 (100), 231 (61), 211 (29), 183 (6), 169 (5), 121 (5). HRMS (EI): m/z calcd for C15H13F3O: 266.0918; found: 266.0905. IR (ATR): 3463 (vw), 2983 (vw), 1602 (w), 1494 (w), 1446 (m), 1304 (vs), 1271 (s), 1164 (s), 1122 (vs), 1095 (s), 1032 (vs), 928 (m), 910 (m), 765 (vs), 754 (s), 698 (vs) cm-¹.

9

Typical Procedure 2 [100 mol% LaCl 3 ˙2LiCl (6)]: Preparation of 1-Methyl-1,2,3,4-tetrahydronaphthalen-1-ol (3c): In a flame-dried flask, flushed with argon, α-tetralone (2c; 292 mg, 2.00 mmol) was added followed by LaCl3˙2LiCl (6; 3.85 mL, c = 0.52 M in THF, 100 mol%) and the reaction mixture was stirred for 1 h. Then, MeMgCl (1c; 0.74 mL, c = 2.99 M in THF, 2.20 mmol) was added at 0 ˚C. The ice-bath was removed. After GC analysis of a hydrolyzed aliquot showed full conversion sat. NH4Cl solution (50 mL) was added and the layers were separated followed by extraction using Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography (pentane-Et2O = 9:1 + 1.0 vol% Et3N) furnished the alcohol 3c as a white solid (307 mg, 95%); mp 92-94 ˚C. ¹H NMR (300 MHz, C6D6): δ = 7.52-7.58 (m, 1 H), 7.04-7.11 (m, 1 H), 6.98-7.04 (m, 1 H), 6.84-6.90 (m, 1 H), 2.39-2.60 (m,
2 H), 1.42-1.70 (m, 5 H), 1.39 (s, 3 H). ¹³C NMR (75 MHz, C6D6): δ = 143.7, 136.2, 128.8, 127.1, 126.9, 126.5, 70.2, 40.0, 31.1, 30.2, 20.7. MS (70 eV, EI): m/z (%) = 162 (1) [M+], 147 (100), 129 (56), 119 (17), 91 (32), 84 (34), 44 (6). HRMS (EI): m/z calcd for C11H14O: 162.1045; found: 162.1040. IR (ATR): 3313 (m), 2969 (w), 2933 (m), 2865 (w), 1487 (m), 1440 (m), 1366 (m), 1337 (m), 1284 (m), 1230 (w), 1184 (m), 1152 (m), 1103 (s), 1066 (m), 1048 (m), 990 (m), 949 (m), 930 (s), 854 (m), 761 (vs), 728 (s), 686 (s) cm-¹.