Selective Mg Insertion into Substituted Mono- and Dichloro Arenes in the Presence of LiCl: A New Preparation of Boscalid

Abstract

The LiCl-mediated Mg insertion into polysubstituted aryl chlorides bearing up to three chloro substituents in ortho or meta position selectively leads to Grignard reagents which readily react with various electrophiles. As an application, we have developed a new formal synthesis of boscalid.

Key words

insertion - magnesium - lithium - aryl chlorides - boscalid

References and Notes

• 1a Torborg C. Beller M. Adv. Synth. Catal.  2009,  351:  3027 
• 1b Glasnov TN. Kappe CO. Adv. Synth. Catal.  2010,  352:  3089 
• 1c Felpin F.-X. Fouquet E. Zakri C. Adv. Synth. Catal.  2009,  351:  649 
• 1d Wetzel A. Ehrhardt V. Heinrich MR. Angew. Chem. Int. Ed.  2008,  47:  9130 ; Angew. Chem. 2008, 120, 9270
• 1e Spivey AC. Tseng C.-C. Hannah JP. Gripton CJG. de Fraine P. Parr NJ. Scicinski JJ. Chem. Commun.  2007,  2926 
• 1f Eicken K, Goetz N, Harreus A, Ammermann E, Lorenz G, and Rang H. inventors; Eur. Patent  EP0545099.  (BASF AG, Ludwigshafen)
• 2 Ramsden HE. Balint AE. Whitford WR. Walburn JJ. Cserr R. J. Org. Chem.  1957,  22:  1202 
• 3 Sell MS. Hanson MV. Rieke RD. Synth. Commun.  1994,  24:  2379 
• 4 For a review, see: Lai Y.-H. Synthesis  1981,  585 
• 5a Rieke RD. Science  1972,  94:  1260 
• 5b Rieke RD. Hudnall PM. J. Am. Chem. Soc.  1972,  94:  7178 
• 5c Rieke RD. Hanson MV. Tetrahedron  1997,  53:  1925 
• 5d Rieke RD. Top. Curr. Chem.  1975,  59:  1 
• 5e Rieke RD. Acc. Chem. Res.  1977,  10:  301 
• 5f Rieke RD. Aldrichimica Acta  2000,  33:  52 
• 6a Piller FM. Appukkuttan P. Gavryushin A. Helm M. Knochel P. Angew. Chem. Int. Ed.  2008,  47:  6802 ; Angew. Chem. 2008, 120, 6907
• 6b Piller FM. Metzger A. Schade MA. Haag BA. Gavryushin A. Knochel P. Chem. Eur. J.  2009,  15:  7192 
• 7 The yields of the Grignard reagents were determined by titration using I₂: Krasovskiy A. Knochel P. Synthesis  2006,  890 
• 9 Knochel P. Yeh MCP. Berk SC. Talbert J. J. Org. Chem.  1988,  53:  2390 
• 10a

  Preparation of (4-Fluorophenyl)(thiophen-2-yl)-methanone (10): The freshly prepared and titrated (4-fluorophenyl)magnesium chloride (4b; 1.59 mL, 1 mmol) prepared according to TP1 (2 h, 0.63 M, 65%), was trans-metalated with CuCN˙2LiCl (1 M in THF, 1.1 mL, 1.1 mmol) at -20 ˚C and the mixture was stirred for 30 min. After addition of thiophene-2-carbonyl chloride (117 mg, 0.8 mmol) the resulting solution was stirred for 30 min at this temperature. The reaction was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatog-raphy (isohexane-Et₂O, 50:1) to give 10 as a white solid (151 mg, 73%).

• 10b Analytical data matches the literature: Zhao W. Carreira EM. Chem. Eur. J.  2007,  13:  2671 
• 14 Metzger A. Bernhardt S. Manolikakes G. Knochel P. Angew. Chem. Int. Ed.  2010,  49:  4665 
• 15a

  Preparation of 3-[(Triisopropylsilyl)oxy]benz-aldehyde (14): To the freshly prepared and titrated {3-[(triisopropylsilyl)oxy]phenyl}magnesium chloride (6c; 1.45 mL, 1 mmol) prepared according to TP1 (3 h, 0.69 M, 74%), was added N,N-dimethylformamide (80 mg, 1.1 mmol) at -20 ˚C and the mixture was stirred for 30 min. The reaction was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography (isohexane-Et₂O, 20:1) to give 14 as a yellow oil (267 mg, 96%).

• 15b Analytical data matches the literature: Joncour A. Liu JM. Décor A. Thoret S. Wdzieczak-Bakala J. Bignon J. Baudoin O. ChemMedChem  2008,  3:  1731 
• 16a

  Preparation of 3,5-Dichlorobenzoic Acid (15): The freshly prepared and titrated (3,5-dichlorophenyl)-magnesium chloride (8a; 1.54 mL, 1 mmol) prepared according to TP1 (30 min, 0.65 M, 73%), was added to a flask filled with anhyd CO₂ (g). Then, anhyd CO₂ (g)was bubbled through the reaction mixture (ca. 5 min) until a balloon attached to the reaction flask by a short length rubber tubing and a needle adapter was inflated. The reaction mixture was stirred for 1 h at 25 ˚C and then diluted with Et₂O (15 mL) and extracted with sat. aq NaHCO₃ (3 × 20 mL). The combined aq phases were carefully acidified with HCl (5 mL) until pH <5 and extracted with Et₂O (3 × 30 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give 15 as a yellow solid (189 mg, 99%).

• 16b Analytical data matches the literature: Heiss C. Marzi E. Schlosser M. Eur. J. Org. Chem.  2003,  4625 
• 19a Negishi E. Valente LF. Kobayashi M. J. Am. Chem. Soc.  1980,  102:  3298 
• 19b Negishi E. Acc. Chem. Res.  1982,  15:  340 
• 20a Manolikakes G. Muñoz Hernandez C. Schade MA. Metzger A. Knochel P. J. Org. Chem.  2008,  73:  8422 
• 20b Manolikakes G. Schade MA. Muñoz Hernandez C. Mayr H. Knochel P. Org. Lett.  2008,  10:  2765 
• 22 Walker SD. Barder TE. Martinelli JR. Buchwald SL. Angew. Chem. Int. Ed.  2004,  43:  1871 

8

Preparation of the Grignard Reagents (TP1): A dry and argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with LiCl (530 mg, 12.5 mmol) and heated with a heat gun under high vacuum for 10 min. Magnesium turnings (608 mg, 25 mmol) and THF (10 mL) were added and the magnesium was activated with 1,2-dibromoethane (1 drop per mmol). After 5 min of stirring, the aryl chloride (10 mmol) was added and the reaction mixture was stirred for the indicated time at 25 ˚C. GC analysis of a quenched reaction aliquot showed complete conversion. Then, the supernatant solution was cannulated to a new, dry and argon-flushed Schlenk flask and the yield was determined by iodometric titration.

11

Preparation of N , N -Dimethyl-4-[(triisopropylsilyl)-oxy]benzamide (11): To the freshly prepared and titrated {4-[(triisopropylsilyl)oxy]phenyl}magnesium chloride (4c; 1.56 mL, 1 mmol) prepared according to TP 1 (4 h, 0.64 M, 64%), was added dimethylcarbamoyl chloride (86 mg, 0.8 mmol) at -20 ˚C and the mixture was stirred for 30 min. The reaction was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography (isohexane-Et₂O, 10:1) to give 11 as a colorless oil (260 mg, 81%). IR (ATR): 2944, 2867, 1634, 1604, 1514, 1490, 1463, 1387, 1261, 1168, 1102, 1078, 1013, 997, 908, 882, 845, 766, 752, 709, 684, 675 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.29-7.33 (m, 2 H), 6.84-6.88 (m, 2 H), 3.03 (s, 6 H), 1.20-1.31 (m, 3 H), 1.08 (d, J = 7.2 Hz, 18 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 171.6, 157.3, 129.0, 128.7, 119.5, 36.4 (br), 17.8, 12.6. MS (70 eV, EI): m/z (%) = 321 (22) [M⁺], 279 (18), 278 (100), 277 (12), 250 (39), 223 (11), 222 (57), 208 (18), 111 (11), 110 (25), 103 (19), 72 (88). HRMS (EI): m/z calcd for C₁₈H₃₁NO₂Si: 321.2124; found: 321.2118.

12

Preparation of 2-(3-Chlorophenyl)thiophene (12): The freshly prepared and titrated (3-chlorophenyl)magnesium chloride (6a; 1.33 mL, 1 mmol) prepared according to TP1 (45 min, 0.75 M, 72%), was transmetalated with ZnCl₂ (1 M in THF, 1.1 mL, 1.1 mmol) at 25 ˚C. After addition of 2-iodothiophene (168 mg, 0.8 mmol), Pd(dba)₂ (17 mg, 3 mol%) and P(o-furyl)₃ (14 mg, 6 mol%) the resulting solution was stirred for 1 h at 25 ˚C. The reaction mixture was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography(isohexane) to give 12 as a colorless solid (165 mg, 85%); mp 25 ˚C. IR (ATR): 3104, 3066, 3035, 1932, 1856, 1794, 1658, 1589, 1563, 1529, 1479, 1466, 1419, 1256, 1215, 1172, 1078, 1056, 979, 874, 856, 826, 774, 763, 752, 734, 693, 680 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.57-7.58 (m, 1 H), 7.44-7.48 (m, 1 H), 7.28-7.30 (m, 3 H), 7.20-7.24 (m, 1 H), 7.06 (dd, J = 5.0, 3.6 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 142.7, 136.1, 134.8, 130.1, 128.1, 127.3, 125.9, 125.5, 124.0, 123.8. MS (70 eV, EI): m/z (%) = 196 (36), 195 (12), 194 (100) [M⁺], 159 (13), 149 (16), 115 (32). HRMS (EI): m/z calcd for C₁₀H₇ClS: 193.9957; found: 193.9952.

13

Preparation of 4-(3-Fluorophenyl)-2,6-dimethoxy-pyrimidine (13): The freshly prepared and titrated (3-fluorophenyl)magnesium chloride (6b; 1.56 mL, 1 mmol) prepared according to TP1 (4 h, 0.64 M, 60%), was transmetalated with ZnCl₂ (1 M in THF, 1.1 mL, 1.1 mmol) at 25 ˚C. After addition of 4-iodo-2,6-dimethoxypyrimidine (213 mg, 0.8 mmol), Pd(dba)₂ (17 mg, 3 mol%) and P(o-furyl)₃ (14 mg, 6 mol%) the resulting solution was stirred for 3 h at 25 ˚C. The reaction mixture was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatog-raphy (isohexane-Et₂O, 10:1) to give 13 as a light yellow solid (173 mg, 74%); mp 53.1-54.4 ˚C. IR (ATR): 3080, 2954, 2361, 1567, 1481, 1462, 1352, 1258, 1242, 1199, 1160, 1099, 1018, 982, 922, 886, 825, 802, 784, 777, 706, 662 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.75-7.79 (m, 2 H), 7.37-7.44 (m, 1 H), 7.11-7.17 (m, 1 H), 6.74 (s, 1 H), 4.07 (s, 3 H), 4.00 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 172.7, 165.5, 164.5 (d, J = 2.8 Hz), 163.1 (d, J = 246 Hz), 139.1 (d, J = 7.8 Hz), 130.1 (d, J = 8.1 Hz), 122.5 (d, J = 2.8 Hz), 117.4 (d, J = 21.6 Hz), 114.0 (d, J = 23.0 Hz), 97.4, 54.8, 53.9. MS (70 eV, EI): m/z (%) = 235 (18), 234 (100) [M⁺], 233 (74), 219 (18), 205 (23), 204 (56), 203 (13), 189 (24), 163 (16), 146 (15). HRMS (EI): m/z calcd for C₁₂H₁₁FN₂O₂: 234.0805; found: 234.0808.

17

Preparation of 3′-Chloro-5′-fluoro-(1,1′-biphenyl)-3-carbonitrile (16): The freshly prepared and titrated (3-chloro-5-fluorophenyl)magnesium chloride (8b; 1.49 mL, 1 mmol) prepared according to TP1 (45 min, 0.67 M, 67%), was transmetalated with ZnCl₂ (1 M in THF, 1.1 mL, 1.1 mmol) at 25 ˚C. After addition of 3-iodobenzonitrile (183 mg, 0.8 mmol), Pd(dba)₂ (17 mg, 3 mol%) and P(o-furyl)₃ (14 mg, 6 mol%) the resulting solution was stirred for 2 h at 25 ˚C. The reaction mixture was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chroma-tography (isohexane-Et₂O, 10:1) to give 16 as a colorless solid (211 mg, 91%); mp 118.7-120.2 ˚C. IR (ATR): 307, 2362, 2338, 2231, 1588, 1574, 1444, 1396, 1324, 1308, 1276, 1202, 1175, 1164, 10094, 1069, 945, 916, 890, 866, 837, 791, 748, 694, 680 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.74-7.81 (m, 2 H), 7.66-7.70 (m, 1 H), 7.54-7.60 (m, 1 H), 7.33-7.34 (m, 1 H), 7.11-7.17 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 162.9 (d, J = 250 Hz), 141.9 (d, J = 8.7 Hz), 139.9, 135.8 (d, J = 11.0 Hz), 131.8, 131.3, 130.5, 129.9, 123.2, 118.2, 116.0 (d, J = 25.0 Hz), 113.4, 112.6 (d, J = 23.0 Hz). MS (70 eV, EI): m/z (%) = 233 (32), 232 (14), 231 (100) [M⁺], 196 (17), 195 (22), 169 (13), 58 (11), 43 (28). HRMS (EI): m/z calcd for C₁₃H₇ClFN: 231.0251; found: 231.0245.

18

Preparation of {3-chloro-5-[(triisopropylsilyl)-oxy]phenyl}(2,4-dichlorophenyl)methanone (17): The freshly prepared and titrated {3-chloro-5-[(triisopropylsilyl)-
oxy]phenyl}magnesium chloride (8c; 1.43 mL, 1 mmol) prepared according to TP1 (45 min, 0.70 M, 80%), was transmetalated with CuCN˙2LiCl (1 M in THF, 1.1 mL, 1.1 mmol) at -20 ˚C and the mixture was stirred for 30 min. After addition of 2,4-dichlorobenzoyl chloride (168 mg, 0.8 mmol) the resulting solution was stirred for 30 min at this temperature. The reaction mixture was then quenched with sat. aq NH₄Cl solution (10 mL) and the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatog-raphy (isohexane-Et₂O, 50:1) to give 17 as a colorless oil (366 mg, 80%). IR (ATR): 2946, 2867, 1718, 1606, 1595, 1566, 1501, 1453, 1433, 1398, 1318, 1254, 1199, 1137, 1112, 1065, 1025, 999, 964, 921, 880, 854, 799, 762, 738, 688 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.48 (d, J = 1.7 Hz, 1 H), 7.35-7.38 (m, 1 H), 7.27-7.32 (m, 2 H), 7.09-7.14 (m, 2 H), 1.16-1.28 (m, 3 H), 1.07 (d, J = 7.2 Hz, 18 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 192.8, 157.2, 138.5, 137.0, 136.3, 135.3, 132.5, 130.1, 130.1, 127.2, 125.5, 122.6, 119.2, 17.8, 12.5. MS (70 eV, EI): m/z (%) = 458 (8) [M⁺], 417 (43), 416 (23), 415 (98), 414 (43), 413 (100), 389 (17), 388 (11), 387 (53), 386 (16), 385 (51), 357 (16), 356 (38), 354 (41), 279 (13), 251 (25), 249 (37), 179 (15), 178 (17), 177 (11), 174 (58), 173 (84), 145 (16), 95 (44), 94 (10), 79 (14), 75 (10), 44 (15), 43 (11), 41 (17). HRMS (EI):
m/z calcd for C₂₂H₂₇Cl₃O₂Si: 456.0846; found: 458.0842.

21

Preparation of 4′-Chloro-(1,1′-biphenyl)-2-amine (2):^¹b The freshly prepared and titrated (4-chlorophenyl)-magnesium chloride (4a; 25 mL, 19.3 mmol) prepared according to TP1 (30 min, 0.77 M, 70%), was transmetalated with ZnCl₂ (1 M in THF, 19.3 mL, 19.3 mmol) and then slowly added to a 1 M premixed solution of 2-bromoaniline (3.15 g, 18.3 mmol), Pd(OAc)₂ (45 mg, 1 mol%), SPhos (164 mg, 1 mol%) in THF (19 mL). The resulting solution was stirred for 3 h at 25 ˚C. The reaction mixture was then quenched with sat. aq NH₄Cl solution (150 mL) and the resulting mixture was extracted with Et₂O (3 × 150 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography (CH₂Cl₂) to give 2 as a yellow solid (2.75 g, 70%).