Magnesium-Halogen Exchange

Chem 215

Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Ahn Vu, V. Angew. Chem., Int. Ed. Engl. 2003, 42, 4302. General References on the Preparation and Reactions of Grignard Reagents:

• Unlike many lithium-halogen exchange protocols, only one equivalent of i-PrMgX is used in typical experimental procedures. • THF is the most common solvent. Ethyl ether has been employed as a solvent for selective exchange of geminal dihalides to generate magnesium carbenoids. • The reactivity of Grignard reagents is highly temperature dependant. Only highly reactive electrophiles such as aldehydes and ketones react at significant rates below 0 °C. This allows for the preparation of organomagnesium reagents containing cyano, nitro, ester, and imine functional groups, provided that the rate of the exchange reaction is fast enough to allow for exchange at temperatures below 0 °C. • The rate of magnesium-halogen exchange is accelerated by electron-withdrawing groups on the aromatic ring, and is slowed by electron-donating groups:
I MgBr

Main Group Metals in Organic Synthesis, Yamamoto, H., Oshima, K., Eds.; John Wiley and Sons: New York, 2004. Handbook of Grignard Reagents, Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996. Organomagnesium Methods in Organic Synthesis, Wakefield, B. J.; Academic Press: San Diego, 1995.
Development and General Aspects:
RX + R'MgX' RMgX' + R'X

THF, –20 °C, 30 min

• Analogous to lithium-halogen exchange. The position of the equilibrium varies with the stabilities of the carbanion intermediates involved (sp >> sp2 >> sp3).
Br + EtMgBr Et2O
20 °C, 12 h



MgBr +


Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Ahn Vu, V.; Knochel, P. Synthesis 2002, 565.
I MgBr

Prévost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. • Although the first example was reported in 1931 (above), the preparation of Grignard reagents via metal-halogen exchange has not been widely used until recently. Knochel and coworkers have demonstrated the functional-group tolerance of magnesium-halogen exchange, which is now the method of choice for the preparation of highly functionalized organomagnesium reagents. • i-PrMgCl or i-PrMgBr are the most common reagents. In most cases, these reagents can be used interchangeably. i-PrMgBr is made by the Grignard reaction of isopropyl bromide and magnesium turnings. It is less soluble than the chloride (solutions are ~0.8 M), and the titre must be checked more often. i-PrMgCl is commercially available as a 2.0 M solution in THF or diethyl ether. • Solutions of i-PrMgX are titrated by the method of Paquette (Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.) According to this procedure, a flame-dried flask is charged with menthol (a non-hygroscopic solid), 1,10-phenanthroline (indicator) and THF. The Grignard reagent is then added until a distinct violet or burgundy color persists.

THF, 25 °C, 1 h OCH3

Cali, P.; Begtrup, M. Synthesis 2002, 63.
I NO2 PhMgCl THF, –40 °C, 30 s NO2 NO2 MgCl NO2

Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610.

Jason Brubaker

P. 1 h CO2CH3 PhN C O –10 °C → 23 °C 75% NPh O Cl MgBr Ortho. G.. –20 °C. Kopp. M. Br F F F Br F F F Br F F F F MgBr F F F MgBr F Varchi.. –10 °C.. 7449. W. 2003. Knochel.. G. Engl. 40 °C.. Korn. Note also the compatibility of the amidine group with the exchange reaction. • Higher temperatures are required for the selective exchange with less effective chelators. 30 min Br Br i-PrMgBr THF. 57. Angew . 1 h CuCN·2LiCl –20 → 25 °C EtO2C 83% O CH3 Knochel. 4875. Jason Brubaker .. Berillon. P. Monguchi. F. G. 65.. benzylic chloride: Abarbri. CO2CH3 Cl CO2CH3 i-PrMgBr THF. Chem. 1701. V. J. Knochel. Knochel.. Jensen. L. –30 °C.. –30 °C. Knochel. and allows for low-temperature exchange. • Secondary alkyl tosylate: OTs O I CH3 Br OCH2OEt NC BrMg i-PrMgBr THF. Cahiez. Dohle..5 h NC Br Bomond. 8108.. F. 37. Tetrahedron a chelating group.. 1999. Zipse. Ricci.. a. P. Dehmel. Y. 5 h CO2 i-PrMgBr –10 °C. P. Kneisel.. Chem. Tetrahedron Lett... Matsumoto. F. Engl. E. Itoh.. H. Ohno. Org. G. W.. Cahiez. Ed. 1992. Et O O NC Br CuCN 2LiCl NC 80% OCH2OEt EtO2C I Delacroix. I. Ahn Vu. 43. Sapountzis. J. 40. F OCH3 Br F OCH3 MgBr OCH3 CO2H i-PrMgBr –78 °C. Synlett 2001. A.. P.. M.. F i-PrMgBr 23 °C. 1998. Ed. 1 h F F MgBr Br Br Br 90% Nishiyama. increases the rate of reaction. K. Chem. F. Knapp. Org. Int... Kneisel. N.• Aryl bromides undergo exchange more slowly than iodides... 4302. Isaka.. I MgBr • Dibromides undergo regioselective exchange of the bromine ortho. 407. K. K. Dohle. 2 h i-PrMgCl THF. F. H. H. K. 477... but electron-poor aryl bromides can still react at temperatures below 0 °ˇC. P. 1.. Angew.Directing Groups: • The presence of an chelating ortho. Chem. M. L. 30 min i-PrMgCl THF. Cahiez. Knochel. Yoshiwara. 2000. Gommermann. 2 h F Functional Groups Compatible with the Magnesium-Halogen Exchange: • Ester. T. Rottlander.. H. 42.. facilitates exchange. K. F.. Nagase. Int. N(CH3)2 N N Br NC Br N(CH3)2 CHO MgBr Bu NC Br 68% N N(CH3)2 OH Bu i-PrMgBr –40 °C.

This allows for quantitative deprotonation before exchange. Synlett 2001. 1 PhCHO Br 73 Murafuji. 1701. 25 °C N iPr N iPr 1.. –25 °C. P.. Ricci. 477. Commun. G. 5 min I MgBr 25. • Imines can be used to mask aryl aldehydes during the magnesium halogen exchange. 1999. 0. 5 min 2. i-PrMgCl –25 °C.. 30 min 89% CN NC MgBr PhCHO NC NH2 I I 1. Nagasue.. M. Knochel. Synthesis 2000.. THF Abarbi. P.. SiO2 Bi O Br H 34% Br a 3 N Bn Br –5. 1 NC O N OEt 59 • Imine: i-PrMgBr THF. M. Jason Brubaker . M.. 37. Aono. Seconi. Nishio.. 1208. 7449. G. Int. Dohle.5 CO2Et Br (CuCN added) F F S N F F OH 80 i-PrMgBr –20 °C.. Cahiez. Dehmel. A. Ed. PhMgCl –30 °C. G.. Ricci. Knochel. 2003. CO2Et I CH3 O CO2Et 87% Br Br N CH3 I MgBr OEt N I CH3 O F F N S Br N Br F F Conditionsa (°C. Knochel. –40 °C. Heterocycle • Amidine. F. O CO2Et –30. • Heteroaromatics: Bomond... 1998. K. phenyl magnesium chloride is first added because it is a strong base and as a magnesium-halogen exchange reagent it is less reactive than i-PrMgX. Tetrahedron Lett. Jensen. i-PrMgBr THF. Angew. 1 Br (CuCN added) O CO2Et 80 i-PrMgBr (1.. 396. L. G. Tanabe. P. BiCl3 2. note also the selective exchange of a diiodide: N(CH3)2 N I I N N(CH3)2 N(CH3)2 1. A.. W. N –20. Lindsay. Chem. A. Kofink... CuCN·2LiCl 2. M. Cahiez. 1..2 equiv).. T. Y. Engl. Knochel.. h) Electrophile Product Yield (%) –40. 10 min CN CN 71% NHMgCl MgCl CHO Bu I NH2 OH Bu Ph I • Tertiary amide: O N I O N Varchi. C. 40. Sugihara. E.. A. 30 min 81% Br • In the above example. Rottlander. G.• Nitrile: OH NC I • Unprotected anilines: i-PrMgBr THF. The low yield of the reaction sequence above is likely attributable to the second step of the procedure. Chem. P. M..5 PhCHO N Br Ph CO2Et N CH3 OH N Bn Ph OEt 75 CO2Et Varchi. D.

G... i-PrMgBr.. Magnesium-Halogen Exchange of Vinyl Iodides: NO2 O I 1. P. 2 (1. ZnBr2. Nitro arene NO2 I Electrophile Product NO2 OH Yield (%) PhCHO Ph 87 • For successful reactions with reactive electrophiles such as allyl bromides and acid halides. 1610. M. Org.5 equiv) NC –40 → 23 °C. Pd(dba)2 (5 mol %) 1 (10 mol %).. which limits the functionalgroup tolerance of this method. Ed. 64. 41. Knochel. THF –70 °C. 1999. Jason Brubaker Sapountzis. • PhMgCl is necessary for a successful reaction. the rate of exchange is enhanced. 18 h Ph Ph 76 2. Angew. PhCHO 60% Ph I 1. • The nitro group must be ortho to the iodide exchanged. L. Chem. 2002. mesityl magnesium bromide is used to prevent competing oxidative addition of the aryl iodide generated in the magnesium-iodide exchange reaction. 3 h 2= 73% I NO2 OH cHex 64 • In the case above. 1080. Ioannis. This new procedure is the best method to date for the preparation of nitroarene organometallics. Engl. transmetallation of the organomagnesium intermediate with CuCN·2LiCl is necessary. J. More reactive Grignard reagents such as i-PrMgCl give complex mixtures. THF 25 °C. 5 min CN NO2 I PhCHO CH3O NO2 I cHexCHO EtO2C NO2 I PhCOBr EtO2C NO2 I PhCHO O2N NO2 I I CO2Et Br O2N O2N EtO2C EtO2C CH3O NO2 CO2Et 1= CN NO2 OH Ph 72 P 3 CO2Et 3. Meta. Boymond. . • When the vinyl iodide is substituted with electron-withdrawing groups or chelating heteratoms. –40 °C. CO2Et 74 • Vinyl Iodides are also suitable substrates for magnesium-halogen exchange. Higher temperatures and longer reactions times are required. mesitylMgBr. P. Cahiez. These electron-deficient arenes tend to undergo electron-transfer reactions. 12 h 2. 5 min FG NO2 MgCl E+ FG NO2 E • Nitro-substituted organometallic reagents are difficult to prepare through classical methods. –40 °C. 5 min 2.• Nitro arenes: NO2 I FG PhMgCl –40 °C. Knochel.and para-nitro substituted aryl iodides give complex mixtures. i-PrMgBr. Chem. PhCHO CH3O Ph OH 95% Ph OH NO2 OH Ph 81 CH3O NO2 Rottlander. NO2 I PhCHO Ph 94 NO2 OH • Pd-catalyzed Negishi cross-coupling reactions are possible after transmetallation with ZnBr2: O NO2 I NC 1. and direct oxidative addition with elemental magnesium or zinc often leads to reduction of the nitro group. Int.

Ed. DMF C6H13 H 71% O I Br 1. Kitagawa. • The lithium trialkyl magnesiates are prepared in situ by the addition of an alkyl lithium (2 equiv) to an alkyl magnesium halide (1 equiv). K. Br CH3O 1. • Magnesiates exhibit a reactivity somewhere between alkyllithium and alkylmagnesium reagents. 0.5 h 2. TMSCl C10H21 93% TMS • It has been proposed that LiCl breaks up aggregates of organomagnesium reagents. Krasovskiy. O Br CuCN·2LiCl I 1. 4215. Chem. CO2Et 1. 7 h 2. P. 1 h 2. H. • Addition of LiCl to the Grignard reagent produces a more active magnesium-halogen exchange reagent C10H21 I 1. i-PrMgCl·LiCl THF. –40 °C. More Reactive Reagent Combinations for Magnesium-Halogen Exchange: • Lithium Trialkyl Magesium Ate Complexes: • Enhanced Reactivity by Addition of Lithium Chloride to i-PrMgCl prior to exchange (1 equiv): OH Br 1. 2001. 2004. K. Chem.5 h 2. Krasovskiy.. A.. 2288.2 equiv) THF..5 h 3. 2 h 2. Chem. i-PrBu2MgLi (1. Br CH3O 84% C6H13 1. Bu3MgLi (1. 66. A.2 equiv) THF. 43. Engl. 2004. H.5 h 2. 0 °C. PhCHO CO2Et Ph OH OH 62% I OH Kopp. 3333. • The exchange reaction is faster and less sensitive to electronic effects (arene substitution). LiCl THF.Alternative.. Knochel. Lett. J. PhCHO NC 81% Ph I CH3O 1.. Bu3MgLi (1. Org. –78 °C. Shinokubo. F. 6. 0 °C. Oshima. 0 °C. –78 °C. Angew. A. Commun. Int. –30 °C. 7 h I 2. 0. Jason Brubaker . EtCHO I OH Et 84% t-BuO t-BuO O 66% Ren.. Org... P. C6H13CHO CH3O 94% OH C6H13 NC Krasovskiy. –40 °C. Knochel. 2004. 0. aryl magnesiates show less funtional group tolerance.2 equiv) THF. 1 h 2. i-PrBu2MgLi (1. A. i-PrMgCl –30 °C. 0. i-PrMgCl·LiCl THF. CH3MgCl. • This more active reagent combination is successful in the exchange of the ortho-phenoxy aryl iodide shown below: Inoue.. i-PrMgCl·LiCl THF. 4333. P. • In accord with their greater reactivity.2 equiv) THF. Knochel.

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