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

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.

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

References and Notes

For recent reviews, see:

<A NAME="RG07109ST-1A">1a</A> Kobayashi S. Sugiura M. Kitagawa H. Lam WW.-L. Chem. Rev.  2002,  102:  2227 

<A NAME="RG07109ST-1B">1b</A> Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 

<A NAME="RG07109ST-2A">2a</A> Imamoto T. Sugiyura Y. Takiyama N. Tetrahedron Lett.  1984,  25:  4233 

<A NAME="RG07109ST-2B">2b</A> Imamoto T. Pure Appl. Chem.  1990,  62:  747 

<A NAME="RG07109ST-2C">2c</A> Martin CL. Overman LE. Rohde JM. J. Am. Chem. Soc.  2008,  130:  7568 

<A NAME="RG07109ST-2D">2d</A> Wang Q. Chen C. Org. Lett.  2008,  10:  1223 

<A NAME="RG07109ST-3">3</A>

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

<A NAME="RG07109ST-4">4</A> Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  497 

<A NAME="RG07109ST-5">5</A> Nicolaou KC. Krasovskiy A. Trepanier VE. Chen DY.-K. Angew. Chem. Int. Ed.  2008,  47:  4217 

<A NAME="RG07109ST-6">6</A>

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).

<A NAME="RG07109ST-7A">7a</A> 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 

<A NAME="RG07109ST-7B">7b</A> For the preparation of Grignard reagents via halogen-magnesium exchange reaction, see: Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 

<A NAME="RG07109ST-8">8</A>

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.

<A NAME="RG07109ST-9">9</A>

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.