Butyllithium-Mediated Coupling of Aryl Bromides with Ketones under In-Situ-Quench (ISQ) Conditions: An Efficient One-Step Protocol Applicable to Microreactor Technology

Abstract

Exploiting the high rate of bromine-lithium exchange reactions, aryl carbinols such as fenpy-type ligands are readily obtained by simply combining a mixture of a ketone and an aryl bromide with butyllithium.

Key words

organometallic reagents - lithiation - amino alcohols - microreactors - nucleophilic addition

References and Notes

• For leading monographs, see:
• 1a Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon/Elsevier; Oxford: 2002. 
• 1b Schlosser M. In Organometallics in Synthesis: A Manual   Schlosser M. Wiley; New York: 2002.  Chap. 1.
• 1c Wakefield BJ. Organolithium Methods   Academic Press; London: 1988. 
• For leading reviews, see:
• 2a Gschwind HW. Rodriguez HR. Org. React. (N.Y.)  1979,  26:  1 
• 2b Snieckus V. Chem. Rev.  1990,  90:  879 
• 3a Wittig G. Pockels U. Droge H. Chem. Ber.  1938,  71:  1903 
• 3b Gilman H. Langham W. Jacoby AL. J. Am. Chem. Soc.  1939,  61:  106 
• 3c For a review on halogen-lithium exchange, see: Bailey WF. Patricia JJ. J. Organomet. Chem.  1988,  352:  1 
• For leading reviews, see:
• 4a Mason BP. Price KE. Steinbacher JL. Bogdan AR. McQuade DT. Chem. Rev.  2007,  107:  2300 
• 4b Ahmed-Omer B. Brandt JC. Wirth T. Org. Biomol. Chem.  2007,  5:  733 
• 4c Watts P. Wiles C. Chem. Commun.  2007,  443 
• 4d Geyer K. Codée JDC. Seeberger PH. Chem. Eur. J.  2006,  12:  8434 
• 4e Jähnisch K. Hessel V. Löwe H. Baerns M. Angew. Chem. Int. Ed.  2004,  43:  407 ; Angew. Chem. 2004, 116, 410
• 4f Schwalbe T. Autze V. Wille G. Chimia  2002,  56:  636 
• 5 A Cytos Lab System (microreactor) from CPC-Systems GmbH was used (see: www.cpc-net.com/cytosls.shtml); for an overview on the various technological developments, see: Thayer AM. Chem. Eng. News  2005,  83 (22):  43 
• For a review, see:
• 6a El Sheikh S. Schmalz H.-G. Curr. Opin. Drug Discovery Dev.  2004,  7:  882 
• For relevant examples, see also:
• 6b Li W. Nelson DP. Jensen MS. Hoerrner RS. Cai D. Larsen RD. Reider PJ. J. Org. Chem.  2002,  67:  5394 
• 6c Therkelsen FD. Rottländer M. Thorup N. Pedersen EB. Org. Lett.  2004,  6:  1991 
• 7 Gilman H. Moore FW. J. Am. Chem. Soc.  1940,  62:  1843 
• 8a Genov M. Kostova K. Dimitrov V. Tetrahedron: Asymmetry  1997,  8:  1869 
• 8b Herrmann WA. Haider JJ. Fridgen J. Lobmaier GM. Spiegler M. J. Organomet. Chem.  2000,  603:  69 
• 10a Fry JL. West JW. J. Org. Chem.  1981,  46:  2177 
• 10b Goldfuss B. Steigelmann M. Khan SI. Houk KN. J. Org. Chem.  2000,  65:  77 
• 10c Goldfuss B. Loeschmann T. Rominger F. Chem. Eur. J.  2004,  21:  5422 
• 11 Compound 12 was recently prepared in only 15% yield from the same starting materials following a stepwise procedure. See: Lomas JS. Adenier A. Cordier C. J. Phys. Org. Chem.  2006,  19:  295 
• 13a Aidhen IS. Ahuja JR. Tetrahedron Lett.  1992,  33:  5431 
• 13b Paleo MR. Castedo L. Dominguez DJ.
  J. Org. Chem.  1993,  58:  2763 
• 14 Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  497 ; Angew. Chem. 2006, 118, 511
• 16 Schmalz H.-G, Schwalbe T, Sakamoto Y, Matsumoto K, and Goto S. inventors; Eur. Patent, EP  1500649A1. 
• 17 Liebehentschel S. Cvengroš J. von Wangelin AJ. Synlett  2007,  2574 

9

The crystallographic data (excluding structure factors) for compounds 10, 14 and 26 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 645156 (for 10), CCDC 679624 (for 14) and CCDC 645157 (for 26). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK [fax: [phone];
e-mail: [e-mail]].

12

In these cases, products arising from direct attack of n-BuLi at the ketone (13, 17) or from ketone reduction (19) were isolated as main products, besides starting material(s)and the debrominated arene.

15

General Procedure A for the Coupling of Aryl Bromides with Ketones (in a flask using n -BuLi): A stirred solution of an aryl bromide (5 mmol) and a ketone (5 mmol) in THF (10 mL) was cooled to -78 °C and n-BuLi (3.75 mL, 6 mmol, 1.6 M in hexane) was added dropwise via syringe. After 1 h at -78 °C, the stirred reaction mixture was allowed to warm to 0 °C. The reaction was quenched by addition of sat. aq NH₄Cl (5 mL) and H₂O (15 mL), extracted with MTBE or Et₂O (20 mL), and the organic layer was washed with brine and dried over MgSO₄. After removal of the solvent in vacuo the crude product was purified by flash chromatography (typically cyclohexane-EtOAc, 30:1).
General Procedure B for the Coupling of Aryl Bromides with Ketones (in a flask using t -BuLi): A stirred solution of an aryl bromide (5 mmol) and a ketone (5 mmol) in THF (10 mL) was cooled to -78 °C and t-BuLi (6.5 mL, 10 mmol, 1.54 M in pentane) was added dropwise via syringe. After
4 h at -78 °C, the cooling bath was removed and the reaction mixture was stirred at r.t. for 2 h. The reaction was quenched by addition of sat. aq NH₄Cl (5 mL) and H₂O (15 mL), extracted with MTBE or EtOAc (3 × 30 mL), and the organic layer was washed with brine and dried over MgSO₄. After removal of the solvent in vacuo the crude product was purified by flash chromatography (typically cyclohexane-EtOAc, 30:1).
(1 R ,2 R ,4 S )-2-(2′-Pyridinyl)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-ol (6): Prepared according to the general procedure A. 2-Bromopyridine (5; 0.79 g, 5 mmol) and fenchone (4; 0.76 g, 5 mmol) were reacted with n-BuLi (4 mL, 6 mmol) to give 6 (1.14 g, 99%) as a white solid; mp 73 °C; [α]_D ²⁰ -39.9 (c = 2.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.42 (s, 3 H), 0.97 (s, 3 H), 1.00 (s, 3 H), 1.13 (m, 1 H), 1.35 (dd, ¹ J = 10.8 Hz, ² J = 1.5 Hz, 1 H), 1.47 (m, 1 H), 1.79 (m, 1 H), 1.84 (m, 1 H), 2.23 (m, 1 H), 2.34 (m, 1 H), 5.79 (br, 1 H), 7.17 (ddd, ¹ J = 7.2 Hz, ² J = 4.2 Hz, ³ J = 1.0 Hz, 1 H), 7.49 (td, ¹ J = 8.2 Hz, ² J = 1.0 Hz, 1 H), 7.67 (m, 1 H), 8.45 (ddd, ¹ J = 4.2 Hz, ² J = 1.8 Hz, ³ J = 1.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.1, 22.2, 24.3, 29.2, 32.5, 42.0, 46.1, 48.9, 51.9, 83.8, 121.6, 123.4, 135.7, 146.2, 162.1. HRMS (EI): m/z calcd for C₁₅H₂₁NO: 231.162; found: 231.162.
(1 R ,2 R ,4 S )-2-(Thiazol-2-yl)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-ol (10): Prepared according to general procedure A. 2-Bromothiazole (9; 0.33 g, 2 mmol) and fenchone (4; 0.30 g, 2 mmol) were reacted with n-BuLi (1.27 mL, 2.4 mmol) to afford 10 (0.437 g, 92%) as a pale yellow solid; mp 43 °C; [α]_D ²⁰ 84.0 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.69 (s, 3 H), 0.92 (s, 3 H), 1.02 (s, 3 H), 1.17-1.23 (m, 1 H), 1.29 (dd, ¹ J = 10.0 Hz, ² J = 2.0 Hz, 1 H), 1.45-1.52 (m, 1 H), 1.73-1.79 (m, 1 H), 1.79-1.80 (m, 1 H), 1.95-2.01 (m, 1 H), 2.68 (dd, ¹ J = 10.0 Hz, ² J = 2.0 Hz, 1 H), 2.95 (br, 1 H), 7.20 (d, J = 3.0 Hz, 1 H), 7.72 (d, J = 3.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.0, 21.8, 25.2, 28.5, 30.6, 40.8, 46.1, 48.6, 53.8, 86.4, 118.0, 141.4, 177.0. MS (EI, 70 eV): m/z (%) = 237 (15), 156 (100), 140 (35), 126 (20), 86 (70), 59 (25). HRMS (EI): m/z calcd for C₁₃H₁₉NOS: 237.1187; found: 237.1185. Anal. Calcd for C₁₃H₁₉NOS: C, 65.78; H, 8.07; N, 5.90. Found: C, 65.77; H, 8.08; N, 5.87.
(1 S ,2 S ,5 R )-2-Isopropyl-5-methyl-1-(pyridin-2-yl)cyclohexanol (14): Prepared according to general procedure B. 2-Bromopyridine (5; 0.79 g, 5 mmol) and menthone (13; 0.77 mg, 5 mmol) were reacted with t-BuLi (7.7 mL, 10 mmol) to afford 14 (0.68g, 58%) as a white solid; mp 70-71 °C; [α]_D ²⁰ -23.2 (c = 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.63 (d, J = 6.8 Hz, 3 H), 0.79 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.93-1.26 (m, 2 H), 1.33 (d, J = 11.9 Hz, 1 H), 1.47-2.03 (m, 6 H), 5.20 (br, 1 H), 7.13 (dd, ¹ J = 4.9 Hz, ² J = 1.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.65 (td, ¹ J = 8.0 Hz, ² J = 2.0 Hz, 1 H), 8.46 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.5, 21.9, 22.3, 23.6, 27.4, 28.4, 35.2, 50.0, 50.7, 77.1, 119.2, 121.5, 136.7, 146.9, 165.3. HRMS (EI): m/z calcd for C₁₅H₂₃NO: 233.1779; found: 233.178. Anal. Calcd for C₁₅H₂₃NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.06; H, 9.94; N, 6.08.
(1 R ,2 R ,4 S )-2-(6-Bromopyridine-2-yl)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-ol (26): Prepared according to general procedure A. 2,6-Dibrompyridine (25; 2.37 g, 10.0 mmol) and fenchone (4; 1.61 mL, 10.0 mmol) were reacted with n-BuLi (7.7 mL, 12.0 mmol) to afford 26 (3.04 g, 9.8 mmol, 98%) as a colorless solid; [α]_D ²⁰ -40.4 (c = 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃, 55 °C): δ = 0.46 (s, 3 H), 0.98 (s, 3 H), 0.99 (s, 3 H), 1.14 (dt, ¹ J = 8.3 Hz, ² J = 16.9 Hz, 1 H), 1.34 (d, J = 10.5 Hz, 1 H), 1.48 (m, 1 H), 1.78-1.83 (m, 2 H), 2.28 (m, 1 H, H-6), 5.45 (s, 1 H), 7.32-7.48 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.1, 22.1, 24.4, 29.2, 32.5, 41.9, 46.2, 48.9, 52.2, 84.0, 121.7, 125.6, 127.1, 137.6, 140.9. Anal. Calcd for C₁₅H₂₀NOBr: C, 58.07; H, 6.50; N, 4.51. Found: C, 58.14; H, 6.53; N, 4.40.
Synthesis of 26 on a 50-gram Scale Using a Microreactor: Stock solutions of reactants were prepared as follows:
A: 2,6-Dibromopyridine (25; 94.76 g, 0.405 mol) and fenchone (4; 76.08 g, 0.50 mol) were dissolved and diluted with anhyd THF to a volume of 1000 mL.
B: n-BuLi (330 mL, 0.52 mol, 1.58 M in hexane) was diluted with anhyd hexane to a volume of 1000 mL.
A microreactor system (Cytos from CPC systems) equipped with a 2-mL microreactor cell and a 15-mL residence unit was flushed with anhyd THF and cooled by means of a cryostat to a temperature of -17 °C. With a flow rate of approximately 1.5 mL/min (each) the two reactant solutions (A and B) were then pumped (parallel) into the reactor. The system was stopped after 6 h. At this time 510 mL of solution A and 570 mL of solution B had been consumed. The collected product solution was carefully quenched by addition of ice-water. The organic phase was separated and the aqueous layer was extracted with Et₂O (3 × 50 mL). The combined organic solutions were then washed with brine, dried over Na₂SO₄, and the solvent was removed in vacuo. The crude product was purified by Kugelrohr distillation (120 °C/0.4 mbar) to yield 26 (51.90 g, 82%).