Myers - Exchange Chem 115

Review: • Unlike many -halogen exchange protocols, only one equivalent of i-PrMgX is used in typical experimental procedures. 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. • THF is the most common solvent. Ethyl has been employed as a solvent for selective exchange of geminal dihalides to generate magnesium carbenoids. General References on the Preparation and Reactions of Grignard Reagents:

Main Group Metals in , Yamamoto, H., Oshima, K., Eds.; John Wiley and • The reactivity of Grignard reagents is highly temperature dependant. Only highly reactive Sons: New York, 2004. such as and react at significant rates below 0 °C. This allows for the preparation of organomagnesium reagents containing cyano, nitro, , Handbook of Grignard Reagents, Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: and functional groups, provided that the rate of the exchange reaction is fast enough New York, 1996. to allow for exchange at temperatures below 0 °C.

Organomagnesium Methods in Organic Synthesis, Wakefield, B. J.; Academic Press: San Diego, 1995. • The rate of magnesium-halogen exchange is accelerated by electron-withdrawing groups on the aromatic ring, and is slowed by electron-donating groups: Development and General Aspects: I MgBr RX + R'MgX' RMgX' + R'X i-PrMgBr THF, –20 °C, 30 min

• Analogous to lithium-halogen exchange. The position of the equilibrium varies with the CO CH 2 3 2 3 CO2CH3 stabilities of the intermediates involved (sp >> sp >> sp ). Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Ahn Vu, V.; Knochel, P. Br Et2O MgBr + EtMgBr + EtBr Synthesis 2002, 565. 20 °C, 12 h I MgBr Prévost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. i-PrMgBr THF, 25 °C, 1 h • 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 OCH3 OCH3 coworkers have demonstrated the functional-group tolerance of magnesium-halogen exchange, which is now the method of choice for the preparation of highly functionalized Cali, P.; Begtrup, M. Synthesis 2002, 63. organomagnesium reagents. I MgCl • i-PrMgCl or i-PrMgBr are the most common reagents. In most cases, these reagents can be NO used interchangeably. i-PrMgBr is made by the of isopropyl 2 PhMgCl NO2 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 THF, –40 °C, 30 s in THF or . NO2 NO2

• Solutions of i-PrMgX are titrated by the method of Paquette (Lin, H.-S.; Paquette, L. A. Synth. Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610. Commun. 1994, 24, 2503.) According to this procedure, a flame-dried flask is charged with (a non-hygroscopic solid), 1,10-phenanthroline (indicator) and THF. The is then added until a distinct violet or burgundy color persists.

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1 • Aryl undergo exchange more slowly than , but electron-poor aryl bromides • Dibromides undergo regioselective exchange of the ortho- to a chelating group. can still react at temperatures below 0 °ˇC. Note also the compatibility of the amidine group with the exchange reaction. I MgBr i-PrMgBr N(CH3)2 N(CH3)2 N(CH3)2 CHO –40 °C, 30 min N N N OH NC Br i-PrMgBr NC MgBr Bu NC Bu Br Br THF, –10 °C, 1.5 h Br Br Br Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701. 68%

Br MgBr Varchi, G.; Jensen, a. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. F F i-PrMgBr F F –78 °C, 30 min • Higher temperatures are required for the selective exchange with less effective chelators. F F F F F F OCH3 OCH3 OCH3 Br MgBr CO2H Br MgBr i-PrMgCl CO2 F F i-PrMgBr THF, 40 °C, 5 h –10 °C, 1 h Br Br Br F F 90% F F Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto, K.; Yoshiwara, H. Br MgBr J. Org. Chem. 1992, 57, 407. F i-PrMgBr F 23 °C, 2 h Functional Groups Compatible with the Magnesium-Halogen Exchange: F F • Ester, benzylic chloride: Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. CO2CH3 CO CH 2 3 CO2CH3 i-PrMgBr Cl Cl PhN C O Ortho- Directing Groups: THF, –30 °C, 1 h –10 °C → 23 °C NPh I MgBr O 75% • The presence of a chelating ortho- group facilitates exchange, increases the rate of reaction, and allows for low-temperature exchange. Delacroix, T.; Berillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108. Et O • Secondary tosylate: Br BrMg Br OTs OCH2OEt i-PrMgBr O OCH2OEt O O i-PrMgCl CuCN·2LiCl CH3 THF, –30 °C, 2 h CuCN 2LiCl NC NC NC THF, –20 °C, 1 h –20 → 25 °C EtO2C EtO2C I 80% CH3 83% Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Kneisel, F. F.; Monguchi, Y.; Knapp, K. M.; Zipse, H.; Knochel, P. Tetrahedron 2002, 43, Ahn Vu, V. Angew . Chem., Int. Ed. Engl. 2003, 42, 4302. 4875.

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2 • Nitrile: • Unprotected anilines: OH NH CHO 2 NHMgCl NH2 OH NC I NC MgBr NC 1. PhMgCl i-PrMgBr PhCHO I I I MgCl I Bu Ph –30 °C, 5 min Bu THF, –40 °C, 30 min 2. i-PrMgCl 89% –25 °C, 10 min CN CN CN • Tertiary : 71% Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Seconi, G.; Knochel, P. Chem. Commun. 2003, 396. O O Br i-PrMgBr N N • In the above example, phenyl is first added because it is a strong THF, –25 °C, 30 min base and as a magnesium-halogen exchange reagent it is less reactive than i-PrMgX. I This allows for quantitative deprotonation before exchange. 81% • Heteroaromatics: Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701. Conditionsa Heterocycle (°C, h) Product Yield (%) • Amidine, note also the selective exchange of a diiodide: Br F F CO2Et N(CH ) N(CH ) –40, 0.5 F F 80 3 2 3 2 N(CH3)2 Br

N N N F N F (CuCN added) F N F 1. CuCN·2LiCl I I i-PrMgBr I MgBr I O OH –20 °C, 5 min 2. CH S S 3 CH3 Br 25, 1.5 PhCHO 75 I O CO Et N N Ph CO2Et 2 CO2Et 87% Br Br Br CO2Et Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. O OEt OEt NN –20, 1 NN 59 NC OEt • Imine: CH3 CH3 I MgBr

i-PrMgBr 1. BiCl3 O OH Bi Br Br –5, 1 PhCHO Br 73 2. SiO2 N N THF, 25 °C H 3 Bn Bn Ph N N 34% iPr iPr –30, 1 Br 80 Br O CO2Et CO2Et Murafuji, T.; Nishio, K.; Nagasue, M.; Tanabe, A.; Aono, M.; Sugihara, Y. Synthesis 2000, 1208. (CuCN added) O

• can be used to mask aryl aldehydes during the magnesium halogen exchange. The ai-PrMgBr (1.2 equiv), THF low yield of the reaction sequence above is likely attributable to the second step of the procedure. Abarbi, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.

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3 • Nitro arenes: • Nitro-substituted organometallic reagents are difficult to prepare through classical NO 2 NO2 NO2 methods. These electron-deficient arenes tend to undergo electron-transfer reactions, and direct with elemental magnesium or zinc often leads to reduction of I PhMgCl MgCl + E E the nitro group. This new procedure is the best method to date for the preparation of FG FG FG –40 °C, 5 min nitroarene organometallics. • The nitro group must be ortho to the exchanged. Meta- and para-nitro substituted Nitro arene Electrophile Product Yield (%) aryl iodides give complex mixtures.

NO 2 NO2 OH • PhMgCl is necessary for a successful reaction. More reactive Grignard reagents such as I i-PrMgCl give complex mixtures. PhCHO Ph 87 • For successful reactions with reactive electrophiles such as allyl bromides and , transmetallation of the organomagnesium intermediate with CuCN·2LiCl is necessary. NO2 NO OH 2 • Pd-catalyzed Negishi cross-coupling reactions are possible after transmetallation with I ZnBr : PhCHO Ph 94 2 O CO2Et 1 = P NO2 1. mesitylMgBr, –40 °C, 5 min NO 2 3 CN CN I 2. ZnBr2, –40 °C, 5 min CO Et NO2 NO OH 3. Pd(dba)2 (5 mol %) 2 2 2 = I NC 1 (10 mol %), 2 (1.5 equiv) NC –40 23 °C, 3 h PhCHO Ph 72 → 73% I

CH O 3 CH3O • In the case above, mesityl magnesium bromide is used to prevent competing oxidative NO addition of the aryl iodide generated in the magnesium-iodide exchange reaction. 2 NO2 OH I cHexCHO cHex 64 Magnesium-Halogen Exchange of Vinyl Iodides: EtO C 2 EtO2C 1. i-PrMgBr, THF NO2 NO O 25 °C, 18 h 2 Ph I I 2. PhCHO PhCOBr Ph 76 OH 60% EtO C 2 EtO2C 1. i-PrMgBr, THF Ph Ph NO –70 °C, 12 h CH3O 2 NO2 OH CH3O Ph I 2. PhCHO PhCHO Ph I 81 OH O N 2 O2N 95% NO 2 Rottlander, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 1999, 64, 1080. NO2 CO2Et I Br • Vinyl Iodides are also suitable substrates for magnesium-halogen exchange. Higher CO2Et 74 O2N temperatures and longer reaction times are required, which limits the functional- I group tolerance of this method.

Sapountzis, Ioannis; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610. • When the vinyl iodide is substituted with electron-withdrawing groups or chelating heteratoms, the rate of exchange is enhanced.

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4 Alternative, More Reactive Reagent Combinations for Magnesium-Halogen Exchange: • Enhanced Reactivity by Addition of to i-PrMgCl prior to exchange (1 equiv):

• Lithium Trialkyl Magnesium Ate Complexes: OH Br 1. i-PrMgCl·LiCl THF, 0 °C, 2 h Ph

OH NC 2. PhCHO NC 1. Bu MgLi (1.2 equiv) 3 81% I THF, –78 °C, 0.5 h C6H13

2. C6H13CHO Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333. CH3O CH3O 94% 1. i-PrMgCl·LiCl THF, –40 °C, 7 h C H C H O 1. Bu MgLi (1.2 equiv) 6 13 I 6 13 Br 3 2. DMF THF, 0 °C, 0.5 h H 2. 71% CH3O Br CH3O 84% 1. i-PrMgCl·LiCl THF, –40 °C, 7 h I I 2. EtCHO Br 1. i-PrBu2MgLi (1.2 equiv) I OH THF, –78 °C, 1 h Et t-BuO t-BuO 2. Br 84% O CuCN·2LiCl O 66% Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.

• Addition of LiCl to the Grignard reagent produces a more active magnesium-halogen 1. i-PrBu MgLi (1.2 equiv) 2 exchange reagent C H THF, 0 °C, 1 h C H 10 21 I 10 21 TMS 2. TMSCl 93% • It has been proposed that LiCl breaks up aggregates of organomagnesium reagents. • This more active reagent combination is successful in the exchange of the ortho-phenoxy aryl iodide shown below: Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.

• The lithium trialkyl magnesiates are prepared in situ by the addition of an alkyl lithium 1. CH3MgCl, LiCl CO2Et (2 equiv) to an alkyl magnesium (1 equiv). THF, –30 °C, 0.5 h CO2Et 2. i-PrMgCl –30 °C, 0.5 h • Magnesiates exhibit a reactivity somewhere between alkyllithium and alkylmagnesium I Ph reagents. 3. PhCHO OH • The exchange reaction is faster and less sensitive to electronic effects (arene substitution). OH OH 62% • In accord with their greater reactivity, aryl magnesiates show less funtional group tolerance. Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 2288.

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